Azelta

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZELTA (AZELTA)

Composition:

Active substance: oseltamivir;

One tablet contains oseltamivir 75.00 mg in the form of oseltamivir phosphate 98.50 mg;

Excipients: microcrystalline cellulose (type 102), crospovidone, microcrystalline cellulose (type 101), colloidal anhydrous silicon dioxide, povidone, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round, biconvex tablets.

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).

The active metabolite is a selective inhibitor of the viral neuraminidase enzyme of influenza viruses, which is a glycoprotein on the surface of the virion. The activity of the viral neuraminidase enzyme is important 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 types A and B in vitro. Oseltamivir phosphate inhibits viral replication and pathogenicity in vitro. Oseltamivir, when administered orally, inhibits replication and pathogenicity of influenza types A and B viruses in animal models of influenza infection in vivo under antiviral exposure levels achieved in humans when using a dose of 75 mg twice daily.

Antiviral activity of oseltamivir has been confirmed 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. Published study data reported higher IC50 values for influenza B viruses, with a median of 8.5 nMol.

Resistance to oseltamivir

Clinical studies

The risk of emergence of influenza viruses with reduced sensitivity or marked resistance to oseltamivir was 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 carrying oseltamivir-resistant virus generally shed the virus for a longer period compared to those with non-resistant virus. However, treatment-emergent resistance to oseltamivir did not affect treatment response and did not lead to prolonged influenza symptoms.

Overall, a higher frequency of resistance to oseltamivir was 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 in otherwise healthy 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 type A virus and shed the virus for a longer duration.

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

Frequency of oseltamivir resistance development in clinical studies

* - * - *
Note: The table referenced at the end of the original text was not provided. If available, it should be included here.

*Complete genotyping was not performed in all studies.

Influenza prophylaxis

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

Clinical and observational data

Natural mutations associated with reduced susceptibility to oseltamivir have been identified in vitro in influenza A and B viruses isolated from patients not exposed to oseltamivir. Resistant strains selected during oseltamivir treatment have been isolated from patients with normal and impaired immunity. The risk of developing resistance to oseltamivir during treatment is higher in immunocompromised patients and younger children.

Resistant influenza viruses isolated from patients receiving oseltamivir treatment, as well as oseltamivir-resistant laboratory strains, have been found to contain 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 occurred during treatment and prophylaxis.

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 are not affected by concomitant food intake.

Distribution

In humans, the mean volume of distribution of the active metabolite at steady state is approximately 23 L. This volume 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 phosphate is extensively converted to oseltamivir carboxylate by esterases, primarily located in the liver. Neither oseltamivir phosphate 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 the active metabolite declines with an elimination 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 the drug is additionally eliminated 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. Administration of oseltamivir at a dose of 2 mg/kg provides the same exposure to oseltamivir carboxylate as that achieved in adults after a single 75 mg dose (approximately 1 mg/kg). The pharmacokinetics of oseltamivir in children and adolescents aged 12 years and older are similar to those in adults.

Geriatric 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 patients does not differ significantly from 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 dosing 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 dysfunction (see section "Dosage and administration").

Pregnant women

A pooled population pharmacokinetic analysis indicates 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 predicted low exposure remains above inhibitory concentrations (IC95 values) and within the range of influenza virus strains at therapeutic levels. Furthermore, observational study data support the benefit of the current dosing regimen for this patient group. Therefore, dose adjustment is not recommended for pregnant women during treatment or prophylaxis of influenza (see section "Use in pregnancy or lactation").

Immunocompromised patients

Population pharmacokinetic analyses have demonstrated 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 impaired renal function, the dose should be adjusted according to the 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

Azelta is indicated for adults and children aged 6 years and older with body weight above 40 kg who have symptoms typical of influenza during 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 6 years and older with body weight above 40 kg after contact with a person clinically diagnosed with influenza during influenza virus circulation;
• appropriate use of Azelta for influenza prophylaxis should be determined on a case-by-case basis, considering circumstances and weighing the patient group requiring protection. In exceptional situations (e.g., in case of mismatch between circulating influenza virus and the virus strain used in vaccination, or during a pandemic), seasonal prophylaxis may be conducted in individuals aged 6 years and older with body weight above 40 kg.

Azelta should not replace influenza vaccination.

The use of antiviral agents for 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 characteristics of circulating influenza viruses, available data on influenza virus susceptibility to antiviral drugs each season, the impact of disease in different geographical regions, and patient population groups.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Body weight less than 40 kg.

Interaction with other medicinal products and other forms of interaction.

