Nomides capsules 30mg, 10pcs

Composition

Active ingredient:

Oseltamivir 30 mg, (as oseltamivir phosphate) 39.4 mg.

Auxiliary substances:  colloidal silicon dioxide (aerosil), copovidone, pregelatinized starch, croscarmellose sodium, sodium stearyl fumarate, talc.

Capsule composition:

capsule body: titanium dioxide – 2.0000%, gelatin – up to 100%;

capsule cap: titanium dioxide-2.0000%, gelatin – up to 100%.

Pharmacological action

Pharmacodynamics

Mechanism of action

The antiviral drug oseltamivir phosphate is a prodrug, its active metabolite (oseltamivir carboxylate, OK) is an effective and selective inhibitor of neuraminidase of influenza viruses type A and B, an enzyme that catalyzes the release of newly formed viral particles from infected cells, their penetration into uninfected cells of the respiratory epithelium and further spread of the virus in the body. Inhibits the growth of influenza virus in vitro and suppresses the replication of the virus and its pathogenicity in vivo, reduces the release of influenza A and B viruses from the body. Studies of clinical isolates of influenza virus have shown that the concentration of OK required to inhibit neuraminidase by 50% (IC50) is 0.1-1.3 nM for influenza A virus and 2.6 nM for influenza B. The median IC50 value for influenza B virus is slightly higher and is 8.5 nM.

Clinical efficacy

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

Natural flu infection studies

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

Oseltamivir significantly reduced the period of clinical manifestations of influenza infection (by 32 hours).

In patients with a confirmed diagnosis of influenza who received oseltamivir, the severity of the disease, expressed as the area under the curve for the total symptom index, was 38% less compared to patients who received placebo. Moreover, in young patients without concomitant diseases, oseltamivir reduced by about 50% the incidence of complications of influenza requiring the use of antibiotics (bronchitis, pneumonia, sinusitis, otitis media). There was clear evidence of the drug’s effectiveness in relation to secondary efficacy criteria related to antiviral activity: oseltamivir caused both a shortening of the time of virus release from the body and a decrease in the area under the “viral titers-time”curve.

Data obtained in the study on oseltamivir therapy in elderly and senile patients show that taking oseltamivir at a dose of 75 mg 2 times a day for 5 days was accompanied by a clinically significant decrease in the median period of clinical manifestations of influenza infection, similar to that in younger adult patients, but the differences did not reach statistical significance. In another study, patients with flu over 13 years of age who had concomitant chronic diseases of the cardiovascular and / or respiratory systems received oseltamivir in the same dosage regimen or placebo. There were no differences in the median period before the decrease in clinical manifestations of influenza infection in the oseltamivir and placebo groups, but the period of temperature increase with oseltamivir was approximately 1 day. The proportion of patients who isolated the virus on days 2 and 4 was significantly lower. The safety profile of oseltamivir in patients at risk did not differ from that in the general population of adult patients.

Treatment of flu in children

A double-blind placebo-controlled study was conducted in children aged 1-12 years (mean age 5.3 years) who had fever (37.8 °C) and one of the symptoms of the respiratory system (cough or rhinitis) during the circulation of the influenza virus in the population. 67% of patients were infected with the influenza A virus and 33% of patients were infected with the influenza B virus. Oseltamivir (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 to placebo. The duration of the disease was defined as the time until cough relief, nasal congestion, fever disappearance, and return to normal activity. In the group of children treated with oseltamivir, the incidence of acute otitis media decreased by 40% compared to the placebo group. Recovery and return to normal activity occurred almost 2 days earlier in children treated with oseltamivir compared to the placebo group.

Another study included children aged 6-12 years with bronchial asthma; 53.6% of patients had a serologically and/or culturally confirmed flu infection. The median duration of the disease did not significantly decrease in the group of patients treated with oseltamivir. However, by the last day 6 of oseltamivir therapy, forced expiratory volume per 1 second (FEV 1) increased by 10.8% compared to 4.7% in patients receiving placebo (p=0.0148).

Prevention of influenza in adults and adolescents

The prophylactic efficacy of oseltamivir in natural influenza infection A and B was demonstrated in 3 separate phase III clinical trials. While taking oseltamivir, about 1% of patients became ill with influenza. Oseltamivir also significantly reduced the frequency of virus isolation and prevented transmission of the virus from one family member to another.

