Oseltamivir-Acrihin, capsules 75 mg 10 pcs

Mechanism of action

Antiviral drug. Oseltamivir is a prodrug, its active metabolite (oseltamivir carboxylate, OC) is an effective and selective inhibitor of influenza virus neuraminidase type A and B – the enzyme that catalyzes the release of newly formed viral particles from infected cells, their penetration into uninfected cells of respiratory epithelium and further spread of virus in the body. Inhibits influenza virus growth in vitro and suppresses virus replication and pathogenicity in vivo, reduces release of influenza A and B viruses from organism.

OC concentration required for 50% neuraminidase inhibition (IC50) is 0.1-1.3 nM for influenza A virus and 2.6 nM for influenza B virus. Median IC50 values for influenza B virus are slightly higher and constitutes 8.5 nM.

Clinical efficacy

In the conducted studies oseltamivir had no effect on influenza antibody formation, including on antibody production in response to administration of inactivated influenza vaccine.

Studies of natural influenza infection.

In clinical studies of oseltamivir conducted during seasonal influenza infection, patients were started on oseltamivir no later than 40 h after the first symptoms of influenza infection appeared. 97% of patients were infected with influenza A virus and 3% of patients were infected with influenza B virus.

Oseltamivir significantly shortened the period of clinical manifestations of influenza infection (by 32 h). In patients with a confirmed diagnosis of influenza who took oseltamivir, the severity of the disease, expressed as the area under the curve for the total index of symptoms, was 38% lower compared to patients receiving placebo. Moreover, in young patients without comorbidities oseltamivir reduced by about 50% the incidence of flu complications requiring antibiotics (bronchitis, pneumonia, sinusitis, otitis media).

There was clear evidence of efficacy of the drug with respect to secondary efficacy criteria relating to antiviral activity: oseltamivir caused both a shortening of the time of virus release from the body and a reduction in the area under the “viral titers-time” curve.

Data obtained in a study on oseltamivir therapy in elderly and senile patients show that administration of oseltamivir at a dose of 75 mg twice daily for 5 days was accompanied by clinically significant reduction in the median period of clinical manifestations of influenza infection, similar to that in adult patients of younger age, but differences did not reach statistical significance. In another study, influenza patients older than 13 years with concomitant chronic diseases of the cardiovascular and/or respiratory systems received oseltamivir in the same dosing regimen or placebo.

There were no differences in the median period before reduction of clinical manifestations of influenza infection in the oseltamivir and placebo groups, but the period of fever when taking oseltamivir was shorter by about 1 day. The proportion of patients excreting the virus on days 2 and 4 became significantly lower. The safety profile of oseltamivir in patients in the risk group did not differ from that in the general population of adult patients.

Influenza treatment in children

In children aged 1-12 years (mean age 5.3 years) who had fever (≥37.8°C) and one of the respiratory system symptoms (cough or rhinitis) while the influenza virus was circulating in the population, a double-blind, placebo-controlled study was conducted. Sixty-seven percent of patients were infected with influenza A virus and 33% of patients were infected with influenza B virus. The drug oseltamivir (when taken no later than 48 h after the first symptoms of influenza infection) significantly reduced the duration of illness (by 35.8 h) compared with placebo. Duration of illness was defined as the time until coughing, nasal congestion, disappearance of fever, and return to normal activity. The incidence of acute otitis media was reduced by 40% in the children treated with oseltamivir compared to the placebo group. Recovery and return to normal activity occurred almost 2 days earlier in children receiving oseltamivir compared to the placebo group.

Another study involved children aged 6-12 years with bronchial asthma; 53.6% of patients had influenza infection confirmed serologically and/or in culture. The median duration of illness in the group of patients receiving oseltamivir did not decrease significantly. But by the last 6 days of therapy with oseltamivir, forced expiratory volume in 1 second (FEF1) increased by 10.8% compared with 4.7% in patients receiving placebo (p=0.0148).

Influenza prevention in adults and adolescents

The preventive efficacy of oseltamivir in natural influenza A and B infection has been proven in 3 separate phase III clinical trials. About 1% of patients became ill with influenza while taking oseltamivir. Oseltamivir also significantly reduced the frequency of virus excretion and prevented transmission from one family member to another.

Adults and adolescents who were in contact with a sick family member began taking oseltamivir within two days of the onset of flu symptoms in family members and continued it for 7 days, which significantly reduced the frequency of flu in contacted individuals by 92 percent.