The pharmacokinetic properties of oseltamivir, such as low plasma protein binding and metabolism independent of the CYP450 and glucuronidation 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 co-administered with probenecid. 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 elimination

Clinically significant interaction with other medicinal products involving competition for renal tubular secretion is unlikely due to the known safety margins of most such drugs, elimination characteristics 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 between oseltamivir and its major metabolite were observed when co-administered with paracetamol, acetylsalicylic acid, cimetidine, antacids (magnesium hydroxide and aluminium 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, the drug was administered concomitantly with commonly used medicinal products such as ACE inhibitors (enalapril, captopril), thiazide diuretics (bendroflumethiazide), antibiotics (penicillin, cephalosporins, azithromycin, erythromycin, doxycycline), H2-receptor antagonists (ranitidine, cimetidine), beta-blockers (propranolol), xanthines (theophylline), sympathomimetics (pseudoephedrine), opioids (codeine), corticosteroids, inhaled bronchodilators, and analgesics (acetylsalicylic acid, ibuprofen, paracetamol). No changes in 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 for illnesses caused by influenza viruses. There are no data on the efficacy of oseltamivir for any illnesses caused by pathogens other than influenza viruses.

Oseltamivir should not be used as a substitute for influenza vaccination. The use of oseltamivir should not affect annual influenza vaccination schedules. Protection against influenza lasts only during the period of drug administration. Oseltamivir should be used for the treatment and prevention of influenza only when reliable epidemiological data indicate circulation of the virus. Susceptibility of circulating influenza virus strains to oseltamivir has been shown to vary significantly; therefore, physicians should consider the most up-to-date information on susceptibility of currently circulating influenza viruses to oseltamivir before deciding on drug 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 therapy initiated if such reactions occur or are suspected.

Severe underlying conditions

There is no information on the safety and efficacy of oseltamivir in patients with severe or unstable medical conditions associated with a high 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 of 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 treatment and prophylaxis in adults and adolescents (13–17 years) with severe renal impairment. There are insufficient clinical data on the use of oseltamivir in children with renal impairment aged 1 year and older to provide dosing recommendations (see section "Pharmacokinetics").

Neuropsychiatric disorders

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

Disposal of unused or expired medication.

Medicinal waste should be minimized in the environment. The medication must not be disposed of via wastewater or household waste. Disposal should be carried out using a dedicated waste collection system, if available.

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. A large amount of post-marketing and observational study data (over 1000 first-trimester exposure outcomes) indicate that oseltamivir does not have teratogenic or fetal/neonatal toxic effects. However, in one observational study, although no overall increase in 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 after first-trimester oseltamivir exposure 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 0.51–5.98). 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 comparison between women with and without oseltamivir exposure—including whether they had influenza—was not possible.

Animal studies do not indicate reproductive toxicity.

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

Breastfeeding

Oseltamivir and its active metabolite are excreted into breast milk in lactating rats. There is very limited information on infants breastfed by mothers receiving oseltamivir 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, likely resulting in subtherapeutic exposure in infants. Considering these data, the pathogenicity of the circulating influenza virus strain, and the mother's clinical condition, oseltamivir may be considered if the potential benefit to the breastfeeding woman is clear.

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.

Oseltamivir does not affect the ability to drive or operate machinery.

Dosage and Administration

Adults and adolescents aged 13 years and older

Treatment

The recommended dosage regimen of the medicinal product is 75 mg of oseltamivir 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 of the medicinal product is 75 mg of oseltamivir twice daily for 10 days (see section "Dosage in special situations. Immunocompromised patients").

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

Post-exposure prophylaxis following close contact with an influenza-infected individual

The recommended dose of the medicinal product Azelta for prophylaxis of influenza following close contact with an infected person is 75 mg of oseltamivir once daily 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). The medication should be initiated no later than within the first 2 days after exposure.

Prophylaxis during seasonal influenza outbreaks

The recommended dose for prophylaxis during seasonal influenza outbreaks is 75 mg of oseltamivir once daily for 6 weeks (or up to 12 weeks for immunocompromised patients; see sections "Special Warnings and Precautions for Use", "Adverse Reactions").

Children aged 6 to 13 years

Treatment

The recommended dosage regimen of the medicinal product is 75 mg of oseltamivir twice daily for 5 days in children aged 6 years and older with body weight over 40 kg who are able to swallow a tablet.

For immunocompromised children aged 6 years and older with body weight over 40 kg who are able to swallow a tablet, the recommended dosage regimen of the medicinal product is 75 mg of oseltamivir twice daily for 10 days (see section "Dosage in special situations. Immunocompromised patients").

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

Post-exposure prophylaxis following close contact with an influenza-infected individual

The recommended dose of the medicinal product Azelta is 75 mg of oseltamivir once daily for 10 days in children aged 6 years and older with body weight over 40 kg (including immunocompromised children) who are able to swallow a tablet, for prophylaxis following contact with an influenza-infected person.

Prophylaxis during seasonal influenza outbreaks

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

The tablet form of the medicinal product should not be used in neonates and children under 6 years of age. This dosage form is not intended for treatment of children with body weight less than 40 kg, nor for administration of doses lower than 75 mg. In all the above-mentioned cases, and for patients who experience difficulty swallowing tablets, oseltamivir medicinal products in an alternative pharmaceutical form and dosage are recommended.

Dosage in special situations

Patients with hepatic impairment

Dosage adjustment is not required for treatment or prophylaxis in patients with hepatic impairment. Studies in children with hepatic impairment have not been conducted.

Patients with renal impairment

Treatment of influenza. Dose adjustment of the medicinal product Azelta is required in adults and adolescents (13–17 years) with moderate or severe renal impairment (see Table 1).