Adults and adolescents who were in contact with a sick family member started oseltamivir within two days after the onset of flu symptoms in family members and continued it for 7 days, which significantly reduced the frequency of flu cases in those who were in contact by 92%.

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.

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

Prevention of flu in children

The preventive efficacy of oseltamivir in natural influenza infection was demonstrated in a study in children aged 1 to 12 years after contact with a sick family member or with someone from a permanent environment. The main parameter of efficacy in this study was the frequency of laboratory-confirmed influenza infection. In a study in children who received oseltamivir (powder for preparing an oral suspension) at a dose of 30 to 75 mg 1 time per day for 10 days, and did not isolate the virus at baseline, the frequency of laboratory-confirmed influenza decreased to 4% (2/47) compared to 21% (15/70) in the placebo group.

Flu prevention in immunocompromised individuals

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

Resistance

Clinical studies

The risk of influenza viruses with reduced sensitivity or resistance to the drug has been studied in clinical studies. In all patients – carriers of the OK-resistant virus, the carriage was temporary, did not affect the elimination of the virus and did not cause a deterioration in the clinical condition.

Patient population	Patients with mutations leading to resistance
	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 was not performed in any of the studies.

When taking oseltamivir for post-exposure prophylaxis (7 days), family contact prophylaxis (10 days), and seasonal prophylaxis (42 days), no cases of resistance to the drug were observed in individuals with normal immune system function. In a 12-week study on seasonal prevention in immunocompromised individuals, there were also no cases of resistance.

Data from individual clinical cases and observational studies

Patients who did not receive oseltamivir were found to have naturally occurring mutations of influenza A and B viruses that had reduced sensitivity to oseltamivir. In 2008, an H275Y substitution mutation leading to resistance was detected in more than 99% of the 2008 H1N1 virus strains circulating in Europe. The 2009 H1N1 influenza virus (“swine flu”) was susceptible to oseltamivir in most cases. Oseltamivir-resistant strains were found in individuals with normal immune system function and immunocompromised individuals treated with oseltamivir. The degree of decreased sensitivity to oseltamivir and the frequency of occurrence of such viruses may vary depending on the season and region. Resistance to oseltamivir was found in patients with H1N1 pandemic influenza treated with the drug, both for treatment and prevention.

The incidence of resistance may be higher in younger and immunocompromised patients. Laboratory strains of influenza viruses resistant to oseltamivir 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 whether to use oseltamivir, the seasonal sensitivity of the influenza virus to the drug should be taken into account (up-to-date information can be found on the WHO website).

PHARMACOKINETICS

Pharmacokinetics

Absorption rate

Oseltamivir phosphate is readily absorbed in the gastrointestinal tract and is highly converted to an active metabolite by hepatic and intestinal esterases. Concentrations of the active metabolite in plasma are determined within 30 minutes, the time to reach the maximum concentration is 2-3 hours, and more than 20 times higher than the concentration of the prodrug. At least 75% of the oral dose enters the systemic circulation in the form of an active metabolite, less than 5% – in the form of the initial drug. Plasma concentrations of both the prodrug and the active metabolite are dose-proportional and independent of food intake.

Distribution

The volume of distribution (Vss) of the active metabolite is 23 liters.

According to animal studies, after oral use of oseltamivir phosphate, its active metabolite was detected in all major foci of infection (lungs, bronchial lavage, nasal mucosa, middle ear, and trachea) in concentrations that provide an antiviral effect.

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

Metabolism

Oseltamivir phosphate is highly converted to the active metabolite by esterases located mainly in the liver. Neither oseltamivir phosphate nor the active metabolite are substrates or inhibitors of cytochrome P450 isoenzymes.

Deduction

It is excreted (>90%) as an active metabolite mainly by the kidneys. The active metabolite does not undergo further transformation and is excreted by the kidneys (>99%) by glomerular filtration and tubular secretion. Renal clearance (18.8 l/h) exceeds the glomerular filtration rate (7.5 l/h), which indicates that the drug is also excreted by tubular secretion. Less than 20% of the drug taken is excreted through the intestines. The half-life of the active metabolite is 6-10 hours

. Pharmacokinetics in special groups of patients

Patients with kidney damage

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

The pharmacokinetics of oseltamivir in patients with end-stage renal insufficiency (with creatinine clearance < 10 ml/min) who are not on dialysis have not been studied.

