oseltamivir: prescribing information – dosing, contraindications, interactions, side effects

Treatment of influenza
Tamiflu is indicated in adults and children including full term neonates who present with symptoms typical of influenza, when influenza virus is circulating in the community. Efficacy has been demonstrated when treatment is initiated within two days of first onset of symptoms.

Prevention of influenza
- Post-exposure prevention in individuals 1 year of age or older following contact with a clinically diagnosed influenza case when influenza virus is circulating in the community.

• The appropriate use of Tamiflu for prevention of influenza should be determined on a case by case basis by the circumstances and the population requiring protection. In exceptional situations (e.g. in case of a mismatch between the circulating and vaccine virus strains, and a pandemic situation) seasonal prevention could be considered in individuals one year of age or older.

• Tamiflu is indicated for post-exposure prevention of influenza in infants less than 1 year of age during a pandemic influenza outbreak (see section 5.2).

Tamiflu is not a substitute for influenza vaccination.

The use of antivirals for the treatment and prevention of influenza should be determined on the basis of official recommendations. Decisions regarding the use of oseltamivir for treatment and prophylaxis should take into consideration what is known about the characteristics of the circulating influenza viruses, available information on influenza drug susceptibility patterns for each season and the impact of the disease in different geographical areas and patient populations (see section 5.1).

Posology

Tamiflu hard capsules and Tamiflu suspension are bioequivalent formulations. 75 mg doses can be administered as either
- one 75 mg capsule or
- one 30 mg capsule plus one 45 mg capsule or
- by administering one 30 mg dose plus one 45 mg dose of suspension.

Commercially manufactured Tamiflu powder for oral suspension (6 mg/ml) is the preferred product for paediatric and adult patients who have difficulties swallowing capsules or where lower doses are needed.

Adults, and adolescents 13 years and over

Treatment: The recommended oral dose is 75 mg oseltamivir twice daily for 5 days for adolescents (13 to 17 years of age) and adults.

Body Weight
Recommended dose for 5 days
Recommended dose for 10 days*
Immunocompromised Patients
> 40 kg
75 mg twice daily
75 mg twice daily
* The recommended treatment duration in immunocompromised adults and adolescents is 10 days. See Special Populations, Immunocompromised Patients for more information.

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

Post-exposure prevention: The recommended dose for prevention of influenza following close contact with an infected individual is 75 mg oseltamivir once daily for 10 days for adolescents (13 to 17 years of age) and adults.

Body Weight
Recommended dose for 10 days

Recommended dose for 10 days
Immunocompromised Patients
> 40 kg
75 mg once daily
75 mg once daily

Therapy should begin as soon as possible within two days of exposure to an infected individual.

Prevention during an influenza epidemic in the community: The recommended dose for prevention of influenza during a community outbreak is 75 mg oseltamivir once daily for up to 6 weeks (or up to 12 weeks in immunocompromised patients, see sections 4.4, 4.8 and 5.1).

Paediatric population

Children 1 to 12 years of age
Tamiflu 30 mg, 45 mg and 75 mg capsules and oral suspension are available for infants and children 1 year of age or older

Treatment: The following weight-adjusted dosing regimens are recommended for treatment of infants and children 1 year of age or older:

Body Weight
Recommended dose for 5 days
Recommended dose for 10 days*
Immunocompromised Patients
10 kg to 15 kg
30 mg twice daily
30 mg twice daily
> 15 kg to 23 kg
45 mg twice daily
45 mg twice daily
> 23 kg to 40 kg
60 mg twice daily
60 mg twice daily
> 40 kg
75 mg twice daily
75 mg twice daily
*The recommended treatment duration in immunocompromised children (≥1 year old) is 10 days. See Special Populations, Immunocompromised Patients for more information.

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

Post-exposure prevention: The recommended post-exposure prevention dose of Tamiflu is:

Body Weight
Recommended dose for 10 days
Recommended dose for 10 days
For Immunocomprmised Patients
10 kg to 15 kg
30 mg once daily
30 mg once daily
> 15 kg to 23 kg
45 mg once daily
45 mg once daily
> 23 kg to 40 kg
60 mg once daily
60 mg once daily
> 40 kg
75 mg once daily
75 mg once daily

Prevention during an influenza epidemic in the community: Prevention during an influenza epidemic has not been studied in children below 12 years of age.

Infants 0 – 12 months of age

Treatment: The recommended treatment dose for infants 0 - 12 months of age is 3 mg/kg twice daily.
This is based upon pharmacokinetic and safety data indicating that this dose in infants 0 - 12 months provides plasma concentrations of the pro-drug and active metabolite that are anticipated to be clinically efficacious with a safety profile comparable to that seen in older children and adults (see section 5.2). The following dosing regimen is recommended for treatment of infants 0 - 12 months of age:

Body weight*
Recommended dose for 5 days
Recommended dose for 10 days**
Immunocompromised Patients
3 kg
9 mg twice daily
9 mg twice daily
4 kg
12 mg twice daily
12 mg twice daily
5 kg
15 mg twice daily
15 mg twice daily
6 kg
18 mg twice daily
18 mg twice daily
7 kg
21 mg twice daily
21 mg twice daily
8 kg
24 mg twice daily
24 mg twice daily
9 kg
27 mg twice daily
27 mg twice daily
10 kg
30 mg twice daily
30 mg twice daily
* This table is not intended to contain all possible weights for this population. For all patients under the age of 1 year, 3 mg/kg should be used to determine dose regardless of the weight of the patient.
Treatment should be initiated as soon as possible within the first two days of onset of symptoms of influenza.
** The recommended duration in immunocompromised infants (0-12 months old) is 10 days. See Special Populations, Immunocompromised Patients for more information.

