Flucap

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUCAP (FLUCAP)

Composition:

Active substance: oseltamivir;

1 capsule contains oseltamivir phosphate equivalent to oseltamivir 30 mg, or 45 mg, or 75 mg;

Excipients: pregelatinized starch, sodium croscarmellose, povidone, talc, sodium stearyl fumarate, hard gelatin capsules;

capsule shell:

30 mg capsules: iron oxide red, iron oxide yellow, titanium dioxide, gelatin, blue ink;

45 mg capsules: iron oxide black, titanium dioxide, gelatin, blue ink;

75 mg capsules: iron oxide red, iron oxide yellow, iron oxide black, titanium dioxide, gelatin, blue ink.

Pharmaceutical form. Capsules.

Main physico-chemical properties:

30 mg capsules: hard gelatin capsules, size "4", with an opaque light-yellow cap and an opaque light-yellow body, marked with blue ink "H" on the cap and "33" on the body, filled with granular powder of white or almost white color;

45 mg capsules: hard gelatin capsules, size "4", with an opaque grey cap and an opaque grey body, marked with blue ink "H" on the cap and "32" on the body, filled with granular powder of white or almost white color;

75 mg capsules: hard gelatin capsules, size "2", with an opaque light-yellow cap and an opaque grey body, marked with blue ink "H" on the cap and "5" on the body, filled with granular powder of white or almost white color.

Pharmacotherapeutic group. Antiviral agents for systemic use. Direct-acting antiviral agents. Neuraminidase inhibitors. Oseltamivir. ATC code J05A H02.

Pharmacological properties.

Pharmacodynamics.

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

Oseltamivir carboxylate inhibits neuraminidase of influenza types A and B viruses in vitro. Oseltamivir phosphate inhibits influenza virus and influenza virus replication in vitro. Following oral administration, oseltamivir suppresses replication and pathogenicity of influenza types A and B viruses in vivo in animal models of influenza infection at antiviral concentrations similar to those achieved in humans at a dose of 75 mg twice daily.

Antiviral activity of oseltamivir has been demonstrated against influenza types A and B viruses in experimental studies involving 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 were 2.6 nmol. In these published studies, higher IC₅₀ values for influenza B viruses were reported, with a median of 8.5 nmol.

Resistance to oseltamivir

Clinical studies. The risk of emergence of influenza viruses with reduced susceptibility or marked resistance to oseltamivir was evaluated during clinical trials. Development of resistance to oseltamivir during treatment was observed more frequently in children than in adults, ranging from less than 1% in adults to 18% in infants under 1 year of age. Children shedding oseltamivir-resistant virus generally excreted the virus for a longer duration compared to those with non-resistant virus. However, treatment-emergent resistance to oseltamivir did not affect treatment response and did not prolong influenza symptom duration.

Overall, a higher frequency of oseltamivir resistance was observed in immunocompromised adults and adolescents who received standard or double-dose oseltamivir for 10 days [14.5% (10/69) in the standard-dose group and 2.7% (2/74) in the double-dose group], compared to data from studies in otherwise healthy adults and adolescents receiving oseltamivir treatment. Most adult patients who developed resistance were post-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 type A virus and shed the virus for a longer duration.

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

Frequency of development of oseltamivir resistance in clinical studies

*Complete genotyping was not performed in all studies.

Influenza prophylaxis

To date, no evidence of drug resistance associated with the use of oseltamivir has been observed in clinical studies of post-exposure influenza prophylaxis (7 days), household post-exposure prophylaxis (10 days), or seasonal influenza prophylaxis (42 days) in immunocompromised patients. Resistance was not observed during a 12-week prophylaxis study in immunocompromised patients.

Clinical and surveillance data. Influenza A and B viruses isolated from patients not treated with oseltamivir have shown naturally occurring mutations associated with reduced susceptibility to oseltamivir in vitro. Resistant strains selected during oseltamivir treatment have been isolated from patients with both normal and impaired immunity. The risk of developing oseltamivir resistance during antiviral treatment is higher in immunocompromised patients and in younger children.

Resistant influenza viruses isolated from patients receiving oseltamivir treatment, as well as oseltamivir-resistant laboratory strains, have been found to carry mutations in neuraminidases N1 and N2. Resistance mutations tended to be subtype-specific. Since 2007, sporadic naturally occurring resistance associated with the H275Y mutation has been detected in seasonal H1N1 strains. Susceptibility to oseltamivir and the prevalence of such viruses have been shown to vary seasonally and geographically. In 2008, H275Y was detected in >99% of circulating H1N1 influenza isolates in Europe. In 2009, the H1N1 influenza virus ("swine flu") was almost uniformly susceptible to oseltamivir, although sporadic reports of resistance during treatment and prophylaxis were received.

