Agrippa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AGRIPPA (AGRYPPA)

Composition:

Active substance: oseltamivir;

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

Excipients:

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

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

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics: white granular or slightly compacted powder in a size 2 capsule; white opaque body, dark yellow cap.

Markings: OS in black (on the cap), 75 in black (on the body).

Pharmacotherapeutic group. Antiviral agents for systemic use. Direct-acting antiviral agents. Neuraminidase inhibitors. Oseltamivir. ATC code J05AH02.

Pharmacological properties.

Pharmacodynamics.

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

Oseltamivir carboxylate inhibits neuraminidase of influenza virus types A and B in vitro. Oseltamivir phosphate inhibits viral replication and pathogenicity in vitro. Orally administered oseltamivir inhibits replication and pathogenicity of influenza virus types A and B in animal models of influenza infection in vivo at antiviral exposures achieved in humans receiving a dose of 75 mg twice daily.

The antiviral activity of oseltamivir has been demonstrated against influenza virus types A and B in experimental studies in healthy volunteers.

The IC50 values of oseltamivir for the neuraminidase enzyme of clinical isolates of influenza virus A ranged from 0.1 nmol to 1.3 nmol, and for influenza virus B were 2.6 nmol. Published study data reported higher IC50 values for influenza virus B, 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 has been evaluated in 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 clinical response and did not lead to prolonged influenza symptoms.

Overall, higher rates of oseltamivir resistance were observed in immunocompromised adults and adolescents receiving 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 involving immunocompetent adults and adolescents receiving oseltamivir treatment. Most adult patients who developed resistance were transplant recipients (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 virus type A and shed the virus for a prolonged period.

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

Frequency of oseltamivir resistance development in clinical trials

Population of patients	Patients with resistance mutations (%)
	Phenotyping*	Geno- and phenotyping*
Adults and adolescents	0.88% (21/2382)	1.13% (27/2396)
Children (1–12 years)	4.11% (71/1726)	4.52% (78/1727)
Infants (<1 year)	18.31% (13/71)	18.31% (13/71)

*Full genotyping was not performed in all studies.

Influenza prophylaxis. There is no evidence of resistance to the medicinal product associated with the use of oseltamivir in clinical studies conducted to date on post-exposure prophylaxis (7 days), household contacts after exposure (10 days), and seasonal influenza prophylaxis (42 days) in immunocompromised patients. During a 12-week prophylaxis study in immunocompromised patients, no emergence of resistance was observed.

Clinical and surveillance data. In influenza viruses A and B isolated from patients without exposure to oseltamivir, natural mutations associated with reduced sensitivity to oseltamivir have been identified in vitro. Resistant strains selected during oseltamivir treatment have been isolated from patients with normal and compromised immunity. The risk of developing resistance to oseltamivir during viral 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, naturally occurring resistance associated with the H275Y mutation has been sporadically detected in seasonal H1N1 strains. Sensitivity 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 isolates in Europe. In 2009, the H1N1 influenza virus ("swine flu") was almost uniformly sensitive to oseltamivir, although sporadic reports of resistance during treatment and prophylaxis were received.

Pharmacokinetics.

Absorption

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

Distribution

In humans, the mean volume of distribution of the active metabolite 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 the active metabolite is low (approximately 3%).

Metabolism

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

Excretion

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 the active metabolite declines with a half-life of 6–10 hours. The fully active metabolite is eliminated by the kidneys. Renal clearance (18.8 L/h) exceeds the glomerular filtration rate (7.5 L/h), indicating that additional elimination occurs via tubular secretion. Less than 20% of the orally administered radiolabeled drug is excreted in feces.

Pharmacokinetics in special populations.

Children aged 1 year and older. The pharmacokinetics of oseltamivir were studied in children aged 1 to 16 years in a single-dose pharmacokinetic study. Multiple-dose pharmacokinetics were studied in a small number of children in a clinical efficacy trial. 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 achieved in adults after a single 75 mg dose (equivalent to approximately 1 mg/kg). The pharmacokinetics of oseltamivir in children and adolescents aged 12 years and older are similar to those in adults.

