Oseltamivir: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OSELTAMIVIR

Composition:

Active substance: oseltamivir;

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

Excipients: pregelatinized starch, sodium croscarmellose, povidone, talc, sodium stearyl fumarate, gelatin capsule*.

* Composition of the gelatin capsule: gelatin, iron oxide yellow (E 172), titanium dioxide (E 171), iron oxide black (E 172), blue printing ink.

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules size 2 with an opaque light-yellow cap marked „75 mg” in blue ink and an opaque grey body marked „LU” in blue ink, containing granular powder white or almost white in color.

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

ATC Code J05A H02.

Pharmacological Properties

Pharmacodynamics

Oseltamivir phosphate is a prodrug of the active metabolite (oseltamivir carboxylate). The active metabolite is a selective inhibitor of the viral neuraminidase enzyme of influenza viruses, a glycoprotein located on the surface of the virion. Viral neuraminidase enzyme activity 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. Orally administered oseltamivir 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 receiving a dose of 75 mg twice daily.

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

The IC50 values of oseltamivir for 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 have 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 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 carrying oseltamivir-resistant virus generally shed the virus for a longer duration compared to those with non-resistant virus. However, treatment-emergent resistance to oseltamivir did not affect treatment response and did not lead to prolonged influenza symptoms.

Overall, a higher incidence of oseltamivir resistance 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 immunocompetent adults and adolescents receiving oseltamivir treatment. Most adult patients who developed resistance were post-transplant patients (8/10 patients in the standard-dose group and 2/2 patients in the double-dose group). The majority of patients with oseltamivir-resistant virus were infected with influenza A virus and shed the virus for a prolonged period.

The frequency of oseltamivir resistance in immunocompromised children (≤12 years) receiving the drug in two studies was 20.7% (6/29). Among the six immunocompromised children who developed oseltamivir resistance during treatment, three received standard dose and three received high (double or triple) dose. Most of these patients 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 (%)
Patient population	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)

*Complete genotyping was not performed in all studies.

Influenza prophylaxis

There is no evidence of emergence of resistance to oseltamivir in clinical studies conducted to date on post-exposure influenza prophylaxis (7 days), household post-exposure influenza prophylaxis (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. Naturally occurring mutations associated with reduced susceptibility to oseltamivir have been identified in vitro in influenza A and B viruses isolated from patients without exposure 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, 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 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 the 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 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, primarily 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 entirely 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 faster than in adults, resulting in lower exposure normalized to body weight. A dose of 2 mg/kg provides the same exposure to oseltamivir carboxylate as that achieved in adults after a single 75 mg dose (equivalent to approximately 1 mg/kg). Pharmacokinetics of oseltamivir in children and adolescents aged 12 years and older are similar to those in adults.

Elderly patients. 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 the elderly 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 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 individuals. 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 this dosing regimen for 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 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 immunocompetent patients with 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, 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 showed no significant additional benefit from doses exceeding the standard dose.

Clinical Characteristics

Indications

Influenza Treatment

Oseltamivir is indicated for the treatment of influenza in adults and children aged 1 year and older who have symptoms of influenza during influenza virus circulation. Efficacy has been demonstrated when treatment was initiated within 2 days of symptom onset.

Influenza Prophylaxis:

prophylaxis of influenza in adults and children aged 1 year and older following close contact with an individual with clinically diagnosed influenza during influenza virus circulation;
the appropriate use of oseltamivir for influenza prophylaxis should be determined on a case-by-case basis, considering the circumstances and weighing the patient population requiring protection. In exceptional situations (e.g., in cases of mismatch between circulating influenza virus and the virus strain included in the vaccine, or during a pandemic), seasonal prophylaxis may be considered in individuals aged 1 year and older.

Oseltamivir should 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 antiviral agents each season, the impact of the disease in different geographical regions, and patient population groups.

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

Interaction with Other Medicinal Products and Other Forms of Interaction

Given the pharmacokinetic properties of oseltamivir, such as low protein binding and metabolism independent of the CYP450 and glucuronidation systems (see section "Pharmacokinetics"), clinically significant interactions with other medicinal products are unlikely.

Probenecid

Dose adjustment is not required for patients with normal renal function when oseltamivir is co-administered with probenecid. 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 minimal interaction between oseltamivir and amoxicillin via this route.

Renal Elimination

Clinically relevant interaction with other medicinal products involving competition for renal tubular secretion is unlikely, due to the known safety margins of most such agents, the 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 receiving medicinal products with a similar elimination pathway and a narrow therapeutic index (e.g., chlorpropamide, methotrexate, phenylbutazone).

