Tamiflu 45 mg Hard Capsules

Update to SPC following completion of paediatric studies NV25719 & NV20234 & downstream population PK & PK/PD analysis

Update to Pl following the completion of paediatric studies NV25719 & NV20234 & downstream population PK & PK/PD analysis

Update Shelf life for 30mg and 45mg capsule strengths from 7 years to 10 years on basis of real time stability data gathered.

4.2     Posology and method of administration

[….]

Immunocompromised patients

Treatment: The recommended oral dose is 75 mg oseltamivir twice daily for 10 days for adults (see sections 4.4, 4.8 and 5.1). 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).

[….]

4.4     Special warnings and precautions for use

[….]

Immunocompromised patients

The efficacy of oseltamivir in either treatment or prophylaxis of influenza in immunocompromised patients has not been firmly established. However, the duration of treatment of influenza in immunocompromised adult patients should be 10 days, as there are no studies of a shorter course of oseltamivir in this patient group (see section 5.1).

[….]

4.8     Undesirable effects

[….]

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, 199 immunocompromised adult patients 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.

[….]

Immunocompromised patients

In a double blind study for the treatment of influenza, a total of 199 adult immunocompromised patients (evaluable for safety) were randomized to receive Tamiflu for 10 days: 98 patients received the standard dose (75 mg twice daily) and 101 patients received the double dose (150 mg twice daily). The safety profile of Tamiflu observed in this study was consistent with that observed in previous clinical trials where Tamiflu was administered for treatment of influenza in non-immunocompromised patients (otherwise healthy patients or “at risk” patients [i.e., those with respiratory and/or cardiac co-morbidities]). The percentage of patients reporting adverse events was lower in the standard dose group compared to the double dose group (49.0% vs 59.4 %, respectively) (See section 5.1).

[….]

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

[….]

Treatment of influenza in immunocompromised adults: A randomized, double blind study, to evaluate safety and characterize the effects of oseltamivir on the development of resistant influenza virus (primary analysis) in influenza-infected adult immunocompromised patients, included 151 patients evaluable for efficacy of oseltamivir (secondary analysis, not powered). The study included solid organ transplant [SOT] patients, haematopoietic stem cell transplant [HSCT] patients, HIV positive patients with a CD4+ cell count <500 cells/mm3, patients on systemic immunosuppressive therapy, and those with haematological malignancy. These patients were randomized to be treated, within 96 hours of symptoms onset, with standard dose (73 patients) or double dose (78 patients) of oseltamivir, for a duration of 10 days.

The median time to resolution of symptoms (TTRS) was similar between the standard dose group (103 hours [90% CI 75.4-110.0]) and double dose group (104 hours [90% CI 65.8-131.0]).  The proportion of patients with secondary infections in the standard dose group and double dose group was comparable (8.2% vs 5.1%).

[….]

An overall higher incidence of oseltamivir-resistance was observed in adult immunocompromised patients treated with standard dose or double dose of oseltamivir for a duration of 10 days [14.9% (10/67) in standard dose group and 2.8% (2/71) in double dose group], compared to data from studies with oseltamivir-treated otherwise healthy adult patients. The majority of patients that developed resistance were transplant recipients (8/10 patients in the standard dose group and 2/2 patients in the double dose group). Most of the patients with oseltamivir-resistant virus were infected with influenza type A and had prolonged viral shedding.

Incidence of Oseltamivir Resistance in Clinical Studies

* Full genotyping was not performed in all studies.

Prophylaxis of Influenza

There has been no evidence for emergence of drug resistance associated with the use of Tamiflu in clinical studies conducted to date in post-exposure (7 days), post-exposure within household groups (10 days) and seasonal (42 days) prevention of influenza in immunocompetent patients. There was no resistance observed during a 12-week prophylaxis study in immunocompromised patients.

[….]

5.2     Pharmacokinetic properties

[….]

Immunocompromised Patients

Population pharmacokinetic analysis indicates that treatment of adult immunocompromised patients with oseltamivir (as described in Section 4.2. Posology and method of administration) results in an increased exposure (of up to 50%) to the active metabolite when compared to adult non-immunocompromised patients with comparable creatinine clearance. Due to the wide safety margin of the active metabolite, no dose adjustments are required in adults due to their immunocompromised status. However, for adult immunocompromised patients with renal impairment, doses should be adjusted as outlined in section 4.2. Posology and method of administration.