Patients with liver damage

Data obtained in vitro and in animal studies on the absence of a significant increase in the AUC of oseltamivir or its active metabolite in patients with mild to moderate hepatic impairment were also confirmed in clinical studies (see “Dosage in special cases”). The safety and pharmacokinetics of oseltamivir phosphate in patients with severe hepatic impairment have not been studied.

Elderly and senile patients

In elderly and senile patients (65-78 years), the exposure of the active metabolite at steady state is 25-35% higher than in younger patients with similar doses of oseltamivir. The half-life of the drug in elderly and senile patients did not significantly differ from that in younger patients. Taking into account data on the drug’s exposure and tolerability in elderly and senile patients, no dose adjustment is required in the treatment and prevention of influenza.

Children aged 1 to 8 years and adolescents

The pharmacokinetics of oseltamivir were studied in children aged 1 to 16 years in a single-dose pharmacokinetic study and in a multi-dose clinical study in a small number of children aged 3-12 years. The rate of elimination of the active metabolite adjusted for body weight is higher in young children than in adults, which leads to lower AUC relative to the specific dose. Taking the drug at a dose of 2 mg / kg and single doses of 30 mg or 45 mg in accordance with the dosage recommendations for children given in the section “Dosage and use”, provides the same AUC of oseltamivir carboxylate, which is achieved in adults after a single dose of a capsule with 75 mg of the drug (equivalent to approximately 1 mg/kg). The pharmacokinetics of oseltamivir in children over 12 years of age are 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 the age of 12 years 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.

Use during pregnancy and lactation

No controlled trials were conducted in pregnant women. However, the results of post-marketing and observational studies have demonstrated the usefulness of the proposed standard dosage regimen for this patient population. The results of the pharmacokinetic analysis showed a lower exposure of the active metabolite (approximately 30% during all trimesters of pregnancy) in pregnant women compared to non-pregnant women. However, the calculated exposure value remains higher than the inhibitory concentrations (IC95 value) and therapeutic values for many influenza virus strains. Changing the dosage regimen in pregnant women during therapy or prevention is not recommended. There were no direct or indirect adverse effects of the drug on pregnancy, embryo-fetal or postnatal development (see “Preclinical data”). When prescribing oseltamivir to pregnant women, both safety data and the course of pregnancy and pathogenicity of the circulating influenza virus strain should be taken into account.

During preclinical studies, oseltamivir and the active metabolite were absorbed into the milk of lactating rats. Data on human breast milk excretion of oseltamivir and the use of oseltamivir in nursing women are limited. Oseltamivir and its active metabolite pass into breast milk in small amounts (see “Preclinical data”), creating subtherapeutic concentrations in the blood of an infant. When prescribing oseltamivir to nursing women, the concomitant disease and pathogenicity of the circulating influenza virus strain should also be considered.

During pregnancy and lactation, oseltamivir is used only if the intended benefit to the mother exceeds the potential risk to the fetus and child.

Mental disorders

Seizures and delirium-like neuropsychiatric disorders have been reported in patients (mainly children and adolescents) taking oseltamivir for the 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 were also reported in patients with influenza who did not receive oseltamivir. The risk of developing neuropsychiatric disorders in patients receiving oseltamivir does not exceed that in patients with influenza who do not receive antiviral drugs.

Careful monitoring of the condition and behavior of patients, especially children and adolescents, is recommended in order to detect signs of abnormal behavior and assess the risk of continuing to take the drug if these phenomena develop.

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

Oseltamivir is not a substitute for vaccination.

Prophylactic use of the drug is possible for epidemiological indications. Recommendations for dose adjustment in patients with renal impairment are presented in the section “Dosage in special cases”.

Contraindications

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

• End-stage renal failure (creatinine clearance < 10 ml/min);

• Severe liver failure;

• Children under 1 year of age.

With caution

Pregnancy, breast-feeding period.

Side effects

In studies on the treatment of influenza in adults/adolescents, the most common adverse reactions (HP) were nausea, vomiting, and headache. Most HPV occurred on the first or second day of treatment and resolved independently within 1-2 days. In studies on flu prevention in adults and adolescents, the most common HPV symptoms were nausea, vomiting, headache, and pain. Vomiting was most common in children. The described changes in most cases did not require discontinuation of the drug.