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

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

Influenza prevention in children Prophylactic efficacy of oseltamivir in natural influenza infection was demonstrated in children from 1 to 12 years after contact with a sick family member or someone in the permanent environment. The primary efficacy parameter was the frequency of laboratory-confirmed influenza infection. In children who received oseltamivir /powder for oral suspension preparation/ in the dose from 30 to 75 mg once a day for 10 days and did not excrete the virus initially, the frequency of laboratory-confirmed influenza infection decreased to 4% (2/47) compared with 21% (15/70) in the placebo group.

Influenza prophylaxis in immunocompromised subjects

In immunocompromised subjects with seasonal influenza infection and no viral release at baseline, prophylactic use of oseltamivir resulted in a reduction in the frequency of laboratory-confirmed influenza infection with clinical symptomatology to 0.4% (1/232) compared with 3% (7/231) in the placebo group. Laboratory-confirmed influenza infection accompanied by clinical symptoms was diagnosed in the presence of oral fever above 37.2°C, cough and/or acute rhinitis (all reported on the same day while taking the drug/placebo), and a positive reverse-transcriptase polymerase chain reaction for influenza virus RNA.

Resistance

Clinical Studies

In all OC-resistant patients, carriage was transient, had no effect on virus elimination, and did not cause worsening of clinical condition.

Patient population

Patients with resistance mutations

Phenotyping* Gene and phenotyping*

Adults and adolescents 4/1245 (0.32%) 5/1245 (0.4%)

Children (1-12 years) 19/464 (4.1%) 25/464 (5.4%)

* Complete genotyping was not done in any of the studies.

No cases of resistance to the drug were noted in individuals with normal immune system function when oseltamivir was administered for post-exposure prophylaxis (7 days), family contact prophylaxis (10 days), and seasonal prophylaxis (42 days).

In a 12-week seasonal prophylaxis study in immunocompromised individuals, no cases of resistance were also observed.

Data from individual clinical cases and observational studies

Naturally occurring mutations of influenza A and B viruses that had reduced sensitivity to oseltamivir were found in patients not receiving oseltamivir. In 2008, an H275Y substitution type mutation leading to resistance was found in more than 99% of the 2008 H1N1 virus strains circulating in Europe. The 2009 H1N1 influenza virus (“swine flu”) was sensitive to oseltamivir in most cases. Oseltamivir-resistant strains were found in individuals with normal immune system function and immunocompromised individuals taking oseltamivir. The degree of desensitization to oseltamivir and the frequency of such viruses may vary by season and region. Resistance to oseltamivir was found in patients with pandemic H1N1 influenza who received the drug for both treatment and prevention.

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

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

Preclinical data

Preclinical data based on standard pharmacological safety, genotoxicity and chronic toxicity studies did not reveal any particular risk to humans.

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

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

Effect on fertility: oseltamivir at a dose of 1500 mg/kg/day had no effect on the generative function of male and female rats.

Teratogenicity: In studies of teratogenicity of oseltamivir at doses up to 1500 mg/kg/day (in rats) and up to 500 mg/kg/day (in rabbits) no effect on embryo-fetal development was found. In studies of antenatal and postnatal development in rats, when oseltamivir was administered at a dose of 1500 mg/kg/day, an increase in the period of labor was observed: the safety limit between human exposure and the maximum no-effect dose in rats (500 mg/kg/day) was 480 times higher for oseltamivir, and 44 times higher for its active metabolite. Exposure in the fetus was 15-20% of that in the mother.

Other: oseltamivir and its active metabolite penetrate into the milk of lactating rats.

According to limited data oseltamivir and its active metabolite penetrate into human breast milk. Based on extrapolation of data from animal studies, their amounts in breast milk may be 0.01 mg/day and 0.3 mg/day, respectively.

Approximately 50% of guinea pigs tested exhibited skin sensitization in the form of erythema when maximum doses of the active substance oseltamivir were administered. Reversible eye irritation in rabbits was also found.

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 baby rats, including death of animals. No undesirable effects were observed when chronically administered at a dose of 500 mg/kg/day from 7 to 21 days postnatal period.

