Tamiflu 75mg Hard Capsules

*
Pharmacy Only: Prescription
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    Roche Registration GmbH
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    No Recent Update
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    Product subject to medical prescription which may not be renewed (A)
  • Active Ingredient(s):

    *Additional information is available within the SPC or upon request to the company

Updated on 25 January 2023

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SmPC tamiflu hard cap 10_Sep 2021 clean.pdf

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  • Document format updated

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Updated on 11 November 2021

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  • Change to section 6 - date of revision

Updated on 17 September 2021

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  • Change to section 3 - how to take/use
  • Change to section 4 - how to report a side effect
  • Change to section 6 - marketing authorisation holder

Updated on 17 September 2021

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  • Change to Section 4.8 – Undesirable effects - how to report a side effect

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Updated on 25 August 2020

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TAM PIL 75 mg hard capsules clean.pdf

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  • Change to section 2 - excipient warnings

Updated on 20 April 2020

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Tamiflu-capsules-SPC-clean.pdf

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  • Change to section 4.2 - Posology and method of administration
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

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

Updated on 20 April 2020

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Tamiflu-75mg-capsules-PL-clean.pdf

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  • Change to section 3 - how to take/use
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update to PL following completion of paediatric studies NV25719 & NV20234 & downstream population PK & PK/PD analysis

Updated on 03 April 2019

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uk-ie-mt-spc-Tamiflu-clean-210219-30mg-45mg-75mg-caps.pdf

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  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text

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

Updated on 24 January 2019

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uk-ie-mt-pil-tamiflu-clean-19-01-11-75mg-caps.pdf

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  • Change to section 3 - how to take/use

Updated on 24 January 2019

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uk-ie-mt-spc-tamiflu-clean-19-01-11-caps.pdf

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties

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Free text change information supplied by the pharmaceutical company

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

Patient Population

Patients with Resistance Mutations (%)

Phenotyping*

Geno- and Phenotyping*

Adults and adolescents

0.6288% (1421/22532377)

 

0.671.12% (1527/22532391)

 

Children (1-12 years)

3.89% (66/1698)

 

4.24% (72/1698)

 

Infants (<1year)

18.31% (13/71)

18.31% (13/71)

* 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.

 

 

Updated on 17 December 2018

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uk-ie-mt-pil-tamiflu-clean-18-11-15-75mg-caps.pdf

Reasons for updating

  • Change to section 3 - how to take/use
  • Change to section 6 - date of revision

Updated on 14 December 2018

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uk-ie-mt-spc-tamiflu-clean-18-11-15-caps.pdf

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

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Updated on 17 August 2018

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uk-ie-mt-pil-Tamiflu-clean-18-08-09-75mg-Caps.pdf

Reasons for updating

  • Change to section 6 - date of revision
  • Change to other sources of information section

Updated on 21 May 2018

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uk-ie-mt-spc-tamiflu-clean-18-04-12-caps.docx

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  • Other

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Updated on 16 April 2018

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uk-ie-mt-pil-tamiflu-clean-18-04-12-75mg-caps.pdf

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  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - date of revision

Updated on 23 March 2018

Reasons for updating

  • New SPC for new product

Legal category:Product subject to medical prescription which may not be renewed (A)

Updated on 23 March 2018

Reasons for updating

  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 10 - Date of revision of the text

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

 





Updated on 18 January 2017

Reasons for updating

  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.1 - List of excipients
  • Change to section 6.3 - Shelf life
  • Change to section 8 - Marketing authorisation number(s)

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company



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.

 

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

[...]

Specific studies have not been conducted to assess the reduction in the risk of complications.

 

Oseltamivir resistance

Clinical studies: The risk of emergence of influenza viruses with reduced susceptibility or frank resistance to oseltamivir has been examined during Roche-sponsored clinical studies. Developing oseltamivir-resistant virus during treatment was more frequent in children than adults, ranging from less than 1% in adults to 18% in infants aged below 1 year. All patientsChildren  who were found to carry oseltamivir-resistant virus in general shed the virus for a prolonged period compared with subjects with susceptible virusd.id so transiently, cleared the virus normally and showed no clinical deterioration.. However treatment-emergent resistance to oseltamivir did not affect treatment response and caused no prolongation of influenza symptoms.

 

Patient Population

Patients with Resistance Mutations (%)

Phenotyping*

Geno- and Phenotyping*

Adults and adolescents

0.62% (14/2253)

4/1,245 (0.32 %)

0.67% (15/2253)

5/1,245 (0.4 %)

Children (1-12 years)

3.89% (66/1698)

19/464 (4.1 %)

4.24% (72/1698)

25/464 (5.4 %)

Infants (<1year)

18.31% (13/71)

18.31% (13/71)

* Full genotyping was not performed in all studies.

 

[...]

Oseltamivir-resistant viruses isolated from oseltamivir-treated patients and oseltamivir-resistant laboratory strains of influenza viruses have been found to contain mutations in N1 and N2 neuraminidases. Resistance mutations tend to be viral sub-type specific. Since 2007 naturally occurring resistance associated with the H275Y mutation in seasonal H1N1 strains has been sporadically detectedbecome widespread. The susceptibility to oseltamivir and the prevalence of such viruses appear to vary seasonally and geographically. In 2008, H275Y was found in > 99 % of circulating H1N1 influenza isolates in Europe. The 2009 H1N1 influenza (“swine flu”) was almost uniformly susceptible to oseltamivir, with only sporadic reports of resistance in connection with both therapeutic and prophylactic regimens.