Treatment and prevention of influenza in adults and adolescents

Table 1 shows HP that occurred most frequently (≥1%) when taking the recommended dose of oseltamivir in studies on the prevention and treatment of influenza in adults and adolescents (75 mg 2 times a day for 5 days for treatment and 75 mg 1 time a day for up to 6 weeks for prevention), and the frequency of which is at least 1% higher compared to placebo. Studies on the treatment of influenza included adults/adolescents without comorbidities 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 similar to that in adults/adolescents without concomitant pathology.

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

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

System-organ class Undesirable reaction	Treatment		Prevention		Frequency categorya
	Oseltamivir (75 mg twice daily) N=2647	Placebo N=1977	Oseltamivir (75 mg 1 time / day) N=1945	Placebo N=1588
Disorders of the gastrointestinal tract
Nausea	0%	6%	8%	4%	very common
Vomiting	8%	3%	2%	1%	often
Nervous system disorders
Headache	2%	1%	17%	16%	very common
Common disorders
Pain1	%	1%	4%	3%	often

a The frequency category is presented only for the oseltamivir group. The following frequency categories were used to estimate the HP frequency: very common (≥1/10); frequent (≥1/100,

The following are adverse events that occurred with a frequency of ≥1% in adults and adolescents treated with oseltamivir as therapy and prevention of influenza infection. These adverse events were either more common in patients treated with 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 infestations (oseltamivir vs. placebo):

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

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

General disorders (oseltamivir vs. placebo):

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

prevention of fatigue (7% vs 7%), pyrexia (2% vs 2%), flu-like disease (1% vs. 2%), dizziness (1% vs 1%), pain in extremity (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%).

Musculoskeletal and connective tissue disorders (oseltamivir vs. placebo):

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

Genital and breast disorders (oseltamivir vs. placebo):

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

Treatment and prevention of influenza infection in the elderly and senile age

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

Prevention of influenza infection in immunocompromised patients

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

Treatment and prevention of influenza infection in children without concomitant diseases aged 1-12 years and patients with bronchial asthma

In studies on the treatment of natural influenza infection in children aged 1 to 12 years of HP, oseltamivir (n = 858) was observed with a frequency of ≥1% and at least 1% more often than placebo (n = 622), vomiting occurred. Children who received the recommended dose of the drug once a day as a post-exposure prophylaxis at home had the most frequent vomiting (8% in the oseltamivir group versus 2% in the group that did not receive preventive treatment). Oseltamivir was well tolerated, and the reported adverse events were consistent with those previously described in the treatment of influenza in children. The following adverse events were reported in children with a frequency of ≥1% in influenza treatment studies (n = 858) or with a frequency of ≥5% in influenza prevention studies (n = 148). These adverse events were more frequently observed in the placebo/no-prophylaxis group, and 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 infestations (oseltamivir vs. placebo):

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

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

treatment – asthma (including exacerbation,3% vs. 4%), nosebleeds (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 disorders and labyrinth disorders (oseltamivir vs. placebo):

treatment – ear pain (1% vs. 1%).

Visual disturbances (oseltamivir vs. placebo):

treatment-conjunctivitis (including redness of the eyes, discharge from the eye and pain in the eyes,1% vs

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

Blood and lymphatic system disorders (oseltamivir vs. placebo):

treatment-lymphadenopathy (

Hearing disorders and labyrinth disorders (oseltamivir vs. placebo):

treatment – damage to the eardrum (

Post-marketing surveillance

The following are some of the adverse events associated with oseltamivir that were observed during the post-marketing follow-up period.The frequency of these adverse events and / or a causal relationship with the use of the drug cannot be established, as the true population size is not known 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, allergies, anaphylactic and anaphylactoid reactions, Quincke’s edema.

Liver and biliary tract disorders: hepatitis, increased activity of “liver” enzymes in patients with flu-like symptoms treated with oseltamivir; fulminant hepatitis (including fatal outcome), liver failure, jaundice.

Neuropsychiatric disorders

Flu 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. Such phenomena can occur both against the background of the development of encephalopathy or encephalitis, and without the manifestation of these diseases.