4.6     Fertility, pregnancy and lactation

Pregnancy

While no controlled clinical studies have been conducted on the use of oseltamivir in pregnant women data on use in pregnancy has been collected 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 (please refer to section 5.1 “Treatment of influenza in pregnant women”; for data on exposure in pregnant women please refer to section 5.2.).  These data in conjunction with animal studies do not (more than 1000 exposed outcomes during the first trimester) indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal or postnatal development (see section 5.3) 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 Pregnant women may receive 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 and the underlying condition of the pregnant woman.

10.     DATE OF REVISION OF THE TEXT

22 February 2018

1.       NAME OF THE MEDICINAL PRODUCT

Tamiflu 30 mg hard capsules
Tamiflu 45 mg hard capsules
Tamiflu 75 mg hard capsules

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

Tamiflu 30 mg hard capsules

Each hard capsule contains oseltamivir phosphate equivalent to 30 mg of oseltamivir.

For the full list of excipients, see section 6.1.

Tamiflu 45 mg hard capsules
Each hard capsule contains oseltamivir phosphate equivalent to 45 mg of oseltamivir.

For the full list of excipients, see section 6.1.

Tamiflu 75 mg hard capsules
Each hard capsule contains oseltamivir phosphate equivalent to 75 mg of oseltamivir.

For the full list of excipients, see section 6.1.

3.       PHARMACEUTICAL form

Tamiflu 30 mg hard capsules

Hard capsule (capsule)

The hard capsule consists of a light yellow opaque body bearing the imprint “ROCHE” and a light yellow opaque cap bearing the imprint “30 mg”. Imprints are blue.

Tamiflu 45 mg hard capsules

The hard capsule consists of a grey opaque body bearing the imprint “ROCHE” and a grey opaque cap bearing the imprint “45 mg”. Imprints are blue.

Tamiflu 75 mg hard capsules
The hard capsule consists of a grey opaque body bearing the imprint “ROCHE” and a light yellow opaque cap bearing the imprint “75 mg”. Imprints are blue.

4.2     Posology and method of administration

[....]

 

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):

Older peopleElderly

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

5.1     Pharmacodynamic properties

[....]

Post-exposure prevention of influenza in infants less than 1 year of age during a pandemic:

Prevention during an influenza pandemic has not been studied in controlled clinical studies in children 0-12 months of age. See Section 5.2 for exposure simulation details.

[....]

5.2     Pharmacokinetic properties

[....]

Post-exposure prevention of influenza in infants less than 1 year of age during a pandemic: Simulation of once daily dosing of 3mg/kg in infants <1 year shows an exposure in the same range or higher than for once daily dosing of 75 mg in adults. Exposure does not exceed that for treatment of infants < 1 year (3 mg/kg twice daily) and is anticipated to result in a comparable safety profile (see Section 4.8). No clinical studies of prophylaxis in infants aged <1 have been performed.   

[....] 

Older peopleElderly

10.     DATE OF REVISION OF THE TEXT

28 April 2016

4.1     Therapeutic indications

Treatment of influenza

Tamiflu is indicated in adults and children including full term neonates In patients one year of age and older 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. This indication is based on clinical studies of naturally occurring influenza in which the predominant infection was influenza A (see section 5.1).

Tamiflu is indicated for the treatment of infants less than 1 year of age during a pandemic influenza outbreak (see section 5.2).

The treating physician should take into account the pathogenicity of the circulating strain and the underlying condition of the patient to ensure there is a potential benefit to the child.

[...]

4.2     Posology and method of administration

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, adolescents or infants and children (1 year of age or older) who are unable to swallow capsules may receive appropriate doses of Tamiflu suspension.

Iinfants 0 – 12 months of ageless than 1 year

In the absence of a suitable formulation, a pharmacy compounded preparation should preferentially be used as the syringe provided in the Tamiflu 12 mg/ml powder for oral suspension pack (with mg markings) does not allow for appropriate dose adjustments and commercially available syringes (with ml markings) may lead to unacceptable dosing inaccuracies (see section 6.6).

Treatment: The recommended treatment dose for infants less than 1 year0 - 12 months of age is between 2 mg/kg twice daily and 3 mg/kg twice daily during a pandemic influenza outbreak. This is based upon limited pharmacokinetic and safety data indicating that thiese doses 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  provide plasma drug exposures in the majority of patients similar to those shown to be clinically efficacious in older children and adults (see section 5.2). The following age-adjusted dosing regimen iss are recommended for treatment of infants 0 - 12 months below 1 year of age:

* This table is not intended to contain all possible weights for this population. For all patients under the age of 1 year of age, 3 mg/kg should be used to determine dose regardless of the weight of the patient.