Pharmacokinetics.

Absorption

After oral administration, oseltamivir phosphate (a prodrug) is readily absorbed in the gastrointestinal tract and is extensively converted to the active metabolite (oseltamivir carboxylate) primarily by hepatic esterases. At least 75% of the orally administered dose reaches systemic circulation as the active metabolite, and less than 5% as the prodrug. Plasma concentrations of both the prodrug and the active metabolite are dose-proportional and are not affected by concomitant food intake.

Distribution

In humans, the mean volume of distribution of oseltamivir carboxylate at steady state is approximately 23 L, which corresponds to the volume of extracellular fluid in the body. Since neuraminidase activity is extracellular, oseltamivir carboxylate reaches all major sites of influenza infection.

Plasma protein binding of oseltamivir carboxylate is low (approximately 3%).

Metabolism

Oseltamivir is extensively converted to oseltamivir carboxylate by esterases, primarily located in the liver. Neither oseltamivir nor the active metabolite are substrates or inhibitors of cytochrome P450 isoenzymes in in vitro studies. No phase 2 conjugates of either compound have been identified in vivo.

Elimination

Absorbed oseltamivir is eliminated primarily (>90%) by conversion to oseltamivir carboxylate, which undergoes no further transformation and is excreted in urine. In most patients, the maximum plasma concentration of oseltamivir carboxylate declines with an elimination half-life of 6–10 hours. The active metabolite is eliminated almost entirely (>99%) by the kidneys. Renal clearance (18.8 L/h) exceeds glomerular filtration rate (7.5 L/h), indicating that the drug is also eliminated via tubular secretion. Less than 20% of an orally administered radiolabeled dose is excreted in feces.

Pharmacokinetics in special populations

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

Elderly patients. Steady-state exposure to the active metabolite was 25–35% higher in elderly individuals (aged 65–78 years) compared to adults under 65 years receiving comparable doses of oseltamivir. The elimination half-life in elderly individuals was similar to that in younger patients. Given drug exposure and tolerability, dose adjustment is not required for elderly patients in the absence of moderate or severe renal impairment (creatinine clearance <60 mL/min) (see section "Dosage and administration").

Patients with renal impairment. Administration of 100 mg oseltamivir phosphate twice daily for 5 days to patients with varying degrees of renal impairment demonstrated that exposure to oseltamivir carboxylate is inversely proportional to the degree of renal function decline. For dosing recommendations, see section "Dosage and administration".

Patients with hepatic impairment. In vitro studies indicate that significant increases in oseltamivir exposure or significant decreases in active metabolite exposure are not expected in patients with hepatic dysfunction (see section "Dosage and administration").

Pregnant women. A combined population pharmacokinetic analysis indicates that the oseltamivir phosphate dosing regimen described in the section "Dosage and administration" results in lower exposure (on average 30% across all trimesters) to the active metabolite in pregnant women compared to non-pregnant women. However, the predicted lower exposure remains above inhibitory concentrations (IC95) for a range of influenza virus strains. Additionally, observational study data support the benefit of this dosing regimen in this patient population. Therefore, dose adjustment in pregnant women for the treatment or prophylaxis of influenza is not required (see section "Use during pregnancy or breastfeeding").

Immunocompromised patients. Population pharmacokinetic analyses have shown that administration of oseltamivir in immunocompromised adults and children (<18 years) results in increased predicted exposure (approximately 5–50%) to the active metabolite compared to patients with normal immunity and comparable creatinine clearance. Given the wide safety margin of the active metabolite, dose adjustment is not required for immunocompromised patients. However, for immunocompromised patients with impaired renal function, the dose should be adjusted according to recommendations in the section "Dosage and administration".

Analysis of pharmacokinetic and pharmacodynamic data from two studies involving immunocompromised patients demonstrated no significant additional benefit from doses exceeding the standard dose.

Clinical characteristics.

Indications.

Influenza treatment

Flucap is indicated for adults and children aged 1 year and older who have symptoms typical of influenza during periods of influenza virus circulation. Efficacy has been demonstrated when treatment was initiated within two days of symptom onset.