Seizures and delirium (including symptoms such as impaired consciousness, disorientation in time and space, abnormal behavior, delusions, hallucinations, agitation, anxiety, and nightmares) have been reported in patients (mainly children and adolescents) taking oseltamivir for the 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 were also reported in patients with influenza who did not receive oseltamivir.

Gastrointestinal disorders: gastrointestinal bleeding after taking oseltamivir (in particular, a link between the phenomena of 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.

Interaction

Clinically significant drug interactions are unlikely according to pharmacological and pharmacokinetic studies. Oseltamivir phosphate is highly converted to the active metabolite by esterases mainly located in the liver. Drug interactions caused by competition for binding to the active sites of esterases are not widely represented in the literature. The low degree of binding of oseltamivir and the active metabolite to plasma proteins does not suggest the presence of interactions associated with the displacement of drugs from protein binding.

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

Cimetidine, a non-specific inhibitor of the cytochrome P450 isoenzyme and competing in the process of tubular secretion with alkaline-type drugs and cations, does not affect the plasma concentrations of oseltamivir and its active metabolite.

Clinically significant drug-drug interactions associated with competition for tubular secretion are unlikely, given the safety reserve for most of these drugs, the elimination pathways of the active metabolite of oseltamivir (glomerular filtration and anionic tubular secretion), as well as the excretory capacity of each of the pathways.

Probenecid leads to an increase in the AUC of the active metabolite of oseltamivir by approximately 2 times (due to a decrease in active tubular secretion in the kidneys). However, no dose adjustment is required when used concomitantly with probenecid, given the safety reserve of the active metabolite.

Concomitant use with amoxicillin does not affect the plasma concentrations of oseltamivir and its components, demonstrating weak competition for elimination by anionic tubular secretion.

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

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

When using oseltamivir with commonly used medications, such as angiotensin-converting enzyme inhibitors (enalapril, captopril), thiazide diuretics (bendroflumetiazid), antibiotics (penicillin, cephalosporins, azithromycin, erythromycin and doxycycline), H2-histamine receptor blockers (ranitidine, cimetidine), beta-blockers No changes in the nature or frequency of adverse events were observed in patients treated with anti-inflammatory drugs (propranolol), xanthines (theophylline), sympathomimetics (pseudoephedrine), opiates (codeine), corticosteroids, inhaled bronchodilators, and non-narcotic analgesics (acetylsalicylic acid, ibuprofen, and paracetamol).

Oseltamivir should be used with caution in combination with drugs that have a narrow therapeutic range (for example, chlorpropamide, methotrexate, butadione).

How to take, course of use and dosage

The drug oseltamivir is taken orally, regardless of food intake or during meals. Tolerability of the drug can be improved if you take it with a meal.

When used by adults, adolescents, or children who cannot swallow the capsule or who have signs of “aging” of the capsules (for example, increased fragility or other physical disorders), 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 without sugar content, honey, light brown sugar or table sugar dissolved in water, sweet dessert, condensed milk with sugar, applesauce or yogurt) in order to hide bitter taste. The mixture must be thoroughly mixed and given to the patient as a whole. You should swallow the mixture immediately after cooking. Detailed recommendations are given in the subsection “Extemporal suspension preparation”.

Standard dosage regimen

Treatment

Taking the drug should be started no later than 2 days after the development of symptoms of the disease.

Adults and adolescents aged ≥ 12 years

The recommended daily dose is 150 mg. The drug is prescribed in a dose of 75 mg (one capsule of 75 mg or one capsule of 30 mg + one capsule of 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 increased effect.

Children weighing more than 40 kg or aged 8-12 years

Children who can swallow capsules can also receive treatment by taking 75 mg (one 75 mg capsule or one 30 mg capsule + one 45 mg capsule) 2 times a day for 5 days.

Children aged 1 to 8 years

The recommended dosage regimen of oseltamivir capsules is 30 and 45 mg.

Body weight	Recommended dose for 5 days
≤15 kg >15-23 kg> >23-40 kg>	30 mg twice daily 45 mg twice daily 60 mg twice daily

It is possible to use a suspension prepared extemporally (see the subsection “Extemporal suspension preparation”).

Prevention

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

Adults and adolescents aged ≥ 12 years

75 mg (one capsule of 75 mg or one capsule of 30 mg + one capsule of 45 mg) 1 time a day inside for at least 10 days after contact with the patient. During a seasonal flu epidemic-75 mg once a day for 6 weeks. The preventive effect lasts as long as the drug is taken.