This dosing recommendation is not intended for premature infants, i.e. those with a post-conceptual age less than 36 weeks. Insufficient data are available for these patients, in whom different dosing may be required due to the immaturity of physiological functions.

Post-exposure prevention: The recommended prophylaxis dose for infants less than 1 year of age during a pandemic influenza outbreak is half of the daily treatment dose. This is based upon clinical data in infants and children 1 year of age or older and adults showing that a prophylaxis dose equivalent to half the daily treatment dose is clinically efficacious for the prevention of influenza. The following age-adjusted dosing prophylaxis regimen is recommended for infants 0 - 12 months of age (see Section 5.2 for exposure simulation):

Age
Recommended dose for 10 days
Recommended dose for 10 days
Immunocompromised Patients
0 - 12 months
3 mg/kg once daily
3 mg/kg once daily

This dosing recommendation is not intended for premature infants, i.e. those with a post-conceptual age less than 36 weeks. Insufficient data are available for these patients, in whom different dosing may be required due to the immaturity of physiological functions.

Prevention during an influenza epidemic in the community: Prevention during an influenza epidemic has not been studied in children 0-12 months of age.

For instructions on preparing the extemporaneous formulation, see section 6.6.

Special populations

Hepatic impairment
No dose adjustment is required either for treatment or for prevention in patients with hepatic dysfunction. No studies have been carried out in paediatric patients with hepatic disorder.

Renal impairment
Treatment of influenza: Dose adjustment is recommended for adults and adolescents (13 to 17 years of age) with moderate or severe renal impairment. Recommended doses are detailed in the table below.

Creatinine clearance
Recommended dose for treatment
> 60 (ml/min)
75 mg twice daily
> 30 to 60 (ml/min)
30 mg (suspension or capsules) twice daily
> 10 to 30 (ml/min)
30 mg (suspension or capsules) once daily
≤ 10 (ml/min)
Not recommended (no data available)
Haemodialysis patients
30 mg after each haemodialysis session
Peritoneal dialysis patients*
30 mg (suspension or capsules) single dose
* Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients; the clearance of oseltamivir carboxylate is expected to be higher when automated peritoneal dialysis (APD) mode is used.
Treatment mode can be switched from APD to CAPD if considered necessary by a nephrologist.

Prevention of influenza: Dose adjustment is recommended for adults and adolescents (13 to 17 years of age) with moderate or severe renal impairment as detailed in the table below.

Creatinine clearance
Recommended dose for prevention
> 60 (ml/min)
75 mg once daily
> 30 to 60 (ml/min)
30 mg (suspension or capsules) once daily
> 10 to 30 (ml/min)
30 mg (suspension or capsules) every second day
≤ 10 (ml/min)
Not recommended (no data available)
Haemodialysis patients
30 mg after every second haemodialysis session
Peritoneal dialysis patients*
30 mg (suspension or capsules) once weekly
* Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients; the clearance of oseltamivir carboxylate is expected to be higher when automated peritoneal dialysis (APD) mode is used.
Treatment mode can be switched from APD to CAPD if considered necessary by a nephrologist.

There is insufficient clinical data available in infants and children (12 years of age and younger) with renal impairment to be able to make any dosing recommendation.

Elderly
No dose adjustment is required, unless there is evidence of moderate or severe renal impairment.

Immunocompromised patients

Treatment: For treatment of influenza, the recommended duration for immunocompromised patients is 10 days (see sections 4.4, 4.8 and 5.1). No dose adjustment is necessary. Treatment should be initiated as soon as possible within the first two days of onset of symptoms of influenza.

Seasonal prophylaxis: Longer duration of seasonal prophylaxis up to 12 weeks has been evaluated in immunocompromised patients (see sections 4.4, 4.8 and 5.1).

Method of administration

Oral use.
Patients who are unable to swallow capsules may receive appropriate doses of Tamiflu suspension.

Posology

Tamiflu suspension and Tamiflu hard capsules are bioequivalent formulations. 75 mg doses can be administered as either
- one 75 mg capsule or
- one 30 mg capsule plus one 45 mg capsule or
- by administering one 30 mg dose plus one 45 mg dose of suspension.

Adults, adolescents or children (> 40 kg) who are able to swallow capsules may receive appropriate doses of Tamiflu capsules.

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

For adolescents (13 to 17 years of age) and adults: The recommended oral dose is 75 mg oseltamivir twice daily for 5 days (or 10 days in immunocompromised patients).

Paediatric population

For infants and children1 year of age or older: The recommended dose of Tamiflu 6 mg/ml oral suspension is indicated in the table below. Tamiflu 30 mg and 45 mg capsules are available as an alternative to the recommended dose of Tamiflu 6 mg/ml suspension.

The following weight-adjusted dosing regimens are recommended for infants and children 1 year of age or older:

Body weight
Recommended dose for
5 days
Recommended dose for
10 days*
Immunocompromised
Patients
Amount of oral suspension to withdraw
10 kg to 15 kg
30 mg twice daily
30 mg twice daily
5 ml twice daily
> 15 kg to 23 kg
45 mg twice daily
45 mg twice daily
7.5 ml twice daily
> 23 kg to 40 kg
60 mg twice daily
60 mg twice daily
10 ml twice daily
> 40 kg
75 mg twice daily
75 mg twice daily
12.5 ml twice daily
*The recommended duration in immunocompromised patients (≥1 year old) is 10 days. See Special Populations, Immunocompromised Patients for more information.

Children weighing > 40 kg and who are able to swallow capsules may receive treatment with the adult dosage of 75 mg capsules twice daily for 5 days as an alternative to the recommended dose of Tamiflu suspension.

For infants less than 1 year of age: The recommended treatment dose for infants 0 - 12 months of age is 3 mg/kg twice daily. This is based upon pharmacokinetic and safety data indicating that this dose in infants 0 - 12 months provides plasma concentrations of the pro-drug and active metabolite that are anticipated to be clinically efficacious with a safety profile comparable to that seen in older children and adults (see section 5.2).