Additional Information

No pharmacokinetic interactions were observed between oseltamivir and its primary metabolite and concurrently administered paracetamol, acetylsalicylic acid, cimetidine, antacids (magnesium hydroxide and aluminum hydroxide, calcium carbonate), rimantadine, or warfarin (in patients receiving 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, and doxycycline), H2-receptor antagonists (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.

There is no mechanism for interaction with oral contraceptives.

Special precautions for use

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

Use of the medicinal product Oseltamivir does not replace vaccination against influenza.

Use of the medicinal product Oseltamivir should not influence the assessment of individuals regarding annual influenza vaccination. Protection against influenza lasts only during administration of the medicinal product. Oseltamivir should be used for treatment and prevention of influenza only when reliable epidemiological data indicate circulation of the virus. It has been demonstrated that susceptibility of influenza virus strains to oseltamivir shows high variability; therefore, the physician should consider the most up-to-date information on susceptibility of currently circulating viruses before prescribing Oseltamivir.

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 underlying conditions

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

Immunocompromised patients

The safety and efficacy of oseltamivir for 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 the medicinal product Oseltamivir is recommended for adults and adolescents (13–17 years) with severe renal impairment for both treatment and prophylaxis. There are insufficient clinical data on use in children aged 1 year and older with renal impairment to provide dosing recommendations (see sections "Dosage and administration", "Pharmacokinetics").

Neuropsychiatric disorders

Neuropsychiatric disorders have been observed in patients with influenza (predominantly in children and adolescents) during oseltamivir use. 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 "Undesirable effects").

Disposal of unused or expired medicinal product. Environmental contamination should be minimized. The medicinal product should not be disposed of via wastewater or household waste. A designated waste collection system should be used for disposal, if available.

Use during pregnancy or breastfeeding

Pregnancy

Influenza is associated with adverse effects on the course of pregnancy and fetal development, and with an increased risk of major congenital malformations, including congenital heart defects. A large amount of post-marketing and observational study data (more than 1000 cases of oseltamivir use during the first trimester) indicates that oseltamivir does not have teratogenic or fetal/neonatal toxic effects.

However, in one observational study, although no increase in 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 after first-trimester exposure to oseltamivir was 1.76% (7 infants out of 397 pregnancies), compared to 1.01% in unexposed pregnancies in the general population (risk ratio 1.75, 95% confidence interval from 0.51 to 5.98). The clinical significance of these findings is unclear due to the limited sample size of the study. Furthermore, the study was not sufficiently powered to reliably assess individual types of major congenital defects; in addition, complete comparison between women exposed and unexposed to oseltamivir was not possible, particularly regarding whether they had influenza.

Animal studies do not indicate reproductive toxicity.

If necessary, use of the medicinal product Oseltamivir 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 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 excretion of oseltamivir into human breast milk. According to some data, oseltamivir and its active metabolite have been detected in breast milk, but at low levels, resulting in a subtherapeutic dose in the infant. Considering these data, as well as the pathogenicity of the circulating influenza virus strain and the health status of the breastfeeding woman, oseltamivir may be considered if there is a clear potential benefit to the 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. The medicinal product Oseltamivir has no effect on reaction speed when driving or operating machinery.

Method of Administration and Dosage

Method of Administration

For oral use.

Patients who cannot swallow capsules may receive appropriate doses of oseltamivir in the form of oral suspension powder.

Dosage

Oseltamivir in capsules and oseltamivir oral suspension are bioequivalent dosage forms.

For children and adult patients who have difficulty swallowing capsules or require a lower dose of the drug, oseltamivir oral suspension powder (6 mg/mL) is recommended.

Adults and adolescents aged 13 years and older

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

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

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

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

Prophylaxis during seasonal influenza epidemic. The recommended dose for prophylaxis during an outbreak of seasonal influenza is 75 mg 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 1 to 12 years

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

For immunocompromised children aged 1 year and older with body weight over 40 kg who are able to swallow capsules, the recommended dosage regimen of oseltamivir is one 75 mg capsule taken orally twice daily for 10 days (see section "Dosage in Special Situations. Immunocompromised Patients" below).

If patients have difficulty swallowing capsules or require a lower dose, oseltamivir oral suspension powder (6 mg/mL) is recommended.

Treatment should be initiated as early as possible, within the first two days of symptom onset.

Post-exposure prophylaxis. The recommended dosage regimen of oseltamivir for post-exposure prophylaxis in children aged 1 year and older with body weight over 40 kg (including immunocompromised children) who are able to swallow capsules is one 75 mg capsule taken orally once daily for 10 days. If patients have difficulty swallowing capsules or require a lower dose, oseltamivir oral suspension powder (6 mg/mL) is recommended.

