Seltavir

INSTRUCTIONS for medical use of the medicinal product SELTAVIR (SELTAVIR)

Composition:

Active substance: oseltamivir;

One hard capsule contains oseltamivir phosphate equivalent to oseltamivir 30 mg;

Excipients: pregelatinized starch, talc, povidone, sodium croscarmellose, sodium stearyl fumarate, hard gelatin capsule No. 4;

Capsule composition: iron oxide red (E 172), iron oxide yellow (E 172), titanium dioxide (E 171), gelatin, purified water;

One hard capsule contains oseltamivir phosphate equivalent to oseltamivir 45 mg;

Excipients: pregelatinized starch, tal007c, povidone, sodium croscarmellose, sodium stearyl fumarate, hard gelatin capsule No. 4;

Capsule composition: iron oxide black (E 172), titanium dioxide (E 171), gelatin, purified water;

One hard capsule contains oseltamivir phosphate equivalent to oseltamivir 75 mg;

Excipients: pregelatinized starch, talc, povidone, sodium croscarmellose, sodium stearyl fumarate, hard gelatin capsule No. 2;

Capsule composition: iron oxide red (E 172), iron oxide yellow (E 172), iron oxide black (E 172), titanium dioxide (E 171), gelatin, purified water.

Dosage form. Hard capsules.

Main physicochemical properties:

30 mg: hard gelatin capsules No. 4 with light-yellow cap and body, marked in blue with "30 mg" on the cap and "M 53" on the body, containing granules from white to almost white;

45 mg: hard gelatin capsules No. 4 with grey cap and body, marked in blue with "45 mg" on the cap and "M 54" on the body, containing granules from white to almost white;

75 mg: hard gelatin capsules No. 2 with light-yellow cap and grey body, marked in blue with "75 mg" on the cap and "M 55" on the body, containing granules from white to almost white.

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, a glycoprotein located on the surface of the virion. The activity of the viral neuraminidase enzyme 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 viruses types A and B in vitro. Oseltamivir phosphate suppresses viral replication and pathogenicity in vitro. Orally administered oseltamivir inhibits replication and pathogenicity of influenza viruses types A and B in animal models of influenza infection in vivo at antiviral exposures achieved in humans when administered at a dose of 75 mg twice daily.

Antiviral activity of oseltamivir has been confirmed against influenza viruses types A and B in experimental studies in healthy volunteers.

The IC₅₀ values of oseltamivir for neuraminidase enzyme of clinical isolates of influenza virus A ranged from 0.1 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 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 shedding oseltamivir-resistant virus generally excreted 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 involving 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 virus type A and shed the virus for a longer duration.

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

Frequency of development of resistance to oseltamivir in clinical studies

Patient population	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

No evidence of drug resistance associated with the use of Seltavir has been observed in clinical studies conducted to date on post-exposure influenza prophylaxis (7 days), household post-exposure prophylaxis (10 days), and 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. 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 oseltamivir resistance during treatment is higher in immunocompromised patients and in younger children.

Resistant influenza viruses isolated from patients treated with oseltamivir, as well as laboratory-selected oseltamivir-resistant 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. Susceptibility to oseltamivir and the prevalence of such viruses have been shown to vary seasonally and geographically. In 2008, the H275Y mutation was detected in >99% of circulating H1N1 isolates in Europe. In 2009, the H1N1 influenza virus ("swine flu") was almost uniformly susceptible to oseltamivir, although sporadic cases of resistance were reported during both prophylactic and therapeutic use of the drug.

Pharmacokinetics

Absorption

Following 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, while less than 5% remains 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 (approximately 23 L) corresponds to the volume of extracellular fluid in the body. Since neuraminidase activity occurs extracellularly, 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, primarily located in the liver. Neither oseltamivir phosphate nor the active metabolite are substrates or inhibitors of 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 into 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 active metabolite is eliminated entirely 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 the orally administered radiolabeled drug is excreted in feces.

Pharmacokinetics in special populations

Children aged 1 year and older

Oseltamivir pharmacokinetics were studied in children aged 1 to 16 years in a single-dose pharmacokinetic study. Multiple-dose pharmacokinetics were evaluated in a small number of children in a clinical efficacy trial. In younger children, elimination of both the prodrug and the active metabolite occurred faster than in adults, resulting in lower exposure expressed as mg/kg dose. A dose of 2 mg/kg provides the same exposure of oseltamivir carboxylate as achieved in adults after a single 75 mg dose (equivalent to approximately 1 mg/kg). Oseltamivir pharmacokinetics 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 receiving similar doses of oseltamivir. The elimination half-life in elderly patients is similar to that in younger patients. Based on drug exposure and tolerability, dose adjustment is not necessary for elderly patients unless they have 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 active metabolite exposure 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 Seltavir 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 individuals. However, the reduced predicted exposure remains above inhibitory concentrations (IC95 values) and within the range effective against influenza virus strains. Furthermore, 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 described 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. Given the wide safety margin of the active metabolite, dose adjustment is not required for immunocompromised patients. However, for immunocompromised patients with renal impairment, dosage should be adjusted according to recommendations in the section "Dosage and administration".