A 3 ml oral dispenser (graduated in 0.1 ml steps) should be used for dosing children 0 - 12 months of age requiring 1 ml to 3 ml of Tamiflu 6 mg/ml oral suspension. For higher doses the 10 ml syringe should be used. The following dosing regimen is recommended for treatment of infants below 1 year of age:

Dosing table of oseltamivir for children less than 1 year of age : 3 mg/kg twice daily

Body
Weight*
Recommended dose for 5 days
Recommended dose for
10 days**
Immunocompromised patients
Amount of oral suspension to withdraw
Dispenser size to use
3 kg
9 mg twice daily
9 mg twice daily
1.5 ml twice daily
3 ml

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of the safety profile
The overall safety profile of Tamiflu is based on data from 6049 adult/adolescent and 1473 paediatric patients treated with Tamiflu or placebo for influenza, and on data from 3990 adult/adolescent and 253 paediatric patients receiving Tamiflu or placebo/no treatment for the prophylaxis of influenza in clinical trials. In addition, 245 immunocompromised patients (including 7 adolescents and 39 children) received Tamiflu for the treatment of influenza and 475 immunocompromised patients (including 18 children, of these 10 Tamiflu and 8 placebo) received Tamiflu or placebo for the prophylaxis of influenza.

In adults/adolescents, the most commonly reported adverse reactions (ARs) were nausea and vomiting in the treatment studies, and nausea in the prevention studies. The majority of these ARs were reported on a single occasion on either the first or second treatment day and resolved spontaneously within 1-2

days. In children, the most commonly reported adverse reaction was vomiting. In the majority of patients, these ARs did not lead to discontinuation of Tamiflu.

The following serious adverse reactions have been rarely reported since oseltamivir has been marketed: Anaphylactic and anaphylactoid reactions, hepatic disorders (fulminant hepatitis, hepatic function disorder and jaundice), angioneurotic oedema, Stevens-Johnson syndrome and toxic epidermal necrolysis, gastrointestinal bleeding and neuropsychiatric disorders.
(Regarding neuropsychiatric disorders, see section 4.4.)

Tabulated list of adverse reactions
The ARs listed in the tables below fall into the following categories: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000). ARs are added to the appropriate category in the tables according to the pooled analysis from clinical studies.

Treatment and prevention of influenza in adults and adolescents:
In adult/adolescent treatment and prevention studies, ARs that occurred the most frequently at the recommended dose (75 mg bid for 5 days for treatment and 75 mg od for up to 6 weeks for prophylaxis) are shown in Table 1.

The safety profile reported in subjects who received the recommended dose of Tamiflu for prophylaxis (75 mg once daily for up to 6 weeks) was qualitatively similar to that seen in the treatment studies, despite a longer duration of dosing in the prophylaxis studies.

Table 1
Adverse reactions in studies investigating Tamiflu for treatment and prevention of influenza in adults and adolescents or through post-marketing surveillance

System Organ
Class (SOC)
Adverse reactions according to frequency
Very common
Common
Uncommon
Rare
Infections and infestations

Bronchitis,
Herpes simplex,
Nasopharyngitis,
Upper respiratory tract infections,
Sinusitis

Blood and lymphatic system disorders

Thrombocytopenia
Immune system disorders

Hypersensitivity reaction
Anaphylactic reactions,
Anaphylactoid reactions
Psychiatric disorders

Agitation,
Abnormal behaviour, Anxiety,
Confusion,
Delusions,
Delirium,
Hallucination,
Nightmares,
Self-injury
Nervous system disorders
Headache
Insomnia
Altered level of consciousness,
Convulsion

Eye disorders

Visual disturbance
Cardiac disorders

Cardiac arrhythmia

System Organ
Class (SOC)
Adverse reactions according to frequency
Very common
Common
Uncommon
Rare
Respiratory, thoracic and mediastinal disorders

Cough,
Sore throat,
Rhinorrhea

Gastrointestinal disorders
Nausea
Vomiting
Abdominal pain
(incl. upper abdominal pain),
Dyspepsia

Gastrointestinal bleedings,
Haemorrhagic colitis
Hepatobiliary disorders

Elevated liver enzymes
Fulminant hepatitis,
Hepatic failure,
Hepatitis
Skin and subcutaneous tissue disorders

Eczema,
Dermatitis,
Rash,
Urticaria
Angioneurotic oedema,
Erythema multiforme,
Stevens-Johnson syndrome,
Toxic epidermal necrolysis
General disorders and administration site conditions

Pain
Dizziness (incl.
vertigo),
Fatigue,
Pyrexia,
Pain in limb

Treatment and prevention of influenza in children:

A total of 1473 children (including otherwise healthy children aged 1-12 years old and asthmatic children aged 6-12 years old) participated in clinical studies of oseltamivir given for the treatment of influenza. Of those, 851 children received treatment with oseltamivir suspension. A total of 158 children received the recommended dose of Tamiflu once daily in a post-exposure prophylaxis study in households (n = 99), a 6-week paediatric seasonal prophylaxis study (n = 49) and a 12-week paediatric seasonal prophylaxis study in immunocompromised subjects (n = 10).

Table 2 shows the most frequently reported ARs from paediatric clinical trials.

Table 2
Adverse reactions in studies investigating Tamiflu for treatment and prevention of influenza in children (age/weight-based dosing [30 mg to 75 mg o.d.])

