Tamiflu

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TAMIFLU® (TAMIFLU®)

Composition:

Active substance: oseltamivir;

1 capsule contains oseltamivir 75.00 mg in the form of oseltamivir phosphate 98.50 mg;

Excipients: pregelatinized starch, talc, povidone K30, sodium croscarmellose, sodium stearyl fumarate;

Capsule shell:

Cap: titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172),
gelatin, printing ink;

Body: titanium dioxide (E 171), black iron oxide (E 172), gelatin, printing ink.

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules size №2 with a matt grey body and a matt light-yellow cap, with "ROCHE" printed on the body and "75 mg" on the cap in blue ink. The capsule contents are a powder ranging from white to yellowish-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, 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 in the body.

Oseltamivir carboxylate inhibits neuraminidase of influenza virus types A and B in vitro. Oseltamivir phosphate suppresses viral replication and pathogenicity in vitro. Oseltamivir, when administered orally, inhibits replication and pathogenicity of influenza virus types A and B in animal models of influenza infection in vivo under antiviral exposure conditions achieved in humans receiving a dose of 75 mg twice daily.

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

The IC50 values of oseltamivir for the neuraminidase enzyme of clinical isolates of influenza virus A ranged from 0.1 nmol to 1.3 nmol, while for influenza virus B they were 2.6 nmol. Published study data have 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 during clinical trials. Development of resistance to oseltamivir during treatment was observed more frequently in children than in adults, ranging from less than 1% in adults to 18% in infants under 1 year of age. Children shedding oseltamivir-resistant virus generally excreted the virus for a longer duration compared to those with non-resistant virus. However, treatment-emergent resistance to oseltamivir did not affect treatment response and did not lead to prolonged influenza symptoms.

Overall, a higher frequency of resistance to oseltamivir was observed in immunocompromised adults and adolescents receiving standard or double doses of 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 post-transplant patients (8/10 patients in the standard-dose group and 2/2 patients in the double-dose group). Most 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 Tamiflu in two studies was 20.7% (6/29). Of the six immunocompromised children who developed oseltamivir resistance 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 development of resistance to oseltamivir in clinical trials

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

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

Clinical and Surveillance Data. Naturally occurring 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 both 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 laboratory-selected resistant strains, 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 observed 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 were received during treatment and prophylaxis use.

Pharmacokinetics.

Absorption

Following oral administration, oseltamivir phosphate (prodrug) is readily absorbed from 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 concomitant food intake.

Distribution

In humans, the mean volume of distribution of the active metabolite at steady state is approximately 23 L, a volume equivalent to that 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 plasma concentration of the active metabolite declines with a half-life of 6–10 hours. The fully active metabolite is eliminated by the kidneys. Renal clearance (18.8 L/h) exceeds the glomerular filtration rate (7.5 L/h), indicating that additional elimination occurs via tubular secretion. Less than 20% of an orally administered radiolabeled dose 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 in 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 (approximately equivalent to 1 mg/kg). 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 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 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 impaired liver function (see section "Dosage and Administration").

Pregnant women

A pooled population pharmacokinetic analysis indicates that the dosing regimen of Tamiflu**®** described in the section "Dosage and Administration" results in lower exposure (on average 30% across all trimesters) to the active metabolite in pregnant women compared to non-pregnant women. However, the predicted lower exposure remains above inhibitory concentrations (IC95 values) and within the range effective against influenza virus strains. Additionally, observational study data support the benefit of the current dosing regimen in this patient population. 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 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. Due to the wide safety margin of the active metabolite, dose adjustment is not required for immunocompromised patients. However, for immunocompromised patients with renal impairment, the dose should be adjusted according to the recommendations 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

Tamiflu® 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 symptom onset.

Influenza prophylaxis:

• prophylaxis of influenza in adults and children aged 1 year and older following close contact with a person diagnosed with clinical influenza during influenza virus circulation;
• appropriate use of Tamiflu® for prophylaxis of influenza 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 case of a mismatch between the circulating influenza virus and the virus strain used in vaccination, or during a pandemic), seasonal prophylaxis may be conducted in individuals aged 1 year and older.