Pharmokinetics

Absorption

Oseltamivir is readily absorbed in the gastrointestinal tract and extensively converted to the active metabolite by hepatic and intestinal esterases. Plasma concentrations of the active metabolite are determined within 30 minutes, time to reach maximum concentrations of 2-3 hours, and are more than 20 times higher than concentrations of prodrug. At least 75% of the ingested dose reaches the systemic bloodstream as the active metabolite, less than 5% as the parent drug. Plasma concentrations of both prodrug and active metabolite are proportional to the dose and do not depend on food intake.

Distribution

Distribution volume (Vss) of active metabolite is 23 l.

According to animal studies, after oral administration oseltamivir its active metabolite was detected in all major foci of infection (lungs, bronchial waters, nasal mucosa, middle ear and trachea) in concentrations ensuring antiviral effect.

Binding of active metabolite with plasma proteins – 3%. Binding of prodrug to plasma proteins is 42%, which is not enough to cause significant drug interactions.

Metabolism

Oseltamivir is extensively converted to active metabolite under the action of esterases, mainly located in the liver. Neither oseltamivir nor the active metabolite are substrates or inhibitors of cytochrome P450 isoenzymes.

Excretion

Excreted (>90%) as the active metabolite mainly by the kidneys. The active metabolite undergoes no further transformation and is excreted by the kidneys (>99%) by glomerular filtration and tubular secretion. Renal clearance (18.8 l/h) exceeds glomerular filtration rate (7.5 l/h), indicating that the drug is also excreted by tubular secretion. Less than 20% of the drug taken is excreted through the intestine. The elimination half-life of the active metabolite is 6-10 hours.

Pharmacokinetics in special groups of patients

Patients with kidney disease

Administration of oseltamivir (100 mg twice daily for 5 days) in patients with various degrees of renal impairment the area under curve “concentration of active metabolite in plasma – time” (AUC oseltamivir carboxylate) is inversely proportional to the decrease of renal function.

Pharmacokinetics of oseltamivir in patients with terminal renal failure (with creatinine clearance ≤10 ml/min) who are not on dialysis has not been studied.

Patients with liver damage

The data obtained in vitro and in animal studies about the absence of a significant increase in the AUC of oseltamivir or its active metabolite in liver dysfunction of mild to moderate severity have been confirmed in clinical trials. Safety and pharmacokinetics of oseltamivir in patients with severe hepatic impairment have not been studied.

Patients of elderly and senile age

In elderly and senile patients (65-78 years) the exposure of the active metabolite in equilibrium is 25-35% higher than in younger patients when similar doses of oseltamivir are prescribed. The half-life of the drug in elderly and senile patients was not significantly different from that in younger patients. Taking into account the data on drug exposure and tolerability in elderly and senile patients, no dose adjustment is required for treatment and prophylaxis of influenza.

Children aged 1 to 8 years and adolescents

Pharmacokinetics of oseltamivir was studied in children aged 1 to 16 years in a single administration pharmacokinetic study and in a clinical study to study multiple administration of the drug in a small number of children aged 3-12 years.

The body weight-adjusted excretion rate of the active metabolite is higher in young children than in adults, resulting in a lower AUC in relation to a specific dose. Administration of the drug at a dose of 2 mg/kg and single doses of 30 mg or 45 mg in accordance with the dosing recommendations provides the same AUC of oseltamivir carboxylate as is achieved in adults after a single dose of a capsule containing 75 mg of the drug (equivalent to approximately 1 mg/kg). Pharmacokinetics of oseltamivir in children over 12 years is the same as in adults.

Indications

Influenza treatment for adults and children over 1 year.

Prevention of influenza in adults and adolescents over 12 years of age who are in groups at high risk of contracting the virus (in military units and large industrial groups, in weakened patients).

Influenza prevention in children over 1 year.

Active ingredient

Oseltamivir

Composition

1 capsule contains:

Active ingredient:

oseltamivir phosphate converted into 100% substance – 98.5 mg, equivalent to 75 mg of oseltamivir;

Excipients:

pregelatinized starch,

povidone (type K30),

croscarmellose sodium,

talc,

sodium stearyl fumarate.

Solid gelatin capsule [Body: iron oxide black dye, titanium dioxide, gelatin; Cap: iron oxide red dye, iron oxide yellow dye, titanium dioxide, gelatin].

How to take, the dosage

Treatment

The drug should be started within 2 days of the development of symptoms.