Influenza prophylaxis

• Prevention of influenza in adults and children aged 1 year and older following close contact with an individual with clinically diagnosed influenza during periods of influenza virus circulation.
• The appropriate use of Flucap for influenza prophylaxis should be determined on a case-by-case basis, taking into account the circumstances and considering the patient population requiring protection. In exceptional situations (e.g., when there is a mismatch between the circulating influenza virus and the virus strain included in the vaccine, or during a pandemic), seasonal prophylaxis may be administered to children aged 1 year and older.

Use of Flucap does not replace influenza vaccination.

The use of antiviral agents for the treatment and prevention of influenza should be based on official recommendations. Decisions regarding the use of oseltamivir for treatment and prophylaxis should take into account characteristics of circulating influenza viruses, available data on influenza virus susceptibility to antiviral drugs each season, and the impact of the disease in different geographical regions and patient populations.

Contraindications.

Hypersensitivity to oseltamivir phosphate or to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

The pharmacokinetic properties of oseltamivir, such as weak protein binding and metabolism independent of the CYP450 and glucuronidase systems (see section "Pharmacokinetics"), suggest that clinically significant interactions with other medicinal products are unlikely.

Probenecid

No dose adjustment is required for patients with normal renal function when oseltamivir is administered concomitantly with probenecid. Concomitant administration of probenecid, a potent inhibitor of the anion pathway of renal tubular secretion, results in approximately a twofold increase in exposure to the active metabolite of oseltamivir.

Amoxicillin

Oseltamivir does not exhibit kinetic interaction with amoxicillin, which is eliminated via the same pathway as oseltamivir, suggesting minimal interaction via this route.

Renal elimination

Clinically significant interactions with other medicinal products involving competition for renal tubular secretion are unlikely due to the known safety margins of most such agents, elimination characteristics of active metabolites (glomerular filtration and anion tubular secretion), and the volume of excretion via these pathways. However, caution should be exercised when prescribing oseltamivir to patients receiving medicinal products with a similar elimination pathway and a narrow therapeutic range (e.g., chlorpropamide, methotrexate, phenylbutazone).

Additional information

No pharmacokinetic interactions were observed between oseltamivir and its active metabolite and paracetamol, acetylsalicylic acid, cimetidine, antacids (magnesium hydroxide and aluminum hydroxide, calcium carbonate), rimantadine, or warfarin (in patients receiving stable doses of warfarin and not suffering from influenza).

In Phase III clinical trials of oseltamivir for the treatment and prevention of influenza, oseltamivir phosphate was administered concomitantly with commonly used medicinal products such as angiotensin-converting enzyme inhibitors (enalapril, captopril), thiazide diuretics (bendroflumethiazide), antibiotics (penicillin, cephalosporins, azithromycin, erythromycin, and doxycycline), H2-receptor blockers (ranitidine, cimetidine), beta-blockers (propranolol), xanthines (theophylline), sympathomimetics (pseudoephedrine), opioids (codeine), corticosteroids, inhaled bronchodilators, and analgesics (acetylsalicylic acid, ibuprofen, and paracetamol). No changes in the safety profile or frequency of adverse reactions were observed when oseltamivir was used concomitantly with these medications.

There is no mechanism of interaction with oral contraceptives.

Special precautions for use.

Oseltamivir is effective only against illnesses caused by influenza viruses. There is no data on the efficacy of oseltamivir for any conditions caused by pathogens other than influenza viruses.

FlucaP medication does not replace influenza vaccination. The use of FlucaP should not affect the assessment of individuals regarding annual influenza vaccination. Protection against influenza lasts only during the administration of this medication. FlucaP should be used for treatment and prevention of influenza only when reliable epidemiological data indicate virus circulation. Susceptibility of circulating influenza virus strains to FlucaP has shown high variability; therefore, physicians should consider the most up-to-date information on circulating virus susceptibility to oseltamivir before deciding on the use of FlucaP.

Severe skin reactions and hypersensitivity reactions

Post-marketing use of oseltamivir has reported cases of anaphylaxis and severe skin reactions, including toxic epidermal necrolysis, Stevens–Johnson syndrome, and erythema multiforme. FlucaP should be discontinued and appropriate treatment initiated if such reactions occur or are suspected.

Severe underlying conditions

There is no information on the safety and efficacy of oseltamivir use in patients with severe or unstable conditions associated with an inevitable 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.

Cardiac/respiratory diseases

The efficacy of oseltamivir in treating individuals with chronic cardiac and/or respiratory diseases has not been established. In such patients, no difference in complication rates between treatment and placebo groups was observed.