Elderly patients. In elderly patients (65–78 years), steady-state exposure to the active metabolite is 25–35% higher than in younger patients (<65 years) when similar doses of oseltamivir are administered. The elimination half-life in elderly individuals is similar to that in younger patients. Based on drug exposure and tolerability, dose adjustment is not necessary for elderly patients, except for those with moderate or severe renal impairment (creatinine clearance <60 mL/min) (see section "Dosage and administration").

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

Patients with hepatic impairment. Based on in vitro studies, no significant increase in oseltamivir exposure or significant decrease in exposure to the active metabolite is expected in patients with hepatic impairment (see section "Dosage and administration").

Pregnant women. Population pharmacokinetic analyses indicate that the dosing regimen of oseltamivir 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 reduced predicted exposure remains above inhibitory concentrations (IC95 values) and within the range effective against influenza virus strains. Additionally, observational study data support the benefit of the current dosing regimen in this patient group. Therefore, dose adjustment is not recommended for pregnant women during treatment or prophylaxis of influenza (see section "Use during pregnancy or breastfeeding").

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

The medicinal product Agrippa is indicated for adults and children aged 1 year and older who have influenza symptoms during influenza virus circulation. Efficacy has been demonstrated when treatment was initiated within 2 days of the first appearance of symptoms.

Influenza prophylaxis

• Prevention of influenza in adults and children aged 1 year and older following close contact with a person with clinically diagnosed influenza during influenza virus circulation.
• The appropriate use of Agrippa for influenza prophylaxis should be determined on a case-by-case basis, taking into account the circumstances and considering the patient group requiring protection. In exceptional situations (e.g., in case of a mismatch between the circulating influenza virus and the influenza virus strain used in vaccination, or during a pandemic), seasonal prophylaxis may be conducted in individuals aged 1 year and older.

Use of Agrippa does not replace influenza vaccination.

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

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 via these mechanisms are unlikely.

Probenecid

No dose adjustment is required for oseltamivir when co-administered with probenecid in patients with normal renal function. Concomitant administration of probenecid, a potent inhibitor of the renal tubular anion secretion pathway, 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, indicating minimal interaction via this route.

Renal excretion

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, characteristics of elimination of active metabolites (glomerular filtration and anion tubular secretion), and the extent of excretion via these pathways. However, caution should be exercised when prescribing oseltamivir to patients taking medicinal products with a similar excretion pathway and a narrow therapeutic index (e.g., chlorpropamide, methotrexate, phenylbutazone).

Additional information

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

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

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 illnesses caused by pathogens other than influenza viruses.

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

Severe skin reactions and hypersensitivity reactions

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

Severe concomitant conditions

There is no information on the safety and efficacy of oseltamivir use in patients with severe or unstable underlying diseases 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 for treatment in individuals with chronic cardiac and/or respiratory diseases has not been established. In such patients, no difference in complication rates was observed between treatment and placebo groups.

Severe renal impairment

Dose adjustment of oseltamivir is recommended for adults and adolescents (13–17 years) with severe renal impairment when used for treatment and prophylaxis. There is insufficient clinical data on use in children aged 1 year and older with renal impairment to provide dosing recommendations (see sections "Pharmacokinetics" and "Dosage and administration").

Neuropsychiatric disorders

Neuropsychiatric events have been observed in influenza patients (predominantly in children and adolescents) receiving oseltamivir. Such events have also been reported in influenza patients not treated with oseltamivir. Close monitoring of patients is required to detect behavioral changes, and the benefit-risk balance of continuing treatment should be carefully evaluated for each patient (see section "Adverse reactions").

Disposal of unused or expired medication.
Medicinal products should not enter the environment. Do not dispose of the medicine via wastewater or household waste. Disposal should be performed through a designated waste collection system, if available.

Excipients

Sodium. This medicinal product contains less than 1 mmol of sodium (23 mg) per capsule, i.e., it is essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Influenza is associated with adverse effects on pregnancy outcomes, fetal development, and an increased risk of major congenital malformations, including congenital heart defects. Extensive 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, while no increased overall risk of congenital malformations was observed, 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 oseltamivir exposure was 1.76% (7 infants out of 397 pregnancies), compared to 1.01% in pregnancies without oseltamivir exposure 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, and complete comparability between oseltamivir-exposed and unexposed women, including whether they had influenza, could not be established.

Animal studies do not indicate reproductive toxicity.