Tamiflu® should not be considered a substitute for 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 information 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.

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

Probenecid

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

Amoxicillin

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

Renal elimination

Clinically important interactions with other medicinal products involving competition for renal tubular secretion are unlikely due to the known safety margins of most such agents, characteristics of elimination of active metabolites (glomerular filtration and anionic 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 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, Tamiflu® 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 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 Tamiflu® was used concomitantly with these agents.

There is no mechanism of interaction with oral contraceptives.

Special precautions.

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

Use of Tamiflu® does not replace influenza vaccination. Use of Tamiflu® should not interfere with patient assessments regarding annual influenza vaccination. Protection against influenza lasts only during the period of Tamiflu® administration. Tamiflu® should be used for treatment and prevention of influenza only when reliable epidemiological data indicate circulation of the virus. Sensitivity of circulating influenza virus strains to Tamiflu® has been shown to be highly variable; therefore, physicians should consider the most up-to-date information on susceptibility of currently circulating influenza viruses to oseltamivir before deciding on the use of Tamiflu®.

Severe skin reactions and hypersensitivity reactions

During post-marketing use of Tamiflu**®, cases of anaphylaxis and severe skin reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme, have been reported. Tamiflu®** 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 use in patients with severe or unstable underlying diseases associated with an inevitable risk of hospitalization.

Immunocompromised patients

The safety and efficacy of oseltamivir for 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 the incidence of complications was observed between treatment and placebo groups.

Severe renal impairment

Dose adjustment of Tamiflu® is recommended for treatment and prophylaxis in adults and adolescents (13–17 years) with severe renal impairment. 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 influenza patients (predominantly in children and adolescents) treated with Tamiflu®. 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 individual patient (see section "Adverse reactions").

Disposal of unused or expired medication. Environmental contamination by medicinal products should be minimized. Medicinal products must 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 pregnancy outcomes, fetal development, and an increased risk of major congenital malformations, including congenital heart defects. A large amount of post-marketing and observational study data on oseltamivir use during pregnancy (more than 1000 first-trimester exposures) indicate no teratogenic or fetal/neonatal toxic effects of oseltamivir.

However, in one observational study, while no overall increase in the risk of congenital malformations was observed, results regarding major congenital heart defects diagnosed within 12 months after birth were inconclusive. In this study, the incidence of major congenital heart defects following first-trimester exposure to oseltamivir was 1.76% (7 infants out of 397 pregnancies), compared to 1.01% in unexposed pregnancies in the general population (risk ratio 1.75, 95% confidence interval 0.51 to 5.98). The clinical significance of these findings is unclear due to the study's limited sample size. Additionally, the study was not sufficiently powered to reliably assess individual types of major congenital malformations, and 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, Tamiflu® may be considered during pregnancy, 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 milk. There is very limited information on infants whose mothers received oseltamivir during lactation and on 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 a subtherapeutic dose in the infant. 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 that Tamiflu® affects fertility in men or women.

Ability to affect reaction speed when driving or operating machinery.

Tamiflu® has no influence on the ability to drive or operate machinery.

Method of Administration and Dosage

Method of Administration

For oral use.

Patients who cannot swallow capsules may receive appropriate doses of Tamiflu® as an oral suspension powder.

Dosage

Tamiflu® capsules and Tamiflu® oral suspension are bioequivalent dosage forms.

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

Adults and adolescents aged 13 years and older

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

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

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

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

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

Children aged 1 to 12 years

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

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

If patients have difficulty swallowing capsules or require a lower dose, Tamiflu® 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 Tamiflu® is one 75 mg capsule taken orally once daily for 10 days in children aged 1 year and older weighing more than 40 kg (including immunocompromised children) who are able to swallow capsules, for prophylaxis following contact with an influenza-infected individual. If patients have difficulty swallowing capsules or require a lower dose, Tamiflu® oral suspension powder (6 mg/mL) is recommended.