Adults and adolescents aged ≥12 years

Take 75 mg (one 75 mg capsule or one 30 mg capsule + one 45 mg capsule) 2 times daily orally for 5 days. Increasing the dose more than 150 mg/day does not increase the effect.

Children with a body weight of >40 kg or ages 8 to 12 years

Children who are able to swallow capsules may also be treated by taking one 75 mg capsule or one 30 mg capsule + one 45 mg capsule 2 times daily for
5 days.

Children 1 to 8 years of age

The recommended dosing regimen for oseltamivir capsules of 30 mg and 45 mg:

Extemporally prepared suspension can be used (see “Extemporally prepared suspension”).

It is possible to use a suspension prepared extemporaneously (see subsection “Extemporaneous preparation of oseltamivir suspension”).

Prevention

The drug should be started at least 2 days after exposure.

Adults and adolescents aged ≥12 years

Take 75 mg (one 75 mg capsule or one 30 mg capsule + one 45 mg capsule) once daily orally for at least 10 days after exposure. During seasonal influenza epidemics, 75 mg once daily for 6 weeks. The prophylactic effect lasts as long as the drug intake lasts.

Children with a body weight of >40 kg or ages 8 to 12 years

Children who can swallow capsules may also receive preventive therapy by taking one 75 mg capsule or one 30 mg capsule + one 45 mg capsule
once daily for 10 days.

Children 1 to 8 years of age

The recommended dosing regimen for oseltamivir is 30 mg and 45 mg capsules:

Extemporally prepared suspension can be used (see “Extemporally prepared suspension”).

It is possible to use a suspension prepared extemporaneously (see “Extemporaneous preparation of oseltamivir suspension”).

Dosage in special cases

Patients with impaired renal function

Treatment

Patients with a creatinine clearance greater than 60 mL/min do not require dose adjustments. In patients with a creatinine clearance of 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. In patients on permanent hemodialysis, oseltamivir at the initial dose of 30 mg can be taken before dialysis if influenza symptoms appear within 48 h between dialysis sessions. To maintain plasma concentrations at therapeutic levels, oseltamivir should be taken 30 mg after each dialysis session. In patients on peritoneal dialysis, oseltamivir should be taken at an initial dose of 30 mg before dialysis, then 30 mg every 5 days. Pharmacokinetics of oseltamivir in patients with end-stage renal failure (with creatinine clearance ≤ 10 ml/min) who are not on dialysis have not been studied. In this regard, there are no dosing recommendations in this group of patients.

Patients with creatinine clearance greater than 60 mL/min do not require dose adjustment. In patients with a creatinine clearance of 30 to 60 mL/min, the dose of oseltamivir should be reduced to 30 mg once daily.

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 once daily. In patients on permanent hemodialysis, oseltamivir at the initial dose of 30 mg can be taken before the start of dialysis (“1st session”). To maintain plasma concentrations at therapeutic levels, oseltamivir should be taken 30 mg after each subsequent odd-numbered dialysis session. In patients on peritoneal dialysis, oseltamivir should be taken at an initial dose of 30 mg before dialysis, then 30 mg every 7 days. Pharmacokinetics of oseltamivir in patients with end-stage renal failure (with creatinine clearance ≤ 10 ml/min) who are not on dialysis have not been studied. In this regard, there are no dosing recommendations in this group of patients.

Patients with liver dysfunction

Dose adjustment is not required during treatment and prophylaxis of influenza in patients with mild to moderate liver dysfunction. Safety and pharmacokinetics of oseltamivir in patients with severe hepatic impairment have not been studied.

Elderly and elderly patients

Dose adjustment for prophylaxis or treatment of influenza is not required.

Patients with compromised immunity (after transplantation)

For seasonal flu prophylaxis in immunocompromised patients aged
≥ 1 year – for 12 weeks, no dose adjustment is necessary.

Children

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

Interaction

According to the data of pharmacological and pharmacokinetic studies, clinically significant drug interactions are unlikely.

Oseltamivir is extensively converted to the active metabolite under the action of esterases, mainly located in the liver. Drug interactions due to competition for binding to active esterase centers are not widely reported in the literature. The low degree of binding of oseltamivir and its active metabolite to plasma proteins does not suggest interactions related to displacement of drugs from binding to proteins.

In vitro studies show that neither oseltamivir nor its active metabolite is a preferred substrate for polyfunctional oxidases of the cytochrome P450 system or for glucuronyltransferases. There is no reason for interaction with oral contraceptives.