System Organ
Class (SOC)
Adverse reactions according to frequency
Very common
Common
Uncommon
Rare
Infections and infestations

Otitis media,

Nervous system disorders

Headache

Eye disorders:

Conjunctivitis
(including red eyes, eye discharge and eye pain)

Ear and labyrinth disorders:

Earache
Tympanic membrane disorder

Respiratory, thoracic and mediastinal disorders
Cough,
Nasal congestion
Rhinorrhoea

Gastrointestinal disorders
Vomiting
Abdominal pain
(incl. upper abdominal pain),
Dyspepsia,
Nausea

Skin and subcutaneous tissue disorders

Dermatitis
(including allergic and atopic dermatitis)

Description of selected adverse reactions

Psychiatric disorders and nervous system disorders
Influenza can be associated with a variety of neurologic and behavioural symptoms which can include events such as hallucinations, delirium, and abnormal behaviour, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease.

In patients with influenza who were receiving Tamiflu, there have been postmarketing reports of convulsions and delirium (including symptoms such as altered level of consciousness, confusion, abnormal behaviour, delusions, hallucinations, agitation, anxiety, nightmares), in a very few cases resulting in self-injury or fatal outcomes. These events were reported primarily among paediatric and adolescent patients and often had an abrupt onset and rapid resolution. The contribution of Tamiflu to those events is unknown. Such neuropsychiatric events have also been reported in patients with influenza who were not taking Tamiflu.

Hepato-biliary disorders
Hepato-biliary system disorders, including hepatitis and elevated liver enzymes in patients with influenza-like illness. These cases include fatal fulminant hepatitis/hepatic failure.

Other special populations

Paediatric population (infants less than one year of age)
In two studies to characterise the pharmacokinetics, pharmacodynamics and safety profile of oseltamivir therapy in 135 influenza infected children less than one year of age, the safety profile was similar among age cohorts with vomiting, diarrohea and diaper rash being the most frequently reported

adverse events (see section 5.2). Insufficient data are available for infants who have a post-conceptual age of less than 36 weeks.

Safety information available on oseltamivir administered for treatment of influenza in infants less than one year of age from prospective and retrospective observational studies (comprising together more than 2,400 infants of that age class), epidemiological databases research and postmarketing reports suggest that the safety profile in infants less than one year of age is similar to the established safety profile of children aged one year and older.

Older people and patients with chronic cardiac and/or respiratory disease
The population included in the influenza treatment studies is comprised of otherwise healthy adults/adolescents and patients “at risk” (patients at higher risk of developing complications associated with influenza, e.g. older people and patients with chronic cardiac or respiratory disease). In general, the safety profile in the patients “at risk” was qualitatively similar to that in otherwise healthy adults/adolescents.

Immunocompromised patients

The treatment of influenza in immunocompromised patients were evaluated in two studies receiving standard dose or high dose regimens (double dose or triple dose) of Tamiflu (see section 5.1). The safety profile of Tamiflu observed in these studies was consistent with that observed in previous clinical trials where Tamiflu was administered for treatment of influenza in non-immunocompromised patients across all age groups (otherwise healthy patients or “at risk” patients [i.e., those with respiratory and/or cardiac co-morbidities]). The most frequent adverse reaction reported in immunocompromised children was vomiting (28%).

In a 12-week prophylaxis study in 475 immunocompromised patients, including 18 children 1 to 12 years of age and older, the safety profile in the 238 patients who received oseltamivir was consistent with that previously observed in Tamiflu prophylaxis clinical studies.

Children with pre-existing bronchial asthma
In general, the adverse reaction profile in children with pre-existing bronchial asthma was qualitatively similar to that of otherwise healthy children.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Summary of the safety profile
The overall safety profile of Tamiflu is based on data from 6049 adult/adolescent and 1473 paediatric patients treated with Tamiflu or placebo for influenza, and on data from 3990 adult/adolescent and 253 paediatric patients receiving Tamiflu or placebo/no treatment for the prophylaxis of influenza in clinical trials. In addition, 245 immunocompromised patients (including 7 adolescents and 39 children) received Tamiflu for the treatment of influenza and 475 immunocompromised patients (including 18 children, of these 10 Tamiflu and 8 placebo) received Tamiflu or placebo for the prophylaxis of influenza.

In adults/adolescents, the most commonly reported adverse reactions (ARs) were nausea and vomiting in the treatment studies, and nausea in the prevention studies. The majority of these ARs were reported on a single occasion on either the first or second treatment day and resolved spontaneously within 1-2 days. In children, the most commonly reported adverse reaction was vomiting. In the majority of patients, these ARs did not lead to discontinuation of Tamiflu.

The following serious adverse reactions have been rarely reported since oseltamivir has been marketed: Anaphylactic and anaphylactoid reactions, hepatic disorders (fulminant hepatitis, hepatic function disorder and jaundice), angioneurotic oedema, Stevens-Johnson syndrome and toxic epidermal necrolysis, gastrointestinal bleeding and neuropsychiatric disorders.
(Regarding neuropsychiatric disorders, see section 4.4.)

Tabulated list of adverse reactions
The ARs listed in the tables below fall into the following categories: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000). ARs are added to the appropriate category in the tables according to the pooled analysis from clinical studies.

Treatment and prevention of influenza in adults and adolescents:
In adult/adolescent treatment and prevention studies, ARs that occurred the most frequently at the recommended dose (75 mg bid for 5 days for treatment and 75 mg od for up to 6 weeks for prophylaxis) are shown in Table 1.

The safety profile reported in subjects who received the recommended dose of Tamiflu for prophylaxis (75 mg once daily for up to 6 weeks) was qualitatively similar to that seen in the treatment studies, despite a longer duration of dosing in the prophylaxis studies.