Severe renal impairment

Dose adjustment of FlucaP is recommended for adults and adolescents (≥13 to <18 years) with severe renal impairment when used for treatment and prophylaxis. There is insufficient clinical data to recommend dosing in children aged 1 year and older with renal impairment (see sections "Dosage and administration", "Pharmacokinetics").

Neuropsychiatric disorders

Neuropsychiatric disorders have been reported in influenza patients (predominantly in children and adolescents) receiving oseltamivir. Such disorders have also been reported in influenza patients not treated with this drug. Patients should be closely monitored for behavioral changes, and the benefit and risk of continuing treatment should be carefully evaluated for each patient (see section "Adverse reactions").

Disposal of unused or expired medication. Environmental release of the medicinal product should be minimized. The medication must not be disposed of via wastewater or household waste. Waste should be disposed of through a designated collection system, if available.

Use during pregnancy or breastfeeding

Pregnancy

Influenza is associated with harmful effects on pregnancy outcomes, fetal development, and an increased risk of major congenital malformations, including congenital heart defects. A large amount of post-marketing and observational study data on oseltamivir use during pregnancy (more than 1000 first-trimester exposures) indicate no teratogenic or fetal/neonatal toxicity of oseltamivir.

However, in one observational study, despite no increase in overall risk of congenital malformations, results regarding major congenital heart defects diagnosed within 12 months after birth were inconclusive. In this study, the rate of major congenital heart defects following first-trimester exposure to oseltamivir was 1.76% (7 infants out of 397 pregnancies), compared to 1.01% in unexposed pregnancies in the general population (risk ratio 1.75, 95% confidence interval 0.51 to 5.98). The clinical significance of these findings is unclear due to the study's limited sample size. Additionally, the study was not sufficiently powered to reliably assess individual types of major congenital malformations; furthermore, complete comparison between women who did and did not take oseltamivir was not possible, particularly regarding whether they had influenza.

Animal studies do not indicate reproductive toxicity.

If necessary, oseltamivir use during pregnancy may be considered, taking into account available safety and efficacy data, as well as the pathogenicity of the circulating influenza virus strain.

Breastfeeding

In lactating rats, oseltamivir and its active metabolite pass into breast milk. Information is limited regarding breastfeeding mothers who have taken oseltamivir and the excretion of oseltamivir into human breast milk. According to some data, oseltamivir and its active metabolite have been detected in breast milk, but at low levels, potentially resulting in a subtherapeutic dose to the infant. Considering these data, the pathogenicity of the circulating influenza virus strain, and the mother's clinical condition, oseltamivir administration may be considered if the potential benefit to the mother is clearly evident.

Fertility

Based on preclinical data, there is no evidence of an effect of oseltamivir on fertility in men or women.

Ability to affect reaction speed when driving or operating machinery

FlucaP has no effect on the ability to drive or operate machinery.

Dosage and Administration

Administration

For oral use.

Patients who are unable to swallow capsules may receive appropriate doses of the medicinal product Flucap in the form of powder for oral suspension.

Dosage

Doses of 75 mg can be taken as:

1 capsule of 75 mg, or

1 capsule of 30 mg plus 1 capsule of 45 mg.

Adults and adolescents aged 13 years and older

Treatment. The recommended dosage regimen for the medicinal product Flucap is one 75 mg capsule taken orally twice daily for 5 days in adults and adolescents (13–17 years) with body weight over 40 kg.

For immunocompromised patients (adults and adolescents aged 13–17 years with body weight over 40 kg), the recommended dosage regimen for Flucap is one 75 mg capsule taken orally twice daily for 10 days (see section "Dosage in special situations. Immunocompromised patients" below).

Treatment should be initiated on the first or second day of onset of influenza symptoms.

Post-exposure prophylaxis. The recommended dose of Flucap for prevention of influenza after close contact with an infected individual is 75 mg once daily orally for 10 days in adults and adolescents (13–17 years) with body weight over 40 kg, including immunocompromised patients (adults and adolescents aged 13–17 years with body weight over 40 kg). Treatment should be initiated as soon as possible within two days of contact with an infected individual.

Seasonal prophylaxis during influenza season. The recommended dose for prophylaxis during seasonal influenza outbreaks is 75 mg once daily for 6 weeks (or up to 12 weeks for immunocompromised patients; see sections "Special precautions for use" and "Adverse reactions").