The need for oseltamivir use during pregnancy may be considered based on 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 are excreted into milk. There is very limited information on infants whose mothers received oseltamivir during lactation and on the excretion of oseltamivir into human breast milk. Limited data show that oseltamivir and its active metabolite are present in breast milk, but at low levels, potentially resulting in subtherapeutic exposure in infants. Considering these data, as well as the pathogenicity of the circulating influenza virus strain and the mother's clinical condition, oseltamivir may be considered if there is a clear potential benefit to the breastfeeding woman.

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.

This medicinal product does not affect the ability to drive or operate machinery.

Method of Administration and Dosage

Method of Administration

For oral use. Patients who cannot swallow capsules may receive appropriate doses as oseltamivir suspension.

Dosage

Adults and Adolescents Aged 13 Years and Older

Treatment. The recommended dosage regimen of Agrippa is one 75 mg capsule taken orally twice daily for 5 days in adults and adolescents (13–17 years) weighing more than 40 kg.

For immunocompromised patients (adults and adolescents aged 13–17 years weighing more than 40 kg), the recommended dosage regimen of Agrippa is one 75 mg capsule taken orally twice daily for 10 days (see subsection "Dosage in Special Situations. Immunocompromised Patients").

Treatment should be initiated as soon as possible, within the first two days of onset of influenza symptoms.

Post-Exposure Prophylaxis. The recommended dose of Agrippa for influenza prophylaxis following close contact with an infected individual is 75 mg once daily orally for 10 days in adults and adolescents (13–17 years) weighing more than 40 kg, including immunocompromised patients (adults and adolescents aged 13–17 years weighing more than 40 kg). Treatment should be initiated as soon as possible, within two days of exposure to an infected individual.

Seasonal Prophylaxis During Influenza Epidemic. 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 Warnings and Precautions for Use" and "Undesirable Effects").

Children Aged 1 to 12 Years

Treatment. The recommended dosage regimen of Agrippa is one 75 mg capsule taken orally twice daily for 5 days in children aged 1 year and older weighing more than 40 kg who are able to swallow capsules.

For immunocompromised children aged 1 year and older weighing more than 40 kg who are able to swallow capsules, the recommended dosage regimen of Agrippa is one 75 mg capsule taken orally twice daily for 10 days (see subsection "Dosage in Special Situations. Immunocompromised Patients").

Treatment should be initiated as soon as possible, within the first two days of onset of influenza symptoms.

Post-Exposure Prophylaxis. The recommended dosage regimen of Agrippa is one 75 mg capsule taken orally once daily for 10 days in children aged 1 year and older weighing more than 40 kg (including immunocompromised children) who are able to swallow capsules, for prophylaxis following contact with an influenza-infected individual.

Seasonal Prophylaxis During Influenza Epidemic. Efficacy and safety of seasonal prophylaxis during influenza epidemics have not been studied in children under 12 years of age.

Dosage in Special Situations

Patients with Hepatic Impairment

Dosage adjustment is not required for treatment or prophylaxis in patients with hepatic impairment. Safety and pharmacokinetics of oseltamivir in children with hepatic impairment have not been studied.

Patients with Renal Impairment

Treatment of Influenza. Agrippa 75 mg capsules should not be administered to adults and adolescents (13–17 years) with severe or moderate renal impairment (creatinine clearance ≤60 mL/min), as dose reduction is required (in such cases, other formulations of oseltamivir should be used, e.g., 30 mg capsules or oral suspension powder). For creatinine clearance >60 mL/min, the recommended treatment dose is 75 mg twice daily.

Prophylaxis of Influenza. Agrippa 75 mg capsules should not be administered to adults and adolescents (13–17 years) with severe or moderate renal impairment (creatinine clearance ≤60 mL/min), as dose reduction is required (in such cases, other formulations of oseltamivir should be used, e.g., 30 mg capsules or oral suspension powder). For creatinine clearance >60 mL/min, the recommended prophylactic dose is 75 mg once daily.

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

Elderly Patients

Dosage adjustment is not 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 "Special Warnings and Precautions for Use" and "Undesirable Effects"). 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 duration (up to 12 weeks) of seasonal prophylaxis has been studied in immunocompromised patients (see sections "Special Warnings and Precautions for Use" and "Undesirable Effects").