Table 1

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

Influenza prophylaxis. Dose adjustment of the medicinal product Azylta is required in adults and adolescents (13–17 years) with moderate or severe renal impairment (see Table 2).

Table 2

* Data obtained from studies in patients undergoing continuous ambulatory peritoneal dialysis (CAPD); clearance of oseltamivir carboxylate is expected to be higher with automated peritoneal dialysis (APD). The treatment regimen may be changed from APD 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

There is no need to adjust the dose, 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 instructions", "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 duration (up to 12 weeks) of seasonal prophylaxis has been studied in immunocompromised patients (see sections "Special instructions", "Adverse reactions").

Route of administration

Oral.

Tablets should be swallowed whole with water.

Children.

Safety data on the use of oseltamivir for the treatment of influenza in children aged 1 year and older, obtained from prospective and retrospective observational studies, as well as from epidemiological databases 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.

The medicinal product Azielta may be administered to children aged 6 years and older with body weight exceeding 40 kg who are able to swallow tablets.

Overdose.

Cases of oseltamivir overdose have been reported during clinical trials and post-marketing use. In most cases, no adverse reactions were reported. Adverse reactions reported in cases of overdose were similar in nature and distribution to those observed with therapeutic doses of oseltamivir (see section "Adverse reactions").

No specific antidote is known.

Children

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

Adverse reactions.

The overall safety profile of oseltamivir is based on data from treatment of influenza in 6049 adults and/or 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, 8 in the placebo group) received oseltamivir or placebo for influenza prophylaxis.

In adults/adolescents, the most commonly reported adverse events during treatment of influenza were nausea and vomiting; during prophylaxis, nausea was the most common. Most of these adverse reactions occurred infrequently, 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 most cases, adverse reactions did not lead to discontinuation of oseltamivir.

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

The following categories were used to describe the frequency of 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), and frequency not known (cannot be estimated based on available data). Adverse reactions were assigned to a category according to analysis of pooled clinical trial data.

Treatment and prevention of influenza in adults and adolescents

The most commonly observed adverse reactions reported in clinical trials of oseltamivir for treatment and prevention of influenza in adults and adolescents, as well as in the post-marketing period with recommended dosage (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, delusions, delirium, hallucinations, nightmares, self-injury;

Nervous system disorders: very common – headache; common – insomnia; uncommon – disturbance of consciousness, convulsions;

Eye disorders: rare – visual disturbances;

Cardiac disorders: uncommon – cardiac arrhythmias;

Respiratory, thoracic and mediastinal disorders: common – cough, rhinorrhoea, sore throat;

Gastrointestinal disorders: very common – nausea; common – vomiting, abdominal pain (including upper abdominal pain), dyspepsia; rare – gastrointestinal haemorrhage, haemorrhagic colitis;

Hepatobiliary disorders: uncommon – increased liver enzymes; rare – fulminant hepatitis, hepatic 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 prevention 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 oseltamivir suspension. A total of 158 children received the recommended dose of oseltamivir once daily in prophylaxis studies after household exposure (n = 99), in 6-week seasonal prophylaxis trials (n = 49), and in 12-week seasonal prophylaxis trials in immunocompromised children (n = 10).

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

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 disorders;

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

Gastrointestinal disorders: very common – vomiting; common – nausea, abdominal pain (including upper abdominal pain), dyspepsia; frequency not known – diarrhoea;

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

Description of selected adverse reactions

Psychiatric and neurological disorders

Influenza may be associated with various 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 treated with oseltamivir during the post-marketing period, cases of convulsions 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 death. These events were primarily observed in children and adolescents and often had sudden onset and rapid resolution. It is unknown whether neuropsychiatric disorders are related to oseltamivir use, as neuropsychiatric events have also been reported in influenza patients not treated with 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/hepatic 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 with risk factors (patients at increased risk of influenza-related complications, e.g., elderly patients and patients with chronic cardiac or respiratory diseases). Overall, the safety profile in adolescents and adults with chronic cardiac and/or respiratory diseases was qualitatively similar to that in healthy volunteers.

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 of oseltamivir observed in these studies was consistent with that observed in previous clinical trials where oseltamivir was used for treatment of influenza in immunocompetent patients of all age groups (patients without other diseases or patients with risk factors (underlying cardiac and/or respiratory conditions)). 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 prophylaxis.

Children with bronchial asthma

Overall, the adverse reaction profile in children with bronchial asthma was qualitatively similar to that in otherwise healthy children.

Reporting of suspected adverse reactions. Reporting of suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging.

10 tablets in a blister, 1 blister per carton.

Prescription status.

Prescription only.

Manufacturer.

Biopharm Ltd.

Manufacturer’s address and location of operations.

13 Walbrzyska Street, 60-198 Poznan, Poland.

Marketing Authorisation Holder.

SPERKO INTERNATIONAL LIMITED.

Address of Marketing Authorisation Holder.

Spirou Kyprianou, 57, BIBLOSERV BUSINESS CENTRE, 2nd floor, 6051, Larnaca, Cyprus.