Cimetidine, a nonspecific inhibitor of cytochrome P450 system isoenzymes and competes with alkaline and cationic drugs during tubular secretion, does not affect plasma concentrations of oseltamivir and its active metabolite.

Clinically significant interdrug interactions involving competition for tubular secretion are unlikely, given the safety margin for most such drugs, the excretion routes for the active metabolite of oseltamivir (glomerular filtration and anionic tubular secretion), and the excretion capacity of each route.

Probenecid leads to an increase in the AUC of the active metabolite of oseltamivir by approximately 2-fold (due to a decrease in active renal tubular secretion). However, dose adjustment when concomitant use with probenecid is not required, given the safety margin of the active metabolite.

Concomitant use with amoxicillin has no effect on plasma concentrations of oseltamivir and its components, demonstrating a weak competition for excretion by anionic tubular secretion.

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

No pharmacokinetic interactions between oseltamivir, its main metabolite were found when taking simultaneously with paracetamol, acetylsalicylic acid, cimetidine, antacids (magnesium and aluminum hydroxide, calcium carbonate), warfarin, rimantadine or amantadine.

When using oseltamivir with commonly used drugs such as ACE inhibitors (enalapril, captopril), thiazide diuretics (bendroflumethiazide), antibiotics (penicillin, cephalosporins, azithromycin, erythromycin and doxycycline), H2-histamine receptor blockers (ranitidine, cimetidine), beta-adrenoblockers (propranolol), xanthines (theophylline), sympathomimetics (pseudoephedrine), opiates (codeine), glucocorticosteroids, inhaled bronchodilators and non-narcotic analgesics (acetylsalicylic acid, ibuprofen and paracetamol), no changes in the nature or frequency of adverse events were observed.

Caution should be exercised when using oseltamivir in combination with drugs with narrow therapeutic scope (e.g., chlorpropamide, methotrexate, butadion).

Special Instructions

Mental disorders

Mental disorders, seizures and delirium-like neuropsychiatric disorders have been reported in patients (mostly in children and adolescents) who have taken oseltamivir for treatment of influenza. These cases were rarely accompanied by life-threatening actions. The role of oseltamivir in the development of these phenomena is unknown. Similar neuropsychiatric disorders have also been reported in influenza patients who did not receive oseltamivir.

The risk of neuropsychiatric disorders in patients receiving oseltamivir is not greater than that in influenza patients not receiving antiviral medications.

It is recommended to closely monitor the condition and behavior of patients, especially children and adolescents, to identify signs of abnormal behavior and assess the risk of continuing the drug in the development of these phenomena.

There are no data on efficacy of oseltamivir in any diseases caused by pathogens other than influenza A and B viruses.

The drug Oseltamivir-Acrihin is not a substitute for vaccination.

Prophylactic administration of the drug Oseltamivir-Acrihin is possible on epidemiological indications.

Oseltamivir in this dosage form should not be prescribed to children under 1 year.

Instructions for use, handling and disposal

The drug’s entry into the environment should be minimized. The drug should not be disposed of with wastewater or with household waste. If possible, it is necessary to use special systems for disposal of medicines.

Effect on the ability to drive vehicles, mechanisms

Studies on the effect of the drug on the ability to drive vehicles and engage in other potentially dangerous activities requiring increased concentration, attention and speed of psychomotor reactions have not been conducted. Based on the safety profile, the effect of oseltamivir on these activities is unlikely.

Contraindications

Hypersensitivity to oseltamivir or any component of the drug.

The terminal stage of renal failure (creatinine clearance ≤ 10 ml/min).

Children under 1 year.

Severe hepatic failure.

With caution

Pregnancy, period of breastfeeding.

Use in pregnancy and during breastfeeding

Controlled studies in pregnant women have not been conducted. However, the results of post-marketing and observational studies have demonstrated the benefit of the proposed standard dosing regimen for this patient population. Results of the pharmacokinetic analysis showed lower exposure of the active metabolite (approximately 30% in all trimesters of pregnancy) in pregnant women compared to nonpregnant women.

Nevertheless, the estimated exposure value remains above inhibitory concentrations (IC95 value) and therapeutic values for many strains of influenza virus. Changing the dosing regimen in pregnant women for therapy or prophylaxis is not recommended. No direct or indirect adverse effects of the drug on pregnancy, embryo-fetal or postnatal development have been found. When prescribing oseltamivir to pregnant women, both safety data and the course of pregnancy and pathogenicity of the circulating strain of influenza virus should be considered.