Children

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

Oseltamivir is indicated for use in children aged 1 year and older weighing more than 40 kg who are able to swallow capsules.

Overdose

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

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

No specific antidote is known.

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

Adverse Reactions

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

In adults/adolescents receiving oseltamivir in treatment trials, the most commonly reported adverse reactions were nausea and vomiting; in prophylaxis trials, nausea was the most common adverse reaction. Most of these adverse reactions were reported as single events, were transient in nature, typically occurred on the first or second day of treatment, and resolved spontaneously within 1–2 days. In children, the most common adverse event was vomiting. In the majority of cases, these adverse reactions did not lead to discontinuation of oseltamivir.

During post-marketing use of oseltamivir, rare reports of serious adverse reactions have included anaphylactic and anaphylactoid reactions, hepatic disorders (fulminant hepatitis, liver function abnormalities, and jaundice), angioedema, Stevens–Johnson syndrome, toxic epidermal necrolysis, gastrointestinal hemorrhage, and neuropsychiatric disorders (for neuropsychiatric disorders, see section "Special Warnings and Precautions for Use").

Adverse reactions are categorized by frequency as follows: 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); frequency not known (cannot be estimated from available data). Adverse reactions have been assigned to specific categories based on analysis of pooled clinical trial data.

Treatment and Prophylaxis of Influenza in Adults and Adolescents

The most commonly observed adverse reactions reported in clinical trials of oseltamivir for treatment and prophylaxis of influenza in adults and adolescents, as well as during post-marketing use 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), are listed below.

The safety profile observed in patients receiving oseltamivir at the recommended prophylactic dose (75 mg once daily for up to 6 weeks) was similar to that observed in treatment trials, 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 behaviour, anxiety, confusion, delirium, hallucinations, nightmares, self-injury.

Nervous system disorders: very common – headache; common – insomnia; uncommon – disturbance in consciousness, seizures.

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 in upper abdomen), dyspepsia; rare – gastrointestinal hemorrhage, hemorrhagic colitis.

Hepatobiliary disorders: uncommon – increased levels of 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

Overall, 1473 children (including healthy children aged 1–12 years and children with asthma aged 6–12 years) participated in clinical trials of oseltamivir for treatment of influenza. Among them, 851 children received treatment with oseltamivir suspension. A total of 158 children received the recommended dose of oseltamivir once daily in household transmission prophylaxis studies (n=99), in 6-week seasonal prophylaxis studies (n=49), and in 12-week seasonal prophylaxis studies in immunocompromised children (n=10).

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

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 eye pain).

Ear and labyrinth disorders: common – ear pain; uncommon – tympanic membrane disorder.

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 in 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 a variety of neurological and behavioural symptoms, which may include hallucinations, delirium, and abnormal behaviour, sometimes resulting in 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, post-marketing cases of seizures and delirium (including symptoms such as altered level of consciousness, confusion, abnormal behaviour, delusions, hallucinations, agitation, anxiety, and nightmares) have been reported. In some cases, these events led to accidental self-injury or fatal outcomes. These events were primarily observed in children and adolescents and often had sudden onset and rapid resolution. It is unknown whether neuropsychiatric events are related to oseltamivir use, as such disorders have also been reported in influenza patients not treated with this drug.

Hepatobiliary Disorders

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

Additional Information on Specific Patient Groups

Elderly Patients and Patients with Chronic Cardiac and/or Respiratory Diseases

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

Immunocompromised Patients

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

In a 12-week prophylaxis study involving 475 immunocompromised individuals, including 18 children aged 1–12 years, the safety profile in 238 patients receiving oseltamivir was comparable to that observed in clinical trials of oseltamivir for prophylaxis.

Children with Bronchial Asthma

The overall adverse reaction profile in children with bronchial asthma was qualitatively similar to that observed in otherwise healthy children.

Reporting of Suspected Adverse Reactions. All suspected adverse reactions and lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua/.

Shelf Life. 6 years.

Storage Conditions. The medicinal product does not require special storage conditions. Store out of reach of children.

Packaging. 10 hard capsules in a blister, 1 blister per cardboard box.

Prescription Status. Prescription only.

Manufacturer. Balkanpharma-Dupnitsa AD.

Manufacturer's Address and Place of Business.
3 Samokovsko Shose Street, Dupnitsa, 2600, Bulgaria.