*          There is no data available regarding the administration of Tamiflu to infants less than one month of age.

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

This ese age-based dosing recommendations isare not intended for premature infants, i.e. those with a post-conceptual postmenstrual age less than 37 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 regimens are is  recommended for infants below 1 year0 - 12 months of age:

*          There is no data available regarding the administration of Tamiflu to infants less than one month of age.

Thisese age-based  dosing recommendation is are not intended for premature infants, i.e. those with a post-conceptual postmenstrual age less than 3637 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 below 120-12 yearsmonths of age.

4.4     Special warnings and precautions for use

Paediatric population

No data allowing a dose recommendation for premature children (< 367 weeks post-conceptual agepost-menstrual age*) are currently available.

*          Time between first day of last normal menstrual period and day of assessment, gestational age plus post-natal age.

4.6     Fertility, pregnancy and lactation

Pregnancy

While no controlled clinical studies have been conducted on the use of oseltamivir in pregnant women data on use in pregnancy has been collected from post-marketing and observational studies (please refer to section 5.1 “Treatment of influenza in pregnant women”; for data on exposure in pregnant women please refer to section 5.2.). While no controlled clinical studies have been conducted on the use of oseltamivir in pregnant women, there is limited data available from post-marketing and retrospective observational surveillance reports. These data in conjunction with animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal or postnatal development (see section 5.3). Pregnant women may receive Tamiflu, after considering the available safety information, the pathogenicity of the circulating influenza virus strain and the underlying condition of the pregnant woman.

4.8     Undesirable effects

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 124135 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.

5.1     Pharmacodynamic properties

Treatment of influenza infection

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

Treatment of influenza in pregnant women: No controlled clinical studies have been conducted on the use of oseltamivir in pregnant women, however, there is evidence from post-marketing and retrospective observational studies showing benefit of the current dosing regimen in this patient population in terms of lower morbidity/mortality. Results from pharmacokinetic analyses indicate a lower exposure to the active metabolite, however dose adjustments are not recommended for pregnant women in the treatment or prophylaxis of influenza (see section 5.2, Pharmacokinetics, Special Population).

The indication in infants below the age of 1 is based upon extrapolation of efficacy data from older children and the recommended posology is based upon pharmacokinetic modelling data (see Section 5.2).

5.2     Pharmacokinetic properties

Other Sspecial populations

ChildrenPaediatric population

Infants less than 1 year of age: Limited pharmacokinetic and safety data are available for infants less than 1 year of age. Pharmacokinetic modeling was undertaken using these data in addition to data from studies in adults and infants and children 1 year of age or older. The results demonstrate that doses of 3 mg /kg twice daily for infants aged 3 to 12 months and 2.5 mg /kg twice daily for infants aged between 1 and 3 months provide exposures similar to those shown to be clinically efficacious in adults and infants and children 1 year of age or older (see sections 4.1 and 4.2). There are currently no data available in infants less than 1 month of age using Tamiflu. The pharmacokinetics, pharmacodynamics and safety of Tamiflu have been evaluated in two uncontrolled open-label studies including influenza infected children less than one year of age (n=12435). The rate of clearance of the active metabolite, corrected for body-weight, decreases with ages below one year. Metabolite exposures are also more variable in the youngest infants. The available data indicates that the exposure following a 3 mg/kg dose in infants 0 - 12 months of age provides pro-drug and metabolite exposures anticipated to be efficacious with a safety profile comparable to that seen in older children and adults using the approved dose (see sections 4.1 and 4.2).The reported adverse events were consistent with the established safety profile in older children.

There are no data available for infants below 1 year of age for post exposure prevention of influenza. Prevention during an influenza epidemic in the community has not been studied in children below 12 years of age.

[...]

 

Pregnant Women

A pooled population pharmacokinetic analysis indicates that the Tamiflu dosage regimen described in Section 4.2 Posology and method of administration results in lower exposure (30% on average across all trimesters) to the active metabolite in pregnant women compared to non-pregnant women. The lower predicted exposure however, remains above inhibitoy concentrations (IC95 values) and at a therapeutic level for a range of influenza virus strains. In addition, there is evidence from observational studies showing benefit of the current dosing regimen in this patient population. Therefore, dose adjustments are not recommended for pregnant women in the treatment

or prophylaxis of influenza (see section 4.6 Fertility, pregnancy and lactation).