Table 1
Adverse reactions in studies investigating Tamiflu for treatment and prevention of influenza in adults and adolescents or through post-marketing surveillance

System Organ
Class (SOC)
Adverse reactions according to frequency
Very common
Common
Uncommon
Rare
Infections and infestations

Bronchitis,
Herpes simplex,
Nasopharyngitis,
Upper respiratory tract infections,
Sinusitis

Blood and lymphatic system disorders

Thrombocytopenia
Immune system disorders

Hypersensitivity reaction
Anaphylactic reactions,
Anaphylactoid reactions
Psychiatric disorders

Agitation,
Abnormal behaviour, Anxiety,
Confusion,
Delusions,
Delirium,
Hallucination,
Nightmares,
Self-injury
Nervous system disorders
Headache
Insomnia
Altered level of consciousness,
Convulsion

Eye disorders

Visual disturbance
Cardiac disorders

Cardiac arrhythmia

Respiratory, thoracic and mediastinal disorders

Cough,
Sore throat,
Rhinorrhea

Gastrointestinal disorders
Nausea
Vomiting
Abdominal pain
(incl. upper abdominal pain),
Dyspepsia

Gastrointestinal bleedings,
Haemorrhagic colitis
Hepatobiliary disorders

Elevated liver enzymes
Fulminant hepatitis,
Hepatic failure,
Hepatitis
Skin and subcutaneous tissue disorders

Eczema,
Dermatitis,
Rash,
Urticaria
Angioneurotic oedema,
Erythema multiforme,
Stevens-Johnson syndrome,
Toxic epidermal necrolysis
General disorders and administration site conditions

Pain
Dizziness (incl.
vertigo),
Fatigue,
Pyrexia,

System Organ
Class (SOC)
Adverse reactions according to frequency
Very common
Common
Uncommon
Rare
Pain in limb

Treatment and prevention of influenza in children:

A total of 1473 children (including otherwise healthy children aged 1-12 years old and asthmatic children aged 6-12 years old) participated in clinical studies of oseltamivir given for the treatment of influenza. Of those, 851 children received treatment with oseltamivir suspension. A total of 158 children received the recommended dose of Tamiflu once daily in a post-exposure prophylaxis study in households (n = 99), a 6-week paediatric seasonal prophylaxis study (n = 49) and a 12-week paediatric seasonal prophylaxis study in immunocompromised subjects (n = 10).

Table 2 shows the most frequently reported ARs from paediatric clinical trials.

Table 2
Adverse reactions in studies investigating Tamiflu for treatment and prevention of influenza in children (age/weight-based dosing [30 mg to 75 mg o.d.])

System Organ
Class (SOC)
Adverse reactions according to frequency
Very common
Common
Uncommon
Rare
Infections and infestations

Otitis media,

Nervous system disorders

Headache

Eye disorders:

Conjunctivitis
(including red eyes, eye discharge and eye pain)

Ear and labyrinth disorders:

Earache
Tympanic membrane disorder

Respiratory, thoracic and mediastinal disorders
Cough,
Nasal congestion
Rhinorrhoea

Gastrointestinal disorders
Vomiting
Abdominal pain
(incl. upper abdominal pain),
Dyspepsia,
Nausea

Skin and subcutaneous tissue disorders

Dermatitis (including allergic and atopic dermatitis)

Description of selected adverse reactions

Psychiatric disorders and nervous system disorders
Influenza can be associated with a variety of neurologic and behavioural symptoms which can include events such as hallucinations, delirium, and abnormal behaviour, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease.

In patients with influenza who were receiving Tamiflu, there have been postmarketing reports of convulsions and delirium (including symptoms such as altered level of consciousness, confusion, abnormal behaviour, delusions, hallucinations, agitation, anxiety, nightmares), in a very few cases resulting in self-injury or fatal outcomes. These events were reported primarily among paediatric and

adolescent patients and often had an abrupt onset and rapid resolution. The contribution of Tamiflu to those events is unknown. Such neuropsychiatric events have also been reported in patients with influenza who were not taking Tamiflu.

Hepato-biliary disorders
Hepato-biliary system disorders, including hepatitis and elevated liver enzymes in patients with influenza-like illness. These cases include fatal fulminant hepatitis/hepatic failure.

Other special populations

Paediatric population (infants less than one year of age)
In two studies to characterise the pharmacokinetics, pharmacodynamics and safety profile of oseltamivir therapy in 135 influenza infected children less than one year of age, the safety profile was similar among age cohorts with vomiting, diarrohea and diaper rash being the most frequently reported adverse events (see section 5.2). Insufficient data are available for infants who have a post-conceptual age of less than 36 weeks.

Safety information available on oseltamivir administered for treatment of influenza in infants less than one year of age from prospective and retrospective observational studies (comprising together more than 2,400 infants of that age class), epidemiological databases research and postmarketing reports suggest that the safety profile in infants less than one year of age is similar to the established safety profile of children aged one year and older.

Older people and patients with chronic cardiac and/or respiratory disease
The population included in the influenza treatment studies is comprised of otherwise healthy adults/adolescents and patients “at risk” (patients at higher risk of developing complications associated with influenza, e.g. older people and patients with chronic cardiac or respiratory disease). In general, the safety profile in the patients “at risk” was qualitatively similar to that in otherwise healthy adults/adolescents.

Immunocompromised patients

The treatment of influenza in immunocompromised patients were evaluated in two studies receiving standard dose or high dose regimens (double dose or triple dose) of Tamiflu (see section 5.1). The safety profile of Tamiflu observed in these studies was consistent with that observed in previous clinical trials where Tamiflu was administered for treatment of influenza in non-immunocompromised patients across all age groups (otherwise healthy patients or “at risk” patients [i.e., those with respiratory and/or cardiac co-morbidities]). The most frequent adverse reaction reported in immunocompromised children was vomiting (28%).

In a 12-week prophylaxis study in 475 immunocompromised patients, including 18 children 1 to 12 years of age and older, the safety profile in the 238 patients who received oseltamivir was consistent with that previously observed in Tamiflu prophylaxis clinical studies.