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

Clinical Characteristics

Indications

Influenza Treatment

The drug 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:

• prophylaxis of influenza in adults and children aged 1 year and older following close contact with a person clinically diagnosed with influenza during influenza virus circulation;
• appropriate use of the drug for influenza prophylaxis should be determined on a case-by-case basis, considering the circumstances and weighing the group of patients who require protection. In exceptional situations (e.g., in case of mismatch between the circulating influenza virus and the influenza virus strain included in the vaccine, and during a pandemic), seasonal prophylaxis may be conducted in individuals aged 1 year and older.

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

Contraindications

Hypersensitivity to oseltamivir phosphate or to any component of the drug.

Interaction with Other Medicinal Products and Other Forms of Interaction

The pharmacokinetic properties of oseltamivir, such as low 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

Dose adjustment is not required for patients with normal renal function when oseltamivir and probenecid are taken concomitantly. Concomitant administration of probenecid, a potent inhibitor of the anion pathway of renal tubular secretion, results in approximately a doubling of 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 weak 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 of these drugs, characteristics of elimination 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 taking medicinal products with a similar excretion pathway and a narrow therapeutic range (e.g., chlorpropamide, methotrexate, phenylbutazone).

Additional Information

No pharmacokinetic interactions between oseltamivir and its active metabolite were observed when co-administered with 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, the drug was administered concomitantly with commonly used medicinal products such as ACE 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 Selthavir was used concomitantly with the listed medicinal products.

There is no mechanism of interaction with oral contraceptives.

Special precautions

Oseltamivir is effective only against diseases caused by influenza viruses. There are no data on the efficacy of oseltamivir in diseases caused by any pathogens other than influenza viruses.

The use of the drug does not replace influenza vaccination. The use of the drug should not interfere with annual influenza vaccination programs. Protection against influenza lasts only during the period of drug administration. The medicinal product Seltavir should be used for the prevention and treatment of influenza only when reliable epidemiological data indicate virus circulation. The susceptibility of circulating influenza virus strains to the drug has shown high variability; therefore, physicians should consider the most up-to-date information on the susceptibility of currently circulating influenza viruses to oseltamivir before deciding on the use of the drug.

Severe skin reactions and hypersensitivity reactions

During post-marketing use of the drug, cases of anaphylaxis and severe skin reactions, including toxic epidermal necrolysis, Stevens–Johnson syndrome, and erythema multiforme, have been reported. The medicinal product Seltavir 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 in patients with severe or unstable 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 in treating individuals with chronic cardiac and/or respiratory diseases has not been established. In such patients, no difference in the frequency of complications was observed between treatment and placebo groups.

Severe renal impairment

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

Neuropsychiatric disorders

Neuropsychiatric disorders have been reported in patients with influenza (predominantly in children and adolescents) receiving the drug. 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 medicine and expired medicine
Medicinal waste should be minimized to prevent release into the environment. The drug should not be disposed of via wastewater or household waste. A dedicated waste collection system (if available) should be used for disposal.

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 (more than 1000 pregnancy outcomes following first-trimester exposure) indicate no teratogenic or fetal/neonatal toxic effects of oseltamivir.

However, in one observational study, despite no overall increased risk of congenital malformations, the 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 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. Furthermore, complete comparability between women exposed and not exposed to oseltamivir could not be established, particularly regarding whether they had influenza.

Animal studies do not indicate reproductive toxicity.

If necessary, the use of Seltavir during pregnancy may be considered, taking into account the 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 breast 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 were detected 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 clinical condition of the breastfeeding woman, oseltamivir 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 the medicinal product Seltavir on fertility in men or women.

Ability to affect reaction rate while driving or operating machinery

No effect.

Method of Administration and Dosage

Method of Administration

For oral use.

Dosage

The 75 mg dose of the drug can be administered 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 is one 75 mg capsule twice daily orally for 5 days in adults and adolescents (≥13 to <18 years) with body weight above 40 kg.

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

For immunocompromised patients (adults and adolescents aged 13–18 years) with body weight above 40 kg, the recommended dosage regimen of the medicinal product Seltavir is one 75 mg capsule twice daily orally for 10 days.

Post-exposure Prophylaxis. The recommended dose for post-exposure prophylaxis of influenza following contact with an infected individual is 75 mg once daily orally for 10 days in adults and adolescents (≥13 to <18 years) with body weight above 40 kg. Drug administration should begin no later than within the first 2 days after exposure.

Seasonal Prophylaxis during Influenza Epidemic. The recommended dose for prophylaxis during seasonal influenza epidemic is 75 mg once daily for 6 weeks (or up to 12 weeks for immunocompromised patients).