During preclinical studies, oseltamivir and the active metabolite penetrated into the milk of lactating rats. There are limited data on the excretion of oseltamivir with breast milk in humans and the use of oseltamivir in lactating women. Oseltamivir and its active metabolite penetrate into breast milk in small amounts, creating subtherapeutic concentrations in the blood of the infant. When prescribing oseltamivir to breastfeeding women, the concomitant disease and pathogenicity of the circulating strain of influenza virus should also be taken into account.

During pregnancy and during breastfeeding oseltamivir is used only if the estimated benefit to the mother exceeds the potential risk to the fetus and child.

Side effects

Clinical Studies

In studies of influenza treatment in adult/adolescent patients, the most common adverse reactions (HP) were nausea, vomiting, and headache.

The majority of HP occurred on the first or second day of treatment and resolved on their own within 1-2 days. In flu prevention studies in adults and adolescents, the most common HP were nausea, vomiting, headache, and pain. In children, vomiting was the most common. The HPs described did not require drug withdrawal in most cases.

Treatment and prevention of influenza in adults and adolescents

. Table 1 shows the HPs that occurred most frequently (≥1%) when taking the recommended dose of oseltamivir in influenza prevention and treatment studies in adults and adolescents (75 mg 2 times daily for 5 days for treatment and 75 mg once daily up to 6 weeks for prevention) and that had at least a 1% higher incidence compared with placebo. The influenza treatment studies included adults/adolescents without concomitant pathology and high-risk patients, i.e., patients at high risk for influenza complications (elderly and elderly patients, patients with chronic heart or respiratory disease). In general, the safety profile of at-risk patients was consistent with that of adult/adolescent patients without concomitant pathology.

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

Table 1. Percentage of adults/adolescents with HF occurring at ≥1% in the oseltamivir group in influenza infection treatment and prevention trials (difference from placebo ≥1%).

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

The following are adverse events that occurred with a frequency of ≥1% in adults and adolescents who received oseltamivir as therapy and prophylaxis for influenza infection. These adverse events either occurred more frequently in patients receiving placebo, or the difference in frequency between the oseltamivir and placebo groups was less than 1%.

Gastrointestinal disorders (oseltamivir vs placebo): Treatment – diarrhea (6% vs. 7%), abdominal pain (including upper abdominal pain,
2% vs. 3%);

Prevention – diarrhea (3% vs. 4%), upper abdominal pain (2% vs. 2%), dyspepsia (1% vs. 1%).

Infections and invasions (oseltamivir vs placebo):

Treatment – bronchitis (3% vs. 4%), sinusitis (1% vs. 1%), herpes simplex (1% vs. 1%);

Prevention – nasopharyngitis (4% vs. 4%), upper respiratory infections
(3% vs. 3%), influenza infection (2% vs. 3%).

General disorders (oseltamivir vs placebo):

Treatment – dizziness (including vertigo, 2% vs. 3%);

Prevention – fatigue (7% vs. 7%), pyrexia (2% vs. 2%), flu-like illness (1% vs. 2%), dizziness (1% vs. 1%), limb pain (1% vs. 1%).

Nervous system disorders (oseltamivir vs placebo):

Treatment – insomnia (1% vs. 1%);

Prevention – insomnia (1% vs. 1%).

Respiratory, thoracic, and mediastinal disorders (oseltamivir vs. placebo):

Treatment – cough (2% vs. 2%), nasal congestion (1% vs. 1%);

Prevention – nasal congestion (7% vs. 7%), sore throat (5% vs. 5%), cough (5% vs. 6%), rhinorrhea (1% vs. 1%).

Muscular and connective tissue disorders (oseltamivir vs placebo):

Preventive – back pain (2% vs. 3%), arthralgia (1% vs. 2%), myalgia (1% vs. 1%).

Renital and breast disorders (oseltamivir vs placebo):

prophylaxis – dysmenorrhea (3% vs. 3%).

Treatment and prevention of influenza infection in elderly and elderly patients

The safety profile in 942 elderly and elderly patients treated with oseltamivir or placebo was not clinically different from that in younger individuals (under 65 years).