6.6     Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

Extemporaneous formulation

When Tamiflu powder for oral suspension is not available

Commercially manufactured Tamiflu 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.  In the event that When commercially manufactured Tamiflu powder for oral suspension is not available, the pharmacist may compound a suspension (6 mg/ml) from Tamiflu capsules or patients can prepare the suspension from capsules at patients who are unable to swallow capsules may receive appropriate doses of Tamiflu prepared in a pharmacy or prepared at home.

For infants less than 1 year of age, tThe pharmacy preparation should be preferred to home preparation. Detailed information on the home preparation can be found in the package leaflet of Tamiflu capsules under “Making liquid Tamiflu suspension at home”.

Dosing chart for pharmacy compounded 6 mg/ml suspension prepared from Tamiflu capsules for infants less than 1 year of age

Dosing chart for pharmacy compounded 6 mg/ml suspension prepared from Tamiflu capsules for infants 0 to 30 days of age (less than one month of age)

Dosing chart for pharmacy compounded 6 mg/ml suspension prepared from Tamiflu capsules for infants of 31 to 90 days of age (more than one month to three months of age)

Dosing chart for pharmacy compounded 6 mg/ml suspension prepared from Tamiflu capsules for infants 91 to less than 365 days of age (more than three months to twelve months of age)

Dispense the pharmacy compounded suspension with a graduated oral syringe for measuring small amounts of suspension. If possible, mark or highlight the graduation corresponding to the appropriate dose (according to the dosing tables above) on the oral syringe for each patient.

The appropriate dose must be mixed by the caregiver with an equal quantity of sweet liquid food, such as sugar water, chocolate syrup, cherry syrup, dessert toppings (like caramel or fudge sauce) to mask the bitter taste.

Home preparation

When commercially manufactured Tamiflu oral suspension is not available, a pharmacy compounded suspension prepared from Tamiflu capsules mustcan be used (see detailed instructions above). If the commercially manufactured Tamiflu oral suspension and the pharmacy compounded suspension is also not available, Tamiflu suspension may be prepared at home. The pharmacy compounded suspension is the preferred option in infants less than 1 year of age.

When appropriate capsule strengths are available for the dose needed, the dose is given by opening the capsule and mixing its contents with no more than one teaspoon of a suitable sweetened food product. The bitter taste can be masked by products such as sugar water, chocolate syrup, cherry syrup, dessert toppings (like caramel or fudge sauce). The mixture should be stirred and given entirely to the patient. The mixture must be swallowed immediately after its preparation.

When only 75 mg capsules are available, and doses of 30 mg or 45 mg are needed, the preparation of Tamiflu suspension involves additional steps. Detailed instructions can be found in the package leaflet of Tamiflu capsules under “Making liquid Tamiflu suspension at home”.

10.     DATE OF REVISION OF THE TEXT

5 May 2015

4.6     Fertility, pregnancy and lactation

Pregnancy

While no controlled clinical studies have been conducted on the use of oseltamivir in pregnant women data on use in pregnancy has been collected,; however there is evidence limited data available from post-marketing and retrospective observational surveillance studies (please refer to section 5.1 “Treatment of influenza in pregnant women”; for data on exposure in pregnant women please refer to section 5.2.). showing benefit of the current dosing regimen in this patient populationreports. Results from pharmacokinetic analyses indicate a lower exposure to the active metabolite, however dose adjustments are not recommended for pregnant women in the treatment or

prophylaxis of influenza (see section 5.2, Pharmacokinetics, Special Population).

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

Treatment of influenza in pregnant women: No controlled clinical studies have been conducted on the use of oseltamivir in pregnant women, however, there is evidence from post-marketing and retrospective observational studies showing benefit of the current dosing regimen in this patient population in terms of lower morbidity/mortality. Results from pharmacokinetic analyses indicate a lower exposure to the active metabolite, however dose adjustments are not recommended for pregnant women in the treatment or prophylaxis of influenza (see section 5.2, Pharmacokinetics, Special Population).