Children with pre-existing bronchial asthma
In general, the adverse reaction profile in children with pre-existing bronchial asthma was qualitatively similar to that of otherwise healthy children.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Oseltamivir is effective only against illness caused by influenza viruses. There is no evidence for efficacy of oseltamivir in any illness caused by agents other than influenza viruses (see section 5.1).

Tamiflu is not a substitute for influenza vaccination. Use of Tamiflu must not affect the evaluation of individuals for annual influenza vaccination. The protection against influenza lasts only as long as Tamiflu is administered. Tamiflu should be used for the treatment and prevention of influenza only when reliable epidemiological data indicate that influenza virus is circulating in the community.
Susceptibility of circulating influenza virus strains to oseltamivir has been shown to be highly variable (see section 5.1). Therefore, prescribers should take into account the most recent information available on oseltamivir susceptibility patterns of the currently circulating viruses when deciding whether to use Tamiflu.

Severe concomitant condition
No information is available regarding the safety and efficacy of oseltamivir in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalisation.

Immunocompromised patients
The efficacy of oseltamivir in either treatment or prophylaxis of influenza in immunocompromised patients has not been firmly established (see section 5.1).

Cardiac / respiratory disease
Efficacy of oseltamivir in the treatment of subjects with chronic cardiac disease and/or respiratory disease has not been established. No difference in the incidence of complications was observed between the treatment and placebo groups in this population (see section 5.1).

Paediatric population
No data allowing a dose recommendation for premature children (< 36 weeks post-conceptual age) are currently available.

Severe renal impairment
Dose adjustment is recommended for both treatment and prevention in adolescents (13 to 17 years of age) and adults with severe renal impairment. There is insufficient clinical data available in infants and children (1 year of age or older) with renal impairment to be able to make any dosing recommendation (see sections 4.2 and 5.2).

Neuropsychiatric events
Neuropsychiatric events have been reported during administration of Tamiflu in patients with influenza, especially in children and adolescents. These events are also experienced by patients with influenza without oseltamivir administration. Patients should be closely monitored for behavioural changes, and the benefits and risks of continuing treatment should be carefully evaluated for each patient (see section 4.8).

Oseltamivir is effective only against illness caused by influenza viruses. There is no evidence for efficacy of oseltamivir in any illness caused by agents other than influenza viruses (see section 5.1).

Tamiflu is not a substitute for influenza vaccination. Use of Tamiflu must not affect the evaluation of individuals for annual influenza vaccination. The protection against influenza lasts only as long as Tamiflu is administered. Tamiflu should be used for the treatment and prevention of influenza only when reliable epidemiological data indicate that influenza virus is circulating in the community.
Susceptibility of circulating influenza virus strains to oseltamivir has been shown to be highly variable (see section 5.1). Therefore, prescribers should take into account the most recent information available on oseltamivir susceptibility patterns of the currently circulating viruses when deciding whether to use Tamiflu.

Severe concomitant condition
No information is available regarding the safety and efficacy of oseltamivir in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalisation.

Immunocompromised patients
The efficacy of oseltamivir in either treatment or prophylaxis of influenza in immunocompromised patients has not been firmly established(see section 5.1).

Cardiac / respiratory disease
Efficacy of oseltamivir in the treatment of subjects with chronic cardiac disease and/or respiratory disease has not been established. No difference in the incidence of complications was observed between the treatment and placebo groups in this population (see section 5.1).

Paediatric population
No data allowing a dose recommendation for premature children (<36 weeks post-conceptual age) are currently available.

Severe renal impairment
Dose adjustment is recommended for both treatment and prevention in adolescents (13 to 17 years of age) and adults with severe renal impairment. There is insufficient clinical data available in infants and children (1 year of age or older) with renal impairment to be able to make any dosing recommendation (see sections 4.2 and 5.2).

Neuropsychiatric events
Neuropsychiatric events have been reported during administration of Tamiflu in patients with influenza, especially in children and adolescents. These events are also experienced by patients with influenza without oseltamivir administration. Patients should be closely monitored for behavioural changes, and the benefits and risks of continuing treatment should be carefully evaluated for each patient (see section 4.8).

Excipients
This medicinal product contains sorbitol. Patients with hereditary fructose intolerance (HFI) should not take this medicinal product.
Sorbitol may cause gastrointestinal discomfort and mild laxative effect.
This medicinal product contains sodium benzoate. Sodium benzoate (E211) may increase jaundice in newborn babies (up to 4 weeks old).

Pharmacokinetic properties of oseltamivir, such as low protein binding and metabolism independent of the CYP450 and glucuronidase systems (see section 5.2), suggest that clinically significant drug interactions via these mechanisms are unlikely.

Probenecid
No dose adjustment is required when co-administering with probenecid in patients with normal renal function. Co-administration of probenecid, a potent inhibitor of the anionic pathway of renal tubular secretion, results in an approximate 2-fold increase in exposure to the active metabolite of oseltamivir.

Amoxicillin
Oseltamivir has no kinetic interaction with amoxicillin, which is eliminated via the same pathway, suggesting that oseltamivir interaction with this pathway is weak.

Renal elimination
Clinically important drug interactions involving competition for renal tubular secretion are unlikely, due to the known safety margin for most of these substances, the elimination characteristics of the active metabolite (glomerular filtration and anionic tubular secretion) and the excretion capacity of these pathways. However, care should be taken when prescribing oseltamivir in subjects when taking co-excreted agents with a narrow therapeutic margin (e.g. chlorpropamide, methotrexate, phenylbutazone).

Additional information
No pharmacokinetic interactions between oseltamivir or its major metabolite have been observed when co-administering oseltamivir with paracetamol, acetylsalicylic acid, cimetidine, antacids (magnesium and aluminium hydroxides and calcium carbonates), rimantadine or warfarin (in subjects stable on warfarin and without influenza).