Children weighing more than 40 kg or aged 8-12 years

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

Children aged 1 to 8 years

The recommended dosage regimen of oseltamivir capsules is 30 and 45 mg.

Body weight	Recommended dose for 10 days
≤15 kg >15-23 kg> >23-40 kg>	30 mg 1 time per day 45 mg 1 time per day 60 mg 1 time per day

It is possible to use a suspension prepared extemporally (see the subsection “Extemporal suspension preparation”).

Dosage in special cases

Patients with impaired renal function

Treatment

In patients with creatinine clearance greater than 60 ml/min, no dose adjustment is required. 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 creatinine clearance from 10 to 30 ml/min, the dose of oseltamivir should be reduced to 30 mg once a day for 5 days. In patients on continuous hemodialysis, oseltamivir at an initial dose of 30 mg can be taken before dialysis if flu symptoms appear within 48 hours between dialysis sessions. To maintain plasma concentrations at therapeutic levels, oseltamivir should be taken 30 mg after each dialysis session. In patients undergoing peritoneal dialysis, oseltamivir should be taken at an initial dose of 30 mg prior to dialysis, followed by 30 mg every 5 days.

The pharmacokinetics of oseltamivir in patients with end-stage chronic renal failure (with creatinine clearance < 10 ml/min) who are not on dialysis have not been studied. Therefore, there are no recommendations on dosage in this group of patients.

Prevention

In patients with creatinine clearance greater than 60 ml/min, no dose adjustment is required. In patients with a creatinine clearance of 30 to 60 ml/min, the dose of oseltamivir should be reduced to 30 mg once a day. In patients with creatinine clearance from 10 to 30 ml/min, it is recommended to reduce the dose of oseltamivir to 30 mg every other day. In patients on continuous hemodialysis, oseltamivir at an initial dose of 30 mg can be taken before starting dialysis. To maintain plasma concentrations at therapeutic levels, oseltamivir should be taken 30 mg after each subsequent odd dialysis session. In patients undergoing peritoneal dialysis, oseltamivir should be taken at an initial dose of 30 mg prior to dialysis, then 30 mg every 7 days. The pharmacokinetics of oseltamivir in patients with end-stage chronic renal failure (with creatinine clearance < 10 ml/min) who are not on dialysis have not been studied. Therefore, there are no recommendations on dosage in this group of patients.

Patients with impaired liver function

No dose adjustment is required for the treatment and prevention of influenza in patients with mild to moderate hepatic impairment. The safety and pharmacokinetics of oseltamivir in patients with severe hepatic impairment have not been studied.

Elderly and senile patients

No dose adjustment is required to prevent or treat influenza.

Immunocompromised patients (after transplantation)

For seasonal prevention of influenza in immunocompromised patients aged ≥1 year – for 12 weeks, no dose adjustment is required.

Children

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

Extemporal preparation of Nomides®suspension

In cases where adults, adolescents and children have a problem swallowing capsules, 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 (maximum 1 teaspoon) of a suitable sweetened food product (see above) in order to hide the bitter taste. The mixture must be thoroughly mixed and given to the patient as a whole. You should swallow the mixture immediately after cooking.

CAPSULES 75 MG

If patients require a dose of 75 MG, the following instructions should be followed::

1. Holding one 75 mg Nomides ® capsule over a small container, carefully open the capsule and pour the powder into the container.

2. Add a small amount (no more than 1 teaspoon) of a suitable sweetened food product (to hide the bitter taste) and mix well.

3. Mix the mixture thoroughly and drink it immediately after cooking. If there is a small amount of the mixture left in the container, then rinse the container with a small amount of water and drink the remaining mixture.

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

1. While holding one 75 mg capsule of Nomides® over a small container, carefully open the capsule and pour the powder into the container.

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

3. Fill the syringe with the required amount of mixture from the container according to the table below:

Body weight	Recommended dose	Quantity of Nomides ® blend per dose
≤15 kg	30 mg	2 ml
>15-23 kg>	45 mg	3 ml
>23-40 kg>	60 mg	4 ml

There is no need to collect undissolved white powder, since it is an inactive filler. By pressing the plunger of the syringe, insert all its contents into the second container. The remaining unused mixture must be discarded.