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

Dosage in Special Situations

Patients with hepatic impairment

No dose adjustment is required for treatment or prophylaxis in patients with hepatic impairment. The safety and pharmacokinetics of oseltamivir in children with hepatic impairment have not been studied.

Patients with renal impairment

Treatment of influenza. Dose adjustment of oseltamivir is required for adults and adolescents (13–17 years) with moderate or severe renal impairment (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 (suspension) twice daily
from > 10 to 30 mL/min	30 mg (suspension) once daily
≤ 10 mL/min	not recommended (data unavailable)
patients on hemodialysis	30 mg (suspension) after each hemodialysis session
patients on peritoneal dialysis*	30 mg (suspension) 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 medicinal product Oseltamivir is required for adults and adolescents (13–17 years) with moderate or severe renal impairment (see Table 2).

Table 2

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

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

Elderly patients

Dose 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 "Dosage and Administration", "Side Effects"). Dose adjustment is not necessary. Treatment should be initiated as soon as possible within the first two days of symptom onset.

Seasonal prophylaxis. Longer durations (up to 24 weeks) of seasonal prophylaxis have been studied in immunocompromised patients (see sections "Dosage and Administration", "Side Effects").

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, 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 is indicated for use in children aged 1 year and older with body weight above 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 reactions were reported.

Adverse reactions reported following overdose were similar to those observed with therapeutic doses of oseltamivir (see section "Side Effects").

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 oseltamivir to children.

Side effects

The overall safety profile of the medicinal product Oseltamivir is based on data from treatment of influenza in 6049 adults/adolescents and 1473 children who received oseltamivir or placebo, and on data from prophylaxis of influenza in 3990 adults/adolescents and 253 children who received oseltamivir or placebo in clinical trials. In addition, 245 patients with weakened immunity (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, the most common adverse events during oseltamivir treatment for influenza were nausea and vomiting; during prophylaxis, nausea was the most common adverse event. Most of these adverse reactions were isolated, transient, occurred typically on the first or second day of treatment, and resolved spontaneously within 1–2 days. In children, vomiting was the most common adverse event. In most cases, these adverse reactions did not require discontinuation of oseltamivir.

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

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). Frequencies were determined according to pooled analysis of clinical trial data.

Treatment and prophylaxis of influenza in adults and adolescents

Below are the most commonly reported adverse reactions observed in clinical trials of oseltamivir for treatment and prophylaxis of influenza in adults and adolescents, and in the post-marketing period when the recommended dose was used (75 mg twice daily for 5 days for treatment and 75 mg once daily for up to 6 weeks for prophylaxis).

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 behavior, anxiety, confusion, delusions, 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 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 oseltamivir once daily in prophylaxis trials: in household transmission studies (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 reported adverse reactions observed in clinical trials of oseltamivir for treatment and prophylaxis of influenza in children (using age-appropriate dosing from 30 mg to 75 mg once daily):

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

Nervous system disorders: common — headache;

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

Eye disorders: common — conjunctivitis (including eye redness, eye discharge, and eye 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 can be associated with various neurological and behavioral symptoms, which may include hallucinations, delirium, and abnormal behavior, sometimes with fatal outcomes. These events may occur as manifestations of encephalitis or encephalopathy, but may also occur without apparent severe illness.

In the post-marketing period, in patients with influenza treated with oseltamivir, cases of seizures and delirium (including symptoms such as altered level of consciousness, confusion, abnormal behavior, delusions, hallucinations, agitation, anxiety, nightmares) have been reported, which in some cases led to accidental self-harm or death. These events were mainly 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 such disorders have also been reported in influenza patients not receiving this drug.

Hepatobiliary disorders

Disorders of the hepatobiliary system, 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.

Special patient groups

Elderly patients and patients with chronic heart 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 heart or respiratory diseases). Overall, the safety profile in adolescents and adults with chronic heart and/or respiratory diseases was comparable to that in healthy adolescent/adult volunteers.

Immunocompromised patients

Treatment of influenza 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 to treat influenza in non-immunocompromised patients of all age groups (patients without other illnesses or patients with risk factors [underlying heart 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 who received oseltamivir was comparable to that observed in clinical trials of oseltamivir for prophylaxis.

Children with bronchial asthma

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 2 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. 1 blister per cardboard pack.

Prescription status. Prescription only.

Manufacturer. LUPIN LIMITED.

Manufacturer's address and location of business operations.

A 28-1, MIDC Industrial Area, Chikalthana, Aurangabad, Maharashtra 431210, India (IN).