The prevention of influenza infection in immunocompromised patients

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

The treatment and prevention of influenza infection in children without comorbidities aged 1 to 12 years and patients with bronchial asthma

In studies of the treatment of natural influenza infection in children aged
1 year to 12 years of age, HP vomiting was noted with a frequency of ≥1% and at least 1% more often with oseltamivir (n = 858) compared with placebo (n = 622).

In children who received the recommended dose of oseltamivir once daily as post-exposure prophylaxis at home, vomiting
was most common (8% in the oseltamivir group versus 2% in the non-preventive treatment group). Oseltamivir was well tolerated, the reported adverse events were consistent with those previously described in the treatment of influenza in children.

The adverse events reported in children with an incidence of ≥1% in influenza treatment trials (n = 858) or with an incidence of ≥5% in influenza prevention trials (n = 148) are presented below. These adverse events were more frequent in the placebo/no prophylaxis group; the difference between the oseltamivir and placebo/no prophylaxis groups was less than 1%.

Gastrointestinal disorders (oseltamivir vs. placebo): treatment-diarrhea (9% vs. 9%), nausea (4% vs. 4%), abdominal pain (including upper abdominal pain, 3% vs. 3%).

Infections and invasions (oseltamivir vs placebo):

The treatments were otitis media (5% vs. 8%), bronchitis (2% vs. 3%), pneumonia (1% vs. 3%), and sinusitis (1% vs. 2%).

Respiratory, thoracic, and mediastinal disorders (oseltamivir vs. placebo):

Treatment – asthma (including exacerbations, 3% vs. 4%), nasal bleeding (2% vs. 2%);

Prevention – cough (12% vs. 26%), nasal congestion (11% vs. 20%). Skin and subcutaneous tissue disorders (oseltamivir vs placebo): treatment – dermatitis (including allergic and atopic dermatitis, 1% vs 2%). Hearing and labyrinth disorders (oseltamivir vs. placebo):

The treatment was ear pain (1% vs. 1%).

Visual organ disorders (oseltamivir vs placebo):

treatment – conjunctivitis (including eye redness, ocular discharge, and eye pain,
1% vs < 1%).

Additional adverse events noted with flu treatment in children that did not meet the criteria described above.

Blood and lymphatic system disorders (oseltamivir vs placebo): treatment-associated lymphoadenopathy (< 1% vs 1%).

Hearing and labyrinth disorders (oseltamivir vs placebo):

Treatment – Damage to the eardrum (< 1% vs.)

Post-marketing follow-up

The following are the adverse events with oseltamivir that were observed during the post-marketing follow-up period. The frequency of these adverse events and/or a causal relationship to oseltamivir use cannot be determined because the true population size is unknown due to the voluntary nature of the reports.

Skin and subcutaneous tissue disorders: hypersensitivity reactions – dermatitis, skin rash, eczema, urticaria, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis, allergy, anaphylactic and anaphylactoid reactions, Quincke’s edema.

Hepatic and biliary tract disorders: hepatitis, increased “liver” enzyme activity in patients with flu-like symptoms receiving oseltamivir; fulminant hepatitis (including fatal), liver failure, jaundice.

Nervous mental disorders

Influenza infection can be associated with a variety of neurological symptoms and behavioral changes, including symptoms such as hallucinations, delusions, and abnormal behavior. In some cases they can be fatal. These phenomena may occur against the background of encephalopathy or encephalitis or without the manifestation of these diseases. Seizures and delirium (including such symptoms as impaired consciousness, disorientation in time and space, abnormal behavior, delirium, hallucinations, agitation, anxiety, nightmares) have been reported in patients (mostly in children and adolescents) who took oseltamivir to treat influenza. These cases were rarely accompanied by life-threatening acts. The role of oseltamivir in the development of these phenomena is unknown. Similar neuropsychiatric disorders have also been reported in influenza patients who did not receive oseltamivir.

Gastrointestinal disorders: gastrointestinal bleeding after taking oseltamivir (in particular, the connection between hemorrhagic colitis and taking oseltamivir cannot be excluded, since these phenomena disappeared both after the patient recovered from the flu and after discontinuation of the drug).

Visual disorders: visual impairment.

Cardiac disorders: arrhythmia.

Overdose

In most cases of overdose in clinical trials and in post-marketing use of oseltamivir no adverse events were observed.

Similarities

Tamiflu, Nomides, Oseltamivir