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

Dosage in Special Situations

Patients with hepatic impairment

Dosage adjustment is not 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

Influenza treatment. Dose adjustment of Tamiflu® is required in 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 undergoing hemodialysis	30 mg (suspension) after each hemodialysis session
patients undergoing peritoneal dialysis*	30 mg (suspension) single dose

* Data obtained from studies in patients undergoing continuous ambulatory peritoneal dialysis (CAPD); the clearance of oseltamivir carboxylate is expected to be higher with the use of 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 Tamiflu® is required in 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 second hemodialysis session
patients on peritoneal dialysis*	30 mg (suspension) once weekly

* Data obtained from studies in patients undergoing continuous ambulatory peritoneal dialysis (CAPD); the 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 the nephrologist considers it necessary.

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

Elderly patients

Dosage adjustment is not required, except in cases of moderate or severe renal impairment.

Immunocompromised patients

Treatment. The recommended duration of influenza treatment in immunocompromised patients is 10 days (see sections "Special 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 durations (up to 12 weeks) of seasonal prophylaxis have been studied in immunocompromised patients (see sections "Special instructions", "Adverse reactions").

Children

Safety data on the use of Tamiflu® 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.

Administered to children aged 1 year and older with body weight above 40 kg who are able to swallow capsules.

Overdose.

Reports of overdose with Tamiflu® have been received 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 Tamiflu® (see section "Adverse reactions").

A specific antidote is not known.

Children

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

Adverse Reactions

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

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

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

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). Adverse reactions were assigned to a frequency category based on pooled analysis of clinical trial data.

Treatment and Prophylaxis of Influenza in Adults and Adolescents

The most frequently reported adverse reactions observed in clinical trials and post-marketing experience with Tamiflu® for treatment and prophylaxis of influenza in adults and adolescents, when administered 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 Tamiflu® 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, convulsions;

Eye disorders:
Rare – vision disorders;

Cardiac disorders:
Uncommon – cardiac arrhythmias;

Respiratory, thoracic and mediastinal disorders:
Common – cough, rhinorrhea, throat pain;

Gastrointestinal disorders:
Very common – nausea; common – vomiting, abdominal pain (including upper abdominal pain), dyspepsia; rare – gastrointestinal hemorrhage, hemorrhagic colitis;

Hepatobiliary disorders:
Uncommon – increased levels of 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 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. Of these, 851 children received treatment with oseltamivir suspension. A total of 158 children received the recommended dose of Tamiflu® 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 Tamiflu® for treatment and prophylaxis of influenza in children (using age-based dosing 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 disorder;

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

Gastrointestinal disorders:
Very common – vomiting; common – nausea, abdominal pain (including 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 itself may be associated with a variety of neurological and behavioral symptoms, including hallucinations, delirium, and abnormal behavior, which in some cases have led to fatal outcomes. These events may occur as manifestations of encephalitis or encephalopathy, but may also occur in the absence of evident severe illness.

In influenza patients treated with Tamiflu®, post-marketing cases of convulsions and delirium (including symptoms such as altered level of consciousness, confusion, abnormal behavior, delusions, hallucinations, agitation, anxiety, and nightmares) have also been reported. In rare 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 events are related to Tamiflu® use, as similar neuropsychiatric disorders have also been reported in influenza patients not receiving this medication.

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/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 at risk (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 adolescent/adult volunteers.

Immunocompromised Patients

Influenza treatment in immunocompromised patients was evaluated in two studies using standard or high (double or triple) doses of Tamiflu®. The safety profile of Tamiflu® observed in these studies was consistent with that observed in previous clinical trials where Tamiflu® was used for treatment of influenza in non-immunocompromised patients of all age groups (patients without other conditions or patients 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 who received oseltamivir was comparable to that observed in clinical trials of Tamiflu® for prophylaxis.

Children with Bronchial Asthma

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

Shelf Life.

10 years.

Storage Conditions.

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

Packaging.

10 capsules of 75 mg in a blister pack. 1 blister pack in a cardboard box.

Prescription Category.

Prescription only.

Manufacturer.

F. Hoffmann-La Roche Ltd

Manufacturer's Address and Place of Business.

Wurmisweg, 4303 Kaiseraugst, Switzerland
Grenzacherstrasse 124, 4058 Basel, Switzerland