Pregnancy
Influenza is associated with adverse pregnancy and foetal outcomes, with a risk of major congenital malformations, including congenital heart defects. A large amount of data on oseltamivir exposure of pregnant women from post-marketing reports and observational studies (more than 1000 exposed outcomes during the first trimester) indicate no malformative nor feto/neonatal toxicity by oseltamivir.

However, in one observational study, while the overall malformation risk was not increased, the results for major congenital heart defects diagnosed within 12 months of birth were not conclusive. In this study, the rate of major congenital heart defects following oseltamivir exposure during the first trimester was 1.76% (7 infants out of 397 pregnancies) compared to 1.01% in unexposed pregnancies from the general population (Odds Ratio 1.75, 95% Confidence Interval 0.51 to 5.98). The clinical significance of this finding is not clear, as the study had limited power. Additionally, this study was too small to reliably assess individual types of major malformations; moreover women exposed to oseltamivir and women unexposed could not be made fully comparable, in particular whether or not they had influenza.

Animal studies do not indicate reproductive toxicity (see section 5.3).

The use of Tamiflu may be considered during pregnancy if necessary and after considering the available safety and benefit information (for data on benefit in pregnant women please refer to section 5.1 “treatment of influenza in pregnant women”), and the pathogenicity of the circulating influenza virus strain.

Breastfeeding
In lactating rats, oseltamivir and the active metabolite are excreted in milk. Very limited information is available on children breast-fed by mothers taking oseltamivir and on excretion of oseltamivir in breast milk. Limited data demonstrated that oseltamivir and the active metabolite were detected in breast milk, however the levels were low, which would result in a subtherapeutic dose to the infant.
Considering this information, the pathogenicity of the circulating influenza virus strain and the underlying condition of the breastfeeding woman, administration of oseltamivir may be considered, where there are clear potential benefits to breastfeeding mothers.

Fertility
Based on preclinical data, there is no evidence that Tamiflu has an effect on male or female fertility (see section 5.3).

Pregnancy
Influenza is associated with adverse pregnancy and foetal outcomes, with a risk of major congenital malformations, including congenital heart defects. A large amount of data on oseltamivir exposure of pregnant women from post-marketing reports and observational studies (more than 1000 exposed outcomes during the first trimester) indicate no malformative nor feto/neonatal toxicity by oseltamivir.

However, in one observational study, while the overall malformation risk was not increased, the results for major congenital heart defects diagnosed within 12 months of birth were not conclusive. In this study, the rate of major congenital heart defects following oseltamivir exposure during the first trimester was 1.76% (7 infants out of 397 pregnancies) compared to 1.01% in unexposed pregnancies from the general population (Odds Ratio 1.75, 95% Confidence Interval 0.51 to 5.98). The clinical significance of this finding is not clear, as the study had limited power. Additionally, this study was too small to reliably assess individual types of major malformations; moreover women exposed to oseltamivir and women unexposed could not be made fully comparable, in particular whether or not they had influenza.

Animal studies do not indicate reproductive toxicity (see section 5.3).

The use of Tamiflu may be considered during pregnancy if necessary and after considering the available safety and benefit information (for data on benefit in pregnant women please refer to section 5.1 “Treatment of influenza in pregnant women”), and the pathogenicity of the circulating influenza virus strain.

Breastfeeding
In lactating rats, oseltamivir and the active metabolite are excreted in milk. Very limited information is available on children breast-fed by mothers taking oseltamivir and on excretion of oseltamivir in breast milk. Limited data demonstrated that oseltamivir and the active metabolite were detected in breast milk, however the levels were low, which would result in a subtherapeutic dose to the infant.
Considering this information, the pathogenicity of the circulating influenza virus strain and the underlying condition of the breastfeeding woman, administration of oseltamivir may be considered, where there are clear potential benefits to breastfeeding mothers.

Fertility
Based on preclinical data, there is no evidence that Tamiflu has an effect on male or female fertility (see section 5.3).

Tamiflu has no influence on the ability to drive and use machines.

Reports of overdoses with Tamiflu have been received from clinical trials and during post-marketing experience. In the majority of cases reporting overdose, no adverse events were reported.

Adverse events reported following overdose were similar in nature and distribution to those observed with therapeutic doses of Tamiflu, described in section 4.8 Undesirable effects.

No specific antidote is known.

Paediatric population
Overdose has been reported more frequently for children than adults and adolescents. Caution should be exercised when preparing Tamiflu oral suspension and when administering Tamiflu products to children.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antivirals for systemic use, neuraminidase inhibitors ATC code:
J05AH02

Oseltamivir phosphate is a pro-drug of the active metabolite (oseltamivir carboxylate). The active metabolite is a selective inhibitor of influenza virus neuraminidase enzymes, which are glycoproteins found on the virion surface. Viral neuraminidase enzyme activity is important both for viral entry into uninfected cells and for the release of recently formed virus particles from infected cells, and for the further spread of infectious virus in the body.

Oseltamivir carboxylate inhibits influenza A and B neuraminidases in vitro. Oseltamivir phosphate inhibits influenza virus infection and replication in vitro. Oseltamivir given orally inhibits influenza A and B virus replication and pathogenicity in vivo in animal models of influenza infection at antiviral exposures similar to that achieved in man with 75 mg twice daily.

Antiviral activity of oseltamivir was supported for influenza A and B by experimental challenge studies in healthy volunteers.

Neuraminidase enzyme IC50 values for oseltamivir for clinically isolated influenza A ranged from 0.1 nM to 1.3 nM, and for influenza B was 2.6 nM. Higher IC50 values for influenza B, up to a median of 8.5 nM, have been observed in published studies.