5.2     Pharmacokinetic properties

Pregnant Women

A pooled population pharmacokinetic analysis indicates that the Tamiflu dosage regimen

described in Section 4.2 Posology and method of administration results in lower exposure (30% on

average across all trimesters) to the active metabolite in pregnant women compared to

non-pregnant women. The lower predicted exposure however, remains above inhibitory concentrations (IC95 values) and at a therapeutic level for a range of  influenza virus strains. In addition, there is evidence from observational studies  showing benefit of the current dosing regimen in this patient population. Therefore, dose adjustments are not recommended for pregnant women in the treatment

or prophylaxis of influenza (see section 4.6 Fertility, pregnancy and lactation).

10.     DATE OF REVISION OF THE TEXT

23 April 2015

4.       Clinical particulars

4.1     Therapeutic indications

Treatment of influenza

Tamiflu is indicated in adults and children including full term neonates In patients one year of age and older 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. This indication is based on clinical studies of naturally occurring influenza in which the predominant infection was influenza A (see section 5.1).

Tamiflu is indicated for the treatment of infants less than 1 year of age during a pandemic influenza outbreak (see section 5.2).

The treating physician should take into account the pathogenicity of the circulating strain and the underlying condition of the patient to ensure there is a potential benefit to the child.

4.2     Posology and method of administration

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, adolescents or infants and children (1 year of age or older) who are unable to swallow capsules may receive appropriate doses of Tamiflu suspension.

[...] 

Paediatric population

Children 1 to 12 years of age

Iinfants 0 – 12 months of ageless than 1 year

In the absence of a suitable formulation, a pharmacy compounded preparation should preferentially be used as the syringe provided in the Tamiflu 12 mg/ml powder for oral suspension pack (with mg markings) does not allow for appropriate dose adjustments and commercially available syringes (with ml markings) may lead to unacceptable dosing inaccuracies (see section 6.6).

Treatment: The recommended treatment dose for infants less than 1 year0 - 12 months of age is between 2 mg/kg twice daily and 3 mg/kg twice daily during a pandemic influenza outbreak. This is based upon limited pharmacokinetic and safety data indicating that thiese doses 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  provide plasma drug exposures in the majority of patients similar to those shown to be clinically efficacious in older children and adults (see section 5.2). The following age-adjusted dosing regimen iss are recommended for treatment of infants 0 - 12 months below 1 year of age:

* This table is not intended to contain all possible weights for this population. For all patients under the age of 1 year of age, 3 mg/kg should be used to determine dose regardless of the weight of the patient.

*          There is no data available regarding the administration of Tamiflu to infants less than one month of age.

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

This ese age-based dosing recommendations isare not intended for premature infants, i.e. those with a post-conceptual postmenstrual age less than 37 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 regimens are is  recommended for infants below 1 year0 - 12 months of age:

*          There is no data available regarding the administration of Tamiflu to infants less than one month of age.

Thisese age-based  dosing recommendation is are not intended for premature infants, i.e. those with a post-conceptual postmenstrual age less than 3637 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 below 120-12 yearsmonths of age.

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

Method of administration

Oral use..

Adults, adolescents (13 to 17 years of age) or infants and children (1 year of age or older) Patients  who are unable to swallow capsules, may receive appropriate doses of Tamiflu suspension.

4.4     Special warnings and precautions for use

Paediatric population

No data allowing a dose recommendation for premature children (< 367 weeks post-conceptual agepost-menstrual age*) are currently available.

*          Time between first day of last normal menstrual period and day of assessment, gestational age plus post-natal age.

4.8     Undesirable effects

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 124135 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.

Elderly patientsOlder 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. elderly patientsolder 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.

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

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 elderly 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.  

Treatment of influenza in high risk populations: The median duration of influenza illness in olderelderly subjects (≥ 65 years) and in subjects with chronic cardiac and/or respiratory disease receiving oseltamivir 75 mg twice daily for 5 days was not reduced significantly. The total duration of fever was reduced by one day in the groups treated with oseltamivir. In the influenza-positive older people elderly, oseltamivir significantly reduced the incidence of specified lower respiratory tract complications (mainly bronchitis) treated with antibiotics from 19 % (52/268) in the placebo group to 12 % (29/250) in the oseltamivir treated population (p = 0.0156).

The indication in infants below the age of 1 is based upon extrapolation of efficacy data from older children and the recommended posology is based upon pharmacokinetic modelling data (see Section 5.2).