4. In the second container, add a small amount (no more than 1 teaspoon) of a suitable sweetened food product to hide the bitter taste, and mix well.

5. Mix the mixture thoroughly and drink it immediately after cooking. If there is a small amount of the mixture left in the container, then rinse the container with a small amount of water and drink the remaining mixture.

This procedure should be repeated before each dose of the drug.

30 MG AND 45 MG CAPSULES

FOR PROPER DOSING, FOLLOW THE FOLLOWING INSTRUCTIONS:

1. Determine the required number of Nomides ® capsules required to prepare the mixture:

BODY WEIGHT*	NUMBER OF NOMIDES® CAPSULES TO PROVIDE THE RECOMMENDED DOSE FOR THE FOLLOWING PURPOSES: TREATMENT OPTIONS WITHIN 5 DAYS	NUMBER OF NOMIDES® CAPSULES TO PROVIDE THE RECOMMENDED DOSE FOR THE FOLLOWING PURPOSES: PROPHYLAXIS
≤15 kg	1 capsule 30 mg 2 times / day	1 capsule 30 mg 1 time / day
>15-23 kg>	1 capsule 45 mg 2 times/day	1 capsule 45 mg 1 time / day
>23-40 kg>	2 capsules 30 mg 2 times/day	2 capsules 30 mg 1 time/day

* Children weighing >40 kg or aged 8-12 years and adults can receive Nomides® by using one capsule of 45 mg + one capsule of 30 mg 2 times a day for treatment or 1 time a day for prevention.

2. Make sure that the correct dosage of the drug is used (according to the table above). While holding one or more Nomides ® capsules over a small container, carefully open one or more capsules and pour the powder into the container.

3. Add a small amount (no more than 1 teaspoon) of a suitable sweetened food product to hide the bitter taste, and mix well.

4. Mix the mixture thoroughly and drink it immediately after cooking. If there is a small amount of the mixture left in the container, then rinse the container with a small amount of water and drink the remaining mixture.

Repeat this procedure before each dose of the drug.

Overdose

In most cases, overdose during clinical trials and post-marketing use of oseltamivir was not accompanied by any adverse events. In all other cases, the symptoms of overdose corresponded to the adverse events presented in the “Side effect” section.

Special instructions

Extemporal preparation of Nomides® suspension from capsules

In cases where adults, adolescents and children have problems swallowing capsules 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 (maximum 1 teaspoon) of a suitable sweetened food product (chocolate syrup with normal sugar content or without sugar content, honey, light brown sugar or table sugar dissolved in water, sweet dessert, condensed milk with sugar, applesauce or yogurt) in order to hide the bitter taste. The mixture must be thoroughly mixed and given to the patient as a whole. You should swallow the mixture immediately after cooking.

Capsules 75 mg

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

1. Holding one 75 mg Nomides ® capsule over a small container, carefully open the capsule and pour the powder into the container.

2. Add a small amount (no more than 1 teaspoon) of a suitable sweetened food product (to hide the bitter taste) and mix well.

3. Mix the mixture thoroughly and drink it immediately after cooking. If there is a small amount of the mixture left in the container, then rinse the container with a small amount of water and drink the remaining mixture.

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

1. Holding one 75 mg Nomides ® capsule over a small container, carefully open the capsule and pour the powder into the container.

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

3. Fill the syringe with the required amount of mixture from the container according to the following table.

Body weight	Recommended dose	Quantity of Nomides ® blend per 1 dose
≤15 kg	30 mg	2 ml
>15-23 kg>	45 mg	3 ml
>23-40 kg>	60 mg	4 ml

There is no need to collect undissolved white powder, since it is an inactive filler. By pressing the plunger of the syringe, insert all its contents into the second container. The remaining unused mixture must be discarded.

4. In the second container, add a small amount (no more than 1 teaspoon) of a suitable sweetened food product to hide the bitter taste, and mix well.

5. Mix the mixture thoroughly and drink it immediately after cooking. If there is a small amount of the mixture left in the container, then rinse the container with a small amount of water and drink the remaining mixture.

This procedure should be repeated before each dose of the drug.

Form of production

Capsules for oral use 10 pieces per pack

Active ingredient

Oseltamivir

Conditions of release from pharmacies

By prescription

Dosage form

Capsules