Children aged 1 to 12 years.

Treatment. The recommended dosage regimen for the medicinal product Flucap is one 75 mg capsule taken orally twice daily for 5 days in children aged 1 year and older with body weight over 40 kg who are able to swallow capsules.

For immunocompromised children aged 1 year and older with body weight over 40 kg who are able to swallow capsules, the recommended dosage regimen for Flucap is one 75 mg capsule taken orally twice daily for 10 days (see subsection "Dosage in special situations. Immunocompromised patients").

The recommended doses of oseltamivir according to body weight are presented in the table:

Treatment should be initiated as soon as possible, on the first or second day after the onset of influenza symptoms.

Post-exposure prophylaxis. The recommended dose of oseltamivir for post-exposure prophylaxis against influenza, based on body weight, is given in the table:

If patients have difficulty swallowing capsules or require a lower dose of the medication, it is recommended to use FluCap in the form of powder for oral suspension (6 mg/mL).

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

Dosing in special situations

Patients with hepatic impairment

There is no need to adjust the dose for treatment or prophylaxis in patients with hepatic impairment. The safety and pharmacokinetics of oseltamivir in children with hepatic impairment have not been studied.

Patients with renal impairment

Treatment of influenza. Dose adjustment of oseltamivir is required for adults and adolescents (13–17 years) with moderate or severe renal impairment, as shown in the table below:

* Data obtained from studies in patients undergoing continuous ambulatory peritoneal dialysis (CAPD); clearance of oseltamivir carboxylate is expected to be higher with automated continuous cycling peritoneal dialysis (CCPD). The treatment regimen may be changed from CCPD to CAPD if deemed necessary by the nephrologist.

Influenza prophylaxis. Dose adjustment of oseltamivir required for adults and adolescents (13–17 years) with moderate or severe renal impairment is shown in the table:

* Data obtained from studies in patients undergoing continuous ambulatory peritoneal dialysis (CAPD); clearance of oseltamivir carboxylate is expected to be higher with automated continuous cycling peritoneal dialysis (CCPD). Treatment regimens may be switched from CCPD to CAPD if deemed necessary by the nephrologist.

There are insufficient clinical data to provide dosing recommendations for children under 12 years of age with impaired renal function.

Elderly patients

No dose adjustment is required, except in cases of moderate or severe renal impairment.

Immunocompromised patients

Treatment. The recommended duration of influenza treatment in immunocompromised patients is 10 days (see sections "Dosage and Administration", "Adverse Reactions"). Dose adjustment is not required. Treatment should be initiated as soon as possible within the first two days of onset of influenza symptoms.

Seasonal prophylaxis. Longer durations (up to 12 weeks) of seasonal prophylaxis have been studied in immunocompromised patients (see sections "Dosage and Administration", "Adverse Reactions").

Children

Safety data on the use of oseltamivir for the treatment of influenza in children aged 1 year and older, derived from prospective and retrospective observational studies, epidemiological data, and post-marketing experience, indicate that the safety profile in children aged 1 year and older is comparable to the established safety profile in adults.

Indicated for children aged 1 year and older with body weight above 10 kg who are able to swallow a capsule.

Overdose.

Reports of overdose were received during clinical trials and post-marketing use of the medicinal product Flucap. In most cases, no adverse reactions were reported.

Adverse reactions reported in cases of overdose were similar in nature and type to those observed with therapeutic doses of Flucap (see section "Adverse Reactions").

There is no specific antidote.

Children

Overdose was reported more frequently in children than in adults and adolescents. Caution should be exercised when administering the medicinal product Flucap to children.

Side effects

In adults and adolescents receiving oseltamivir for treatment of influenza, the most commonly reported adverse events were nausea and vomiting; for prophylaxis of influenza, the most common adverse event was nausea. These events were generally transient, typically occurring on the first or second day of treatment and resolving within 1–2 days. In children, the most common adverse event was vomiting. In most cases, adverse reactions did not lead to discontinuation of the drug.

During post-marketing use of oseltamivir, rare serious adverse reactions have been reported: anaphylactic and anaphylactoid reactions, hepatic disorders (fulminant hepatitis, liver function abnormalities, and jaundice), angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, gastrointestinal bleeding, and neuropsychiatric disorders (for neuropsychiatric disorders, see section "Special precautions").

The following frequency categories were used to describe adverse reactions: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000). Adverse reactions were assigned to a specific category based on analysis of pooled data from clinical trials.