Children aged ≥1 to <13 years

Treatment. The recommended weight-adjusted dosage regimen for treatment of infants and children aged 1 year and older is as follows:

Body weight	Recommended dose for 5 days
from 10 to 15 kg	30 mg twice daily
> 15 kg to 23 kg	45 mg twice daily
> 23 kg to 40 kg	60 mg twice daily
> 40 kg	75 mg twice daily

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

Post-exposure prophylaxis. Recommended dosage regimen of the drug

Body weight	Recommended dose for 10 days
from 10 to 15 kg	30 mg once daily
> 15 kg to 23 kg	45 mg once daily
> 23 kg to 40 kg	60 mg once daily
> 40 kg	75 mg once daily

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

Dosing in special situations

Patients with hepatic impairment

There is no need to adjust the dose for treatment or prevention 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 the drug is required for adults and adolescents (≥13 to <18 years) with moderate or severe renal impairment (see Table 1).

Table 1

Creatinine clearance	Recommended treatment dose
> 60 mL/min	75 mg twice daily
from > 30 to 60 mL/min	30 mg twice daily
from > 10 to 30 mL/min	30 mg once daily
≤ 10 mL/min	not recommended (data unavailable)
patients undergoing hemodialysis	30 mg after each hemodialysis session
patients undergoing peritoneal dialysis*	30 mg single dose

* 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 the drug is required for adults and adolescents (≥13 to <18 years) with moderate or severe renal impairment (see Table 2).

Table 2

Creatinine clearance	Recommended prophylactic dose
> 60 mL/min	75 mg once daily
> 30 to 60 mL/min	30 mg once daily
> 10 to 30 mL/min	30 mg every other day
≤ 10 mL/min	not recommended (data unavailable)
patients on hemodialysis	30 mg after every second hemodialysis session
patients on peritoneal dialysis*	30 mg once weekly

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

Insufficient data are available to provide dosing 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 oral dose is 75 mg of oseltamivir twice daily for 10 days in adults. Treatment should be initiated as soon as possible within the first two days of symptom onset.

Seasonal prophylaxis. Seasonal influenza prophylaxis for 12 weeks is recommended in immunocompromised patients (see sections "Special precautions" and "Adverse reactions").

Children

The drug may be administered to children aged 1 year and older with body weight above 10 kg who are able to swallow capsules.

Overdose

Cases of overdose have been reported during clinical trials and post-marketing use of the drug. In most of the reported cases, no adverse reactions were observed.

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

There is no specific antidote.

Children

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

Adverse Reactions

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

In adults/adolescents, the most commonly reported adverse reactions during Seltavir treatment in therapeutic influenza studies were nausea and vomiting; in prophylactic studies, nausea was the most common. 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, vomiting was the most frequent adverse event. In most cases, these adverse reactions did not lead to discontinuation of Seltavir.

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 hemorrhage, and neuropsychiatric disorders (for neuropsychiatric disorders, see section "Special precautions for use").

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 frequency category based on analysis of pooled clinical trial data.

Treatment and prophylaxis of influenza in adults and adolescents

The most frequently reported adverse reactions observed in clinical trials of Seltavir for treatment and prophylaxis of influenza in adults and adolescents, as well as in the post-marketing period when used 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 reported in patients receiving Seltavir at the recommended prophylactic dose (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 – disturbance in consciousness, seizures;

Eye disorders: rare – vision disorders;

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 abdominal pain), dyspepsia; rare – gastrointestinal hemorrhage, 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

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 Seltavir once daily in prophylaxis studies: in household transmission 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 frequently reported adverse reactions observed in clinical trials of Seltavir for treatment and prophylaxis of influenza in children (using age-based dosing ranging from 30 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 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 abdominal pain), 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 may be associated with various neurological and behavioral symptoms, including hallucinations, delirium, and abnormal behavior, which in some cases may be fatal. These events may occur as manifestations of encephalitis or encephalopathy, but may also occur without apparent severe illness.

In patients with influenza treated with Seltavir during the post-marketing period, cases of seizures and delirium (including symptoms such as altered level of consciousness, confusion, abnormal behavior, hallucinations, agitation, anxiety, nightmares) have been reported. In isolated 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 these neuropsychiatric disorders are related to Seltavir, as similar neuropsychiatric events have also been reported in influenza patients not receiving this medicinal product.

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 with risk factors (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 comparable to that in healthy adolescent/adult volunteers.

Immunocompromised patients

Influenza treatment in immunocompromised patients was evaluated in two studies using standard or high (double or triple) doses of Seltavir. The safety profile of Seltavir observed in these studies was consistent with that observed in previous clinical trials where Seltavir was used to treat influenza in non-immunocompromised 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 Seltavir for prophylaxis.

Children with bronchial asthma

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and 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

5 years.

Storage conditions

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging

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

Prescription status

Prescription only.

Manufacturer

Macleods Pharmaceuticals Limited.

Manufacturer’s address and location of operations

Village Thedda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.