Clinical studies

Treatment of influenza infection

The indication is based on clinical studies of naturally occurring influenza in which the predominant infection was influenza A.

Oseltamivir is effective only against illnesses caused by influenza virus. Statistical analyses are therefore presented only for influenza-infected subjects. In the pooled treatment study population, which included both influenza-positive and -negative subjects (ITT), primary efficacy was reduced proportionally to the number of influenza-negative individuals. In the overall treatment population, influenza infection was confirmed in 67 % (range 46 % to 74 %) of the recruited patients. Of the older subjects, 64 % were influenza-positive and of those with chronic cardiac and/or respiratory disease 62 % were influenza-positive. In all phase III treatment studies, patients were recruited only during the period in which influenza was circulating in the local community.

Adults and adolescents 13 years of age and older: Patients were eligible if they reported within 36 hours of onset of symptoms, had fever ≥ 37.8 °C, accompanied by at least one respiratory symptom (cough, nasal symptoms or sore throat) and at least one systemic symptom (myalgia, chills/sweats, malaise, fatigue or headache). In a pooled analysis of all influenza-positive adults and adolescents (N = 2,413) enrolled into treatment studies, oseltamivir 75 mg twice daily for 5 days reduced the median duration of influenza illness by approximately one day from 5.2 days (95 % CI 4.9 – 5.5 days) in the placebo group to 4.2 days (95 % CI 4.0 – 4.4 days; p ≤ 0.0001).

Pharmacotherapeutic group: Antivirals for systemic use, neuraminidase inhibitors ATC code:
J05AH02

Oseltamivir phosphate is a pro-drug of the active metabolite (oseltamivir carboxylate). The active metabolite is a selective inhibitor of influenza virus neuraminidase enzymes, which are glycoproteins found on the virion surface. Viral neuraminidase enzyme activity is important both for viral entry into uninfected cells and for the release of recently formed virus particles from infected cells, and for the further spread of infectious virus in the body.

Oseltamivir carboxylate inhibits influenza A and B neuraminidases in vitro. Oseltamivir phosphate inhibits influenza virus infection and replication in vitro. Oseltamivir given orally inhibits influenza A and B virus replication and pathogenicity in vivo in animal models of influenza infection at antiviral exposures similar to that achieved in man with 75 mg twice daily.

Antiviral activity of oseltamivir was supported for influenza A and B by experimental challenge studies in healthy volunteers.

Neuraminidase enzyme IC50 values for oseltamivir for clinically isolated influenza A ranged from 0.1 nM to 1.3 nM, and for influenza B was 2.6 nM. Higher IC50 values for influenza B, up to a median of 8.5 nM, have been observed in published studies.

Clinical studies
Treatment of influenza infection
The indication is based on clinical studies of naturally occurring influenza in which the predominant infection was influenza A.Oseltamivir is effective only against illnesses caused by influenza virus.
Statistical analyses are therefore presented only for influenza-infected subjects. In the pooled treatment study population, which included both influenza-positive and -negative subjects (ITT), primary efficacy was reduced proportionally to the number of influenza-negative individuals. In the overall treatment population, influenza infection was confirmed in 67 % (range 46 % to 74 %) of the recruited patients. Of the older subjects, 64 % were influenza-positive and of those with chronic cardiac and/or respiratory disease 62 % were influenza-positive. In all phase III treatment studies, patients were recruited only during the period in which influenza was circulating in the local community.

Adults and adolescents 13 years of age and older: Patients were eligible if they reported within 36 hours of onset of symptoms, had fever ≥ 37.8 °C, accompanied by at least one respiratory symptom (cough, nasal symptoms or sore throat) and at least one systemic symptom (myalgia, chills/sweats,

malaise, fatigue or headache). In a pooled analysis of all influenza-positive adults and adolescents (N = 2,413) enrolled into treatment studies, oseltamivir 75 mg twice daily for 5 days reduced the median duration of influenza illness by approximately one day from 5.2 days (95 % CI 4.9 – 5.5 days) in the placebo group to 4.2 days (95 % CI 4.0 – 4.4 days; p ≤ 0.0001).

General Information

Absorption
Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate (pro-drug) and is extensively converted by predominantly hepatic esterases to the active metabolite (oseltamivir carboxylate). At least 75 % of an oral dose reaches the systemic circulation as the active metabolite. Exposure to the pro-drug is less than 5 % relative to the active metabolite.
Plasma concentrations of both pro-drug and active metabolite are proportional to dose and are unaffected by co-administration with food.

Distribution
The mean volume of distribution at steady state of the oseltamivir carboxylate is approximately 23 litres in humans, a volume equivalent to extracellular body fluid. Since neuraminidase activity is extracellular, oseltamivir carboxylate distributes to all sites of influenza virus spread.

The binding of the oseltamivir carboxylate to human plasma protein is negligible (approximately 3 %).

Biotransformation
Oseltamivir is extensively converted to oseltamivir carboxylate by esterases located predominantly in the liver. In vitro studies demonstrated that neither oseltamivir nor the active metabolite is a substrate for, or an inhibitor of, the major cytochrome P450 isoforms. No phase 2 conjugates of either compound have been identified in vivo.

Elimination
Absorbed oseltamivir is primarily (> 90 %) eliminated by conversion to oseltamivir carboxylate. It is not further metabolised and is eliminated in the urine. Peak plasma concentrations of oseltamivir carboxylate decline with a half-life of 6 to 10 hours in most subjects. The active metabolite is eliminated entirely by renal excretion. Renal clearance (18.8 l/h) exceeds glomerular filtration rate (7.5 l/h) indicating that tubular secretion occurs in addition to glomerular filtration. Less than 20 % of an oral radiolabelled dose is eliminated in faeces.

Other special populations

Paediatric population