Treatment and prophylaxis of influenza in adults and adolescents

Below are the most frequently reported adverse reactions observed in clinical studies of oseltamivir for treatment and prophylaxis of influenza in adults and adolescents, as well as in post-marketing experience at the recommended dose (75 mg twice daily for 5 days for treatment, and 75 mg once daily for up to 6 weeks for prophylaxis).

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

Infections and infestations: common — bronchitis, herpes simplex, upper respiratory tract infections, nasopharyngitis, sinusitis;

Blood and lymphatic system disorders: rare — thrombocytopenia;

Immune system disorders: uncommon — hypersensitivity reaction; rare — anaphylactic and anaphylactoid reactions;

Psychiatric disorders: rare — agitation, abnormal behavior, anxiety, confusion, delirium, hallucinations, nightmares, self-injury;

Nervous system disorders: very common — headache; common — insomnia; uncommon — impaired consciousness, convulsions;

Eye disorders: rare — visual disturbances;

Cardiac disorders: uncommon — cardiac arrhythmias;

Respiratory, thoracic and mediastinal disorders: common — cough, rhinorrhea, sore throat;

Gastrointestinal disorders: very common — nausea; common — vomiting, abdominal pain (including upper abdomen), dyspepsia; rare — gastrointestinal bleeding, hemorrhagic colitis;

Hepatobiliary disorders: uncommon — increased liver enzymes; rare — fulminant hepatitis, liver failure, hepatitis;

Skin and subcutaneous tissue disorders: uncommon — dermatitis, rash, eczema, urticaria; rare — angioedema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis; frequency not known — allergy, facial swelling;

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

Treatment and prophylaxis of influenza in children

The most commonly reported adverse reactions observed in clinical studies of oseltamivir for treatment and prophylaxis of influenza in children (using age-based dosing from 30 mg to 75 mg once daily):

Infections and infestations: common — otitis media; frequency not known — bronchitis, pneumonia, sinusitis;

Nervous system disorders: common — headache;

Blood and lymphatic system disorders: frequency not known — lymphadenopathy;

Eye disorders: common — conjunctivitis (including eye redness, eye discharge, and pain);

Ear and labyrinth disorders: common — ear pain; uncommon — tympanic membrane disorders;

Respiratory, thoracic and mediastinal disorders: very common — cough, nasal congestion; common — rhinorrhea; frequency not known — asthma (including exacerbations), epistaxis;

Gastrointestinal disorders: very common — vomiting; common — nausea, abdominal pain (including upper abdomen), dyspepsia; frequency not known — diarrhea;

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

Description of selected adverse reactions

Psychiatric and neurological disorders

Influenza itself may be associated with neuropsychiatric disorders, manifesting as hallucinations, delirium, and abnormal behavior, sometimes with fatal outcomes. These events may occur as manifestations of encephalitis or encephalopathy, but may also occur without apparent severe illness.

In patients with influenza receiving oseltamivir, cases of convulsions and delirium (including altered level of consciousness, confusion, abnormal behavior, hallucinations, nightmares, agitation, anxiety) have been reported. In rare cases, these events led to accidental self-injury or death. These events were mainly observed in children and adolescents and often had sudden onset and rapid resolution. It is unknown whether these neuropsychiatric events are related to oseltamivir use, as similar neuropsychiatric disorders have also been reported in influenza patients not receiving this drug.

Hepatobiliary disorders

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

Additional information on specific patient groups

Elderly patients and patients with chronic heart or respiratory diseases

The study population for influenza treatment included healthy adults/adolescents and patients with risk factors (e.g., elderly patients and those with chronic heart or respiratory diseases). Overall, the safety profile in adolescents and adults with chronic heart and/or respiratory diseases was qualitatively similar to that in healthy volunteers.

Immunocompromised patients

Influenza treatment in immunocompromised patients was studied in two trials using standard or high (double or triple) doses of oseltamivir. The safety profile of oseltamivir in these studies was consistent with that observed in previous clinical trials in non-immunocompromised patients of all age groups (patients without other diseases or those with risk factors [concomitant heart and/or respiratory diseases]). The most common adverse reaction in immunocompromised children was vomiting (28%).

Children with bronchial asthma

Overall, the adverse reaction profile in children with bronchial asthma was qualitatively similar to that in children without other diseases.

Reporting of adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 ºC, in a place inaccessible to children.

Packaging.

10 capsules in a blister. 1 blister in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address.

Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.