5.2     Pharmacokinetic properties

Other Sspecial populations

ChildrenPaediatric population

Infants less than 1 year of age: Limited pharmacokinetic and safety data are available for infants less than 1 year of age. Pharmacokinetic modeling was undertaken using these data in addition to data from studies in adults and infants and children 1 year of age or older. The results demonstrate that doses of 3 mg /kg twice daily for infants aged 3 to 12 months and 2.5 mg /kg twice daily for infants aged between 1 and 3 months provide exposures similar to those shown to be clinically efficacious in adults and infants and children 1 year of age or older (see sections 4.1 and 4.2). There are currently no data available in infants less than 1 month of age using Tamiflu. The pharmacokinetics, pharmacodynamics and safety of Tamiflu have been evaluated in two uncontrolled open-label studies including influenza infected children less than one year of age (n=12435). The rate of clearance of the active metabolite, corrected for body-weight, decreases with ages below one year. Metabolite exposures are also more variable in the youngest infants. The available data indicates that the exposure following a 3 mg/kg dose in infants 0 - 12 months of age provides pro-drug and metabolite exposures anticipated to be efficacious with a safety profile comparable to that seen in older children and adults using the approved dose (see sections 4.1 and 4.2).The reported adverse events were consistent with the established safety profile in older children.

There are no data available for infants below 1 year of age for post exposure prevention of influenza. Prevention during an influenza epidemic in the community has not been studied in children below 12 years of age.

Exposure to the active metabolite at steady state was 25 to 35 % higher in elderly older people (age 65 to 78 years) compared to adults less than 65 years of age given comparable doses of oseltamivir. Half-lives observed in the elderlyolder people were similar to those seen in young adults. On the basis of drug exposure and tolerability, dosage adjustments are not required for elderly patientsolder people unless there is evidence of moderate or severe renal impairment (creatinine clearance below 60 ml /min) (see section 4.2).

6.6     Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

Extemporaneous formulation

When Tamiflu powder for oral suspension is not available

Commercially manufactured Tamiflu 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.  In the event that When commercially manufactured Tamiflu powder for oral suspension is not available, the pharmacist may compound a suspension (6 mg/ml) from Tamiflu capsules or patients can prepare the suspension from capsules at patients who are unable to swallow capsules may receive appropriate doses of Tamiflu prepared in a pharmacy or prepared at home.

For infants less than 1 year of age, tThe pharmacy preparation should be preferred to home preparation. Detailed information on the home preparation can be found in the package leaflet of Tamiflu capsules under “Making liquid Tamiflu suspension at home”.

10.     DATE OF REVISION OF THE TEXT

Underlined text has been added, text with strike through deleted:

4.2       Posology and method of administration

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ElderlyOlder people

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

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4.8    Undesirable effects

“Reporting of suspected adverse reactions” added in line with QRD 9

5.2       Pharmacokinetic properties

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ElderlyOlder people

Exposure to the active metabolite at steady state was 25 to 35 % higher in elderly (age 65 to 78 years) compared to adults less than 65 years of age given comparable doses of oseltamivir. Half-lives observed in the elderly were similar to those seen in young adults. On the basis of drug exposure and tolerability, dosage adjustments are not required for elderly patients unless there is evidence of moderate or severe renal impairment (creatinine clearance below 60 ml /min) (see section 4.2).

[…]

10.       DATE OF REVISION OF THE TEXT

25 April 2014

4.2     Posology and method of administration

Posology

[…]

Adults, and Aadolescents (13 to 17 years of age) and adultsand 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.

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.

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.

Infants and cChildren 1 to 12 years of age or older

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

[….]

For Iinfants below less than 1 year of age

In the absence of a suitable formulation, a pharmacy compounded preparation should preferentially be used as the syringe provided in the Tamiflu 12 mg/ml powder for oral suspension pack (with mg markings) does not allow for appropriate dose adjustments and commercially available syringes (with ml markings) may lead to unacceptable dosing inaccuracies (see section 6.6).

Treatment: The recommended treatment dose for infants less than 1 year of age is between 2 mg/kg twice daily and 3 mg/kg twice daily during a pandemic influenza outbreak. This is based upon limited pharmacokinetic and safety data indicating that these doses provide plasma drug exposures in the majority of patients similar to those shown to be clinically efficacious in older children and adults (see section 5.2). The following age-adjusted dosing regimens are recommended for treatment of infants below 1 year of age:

*          There is no data available regarding the administration of Tamiflu to infants less than one month of age.

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6.3       Shelf life

7 years

Storage of the pharmacy compounded suspension

Shelf life of 3 weeks  10 days when stored below 25 °C.

Shelf life of 6 weeks at 2 °C - 8 °C.

6.6     Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.