[...]

6.       PHARMACEUTICAL PARTICULARS

 

6.1     List of excipients

 

Tamiflu 30 mg hard capsules

Capsule core

Pregelatinised starch (derived from maize starch)

Talc

Povidone

Croscarmellose sodium

Sodium stearyl fumarate

 

Capsule shell

Gelatin

Yellow iron oxide (E172)

Red iron oxide (E172)

Titanium dioxide (E171)

 

Printing ink

Shellac

Titanium dioxide (E171)

FD and C Blue 2 (indigo carmine, E132)

 

Tamiflu 45 mg hard capsules

Capsule core

Pregelatinised starch (derived from maize starch)

Talc

Povidone

Croscarmellose sodium

Sodium stearyl fumarate

 

Capsule shell

Gelatin

Black iron oxide (E172)

Titanium dioxide (E171)

 

Printing ink

Shellac

Titanium dioxide (E171)

FD and C Blue 2 (indigo carmine, E132)

 

 

Tamiflu 75 mg hard capsules

Capsule core

Pregelatinised starch (derived from maize starch)

Talc

Povidone

Croscarmellose sodium

Sodium stearyl fumarate

 

Capsule shell

Gelatin

Yellow iron oxide (E172)

Red iron oxide (E172)

Black iron oxide (E172)

Titanium dioxide (E171)

 

Printing ink

Shellac

Titanium dioxide (E171)

FD and C Blue 2 (indigo carmine, E132)

 

 

6.3       Shelf life

 

Tamiflu 30 mg hard capsules

7 years

 

Tamiflu 45 mg hard capsules

7 years

 

Tamiflu 75 mg hard capsules

10 years

 

 

8.       MARKETING AUTHORISATION NUMBER(S)

 

Tamiflu 30 mg hard capsules

EU/1/02/222/003

 

Tamiflu 45 mg hard capsules
EU/1/02/222/004

 

Tamiflu 75 mg hard capsules
EU/1/02/222/001

 


 

 


Updated on 27 May 2016

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

[....]

Updated on 02 June 2015

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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:

 

Body weight*

Recommended dose for 5 days

3 kg

9 mg twice daily

4 kg

12 mg twice daily

5 kg

15 mg twice daily

6 kg

18 mg twice daily

7 kg

21 mg twice daily

8 kg

24 mg twice daily

9 kg

27 mg twice daily

10 kg

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 of age, 3 mg/kg should be used to determine dose regardless of the weight of the patient.

 

Age

Recommended dose for 5 days

0 to 1 month*

2 mg/kg twice daily

> 1 month to 3 months

2.5 mg/kg twice daily

> 3 months to 12 months

3 mg/kg twice daily

*          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:

 

Age

Recommended dose for 10 days

0 to 1 month*

2 mg/kg once daily

> 1 month to 3 months

2.5 mg/kg once daily

> 3 months to0 -  12 months

3 mg/kg once daily

*          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

Body Weight

(rounded to the nearest 0.5 kg)

Dose

(mg)

Volume

per dose

(6 mg/ml)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

Dispenser size

to use

(grading 0.1 ml)

3 kg

9 mg

1.5 ml

1.5 ml twice daily

1.5 ml once daily

2.0 ml or 3.0 ml

3.5 kg

10.5 mg

1.8 ml

1.8 ml twice daily

1.8 ml once daily

2.0 ml or 3.0 ml

4 kg

12 mg

2.0 ml

2.0 ml twice daily

2.0 ml once daily

3.0 ml

4.5 kg

13.5 mg

2.3 ml

2.3 ml twice daily

2.3 ml once daily

3.0 ml

5 kg

15 mg

2.5 ml

2.5 ml twice daily

2.5 ml once daily

3.0 ml

5.5 kg

16.5 mg

2.8 ml

2.8 ml twice daily

2.8 ml once daily

3.0 ml

6 kg

18 mg

3.0 ml

3.0 ml twice daily

3.0 ml once daily

3.0 ml (or 5.0 ml)

6.5 kg

19.5 mg

3.3 ml

3.3 ml twice daily

3.3 ml once daily

5.0 ml

7 kg

21 mg

3.5 ml

3.5ml twice daily

3.5 ml once daily

5.0 ml

7.5 kg

22.5 mg

3.8 ml

3.8 ml twice daily

3.8 ml once daily

5.0 ml

8 kg

24 mg

4.0 ml

4.0 ml twice daily

4.0 ml once daily

5.0 ml

8.5 kg

25.5 mg

4.3 ml

4.3 ml twice daily

4.3 ml once daily

5.0 ml

9 kg

27 mg

4.5 ml

4.5 ml twice daily

4.5 ml once daily

5.0 ml

9.5 kg

28.5 mg

4.8 ml

4.8 ml twice daily

4.8 ml once daily

5.0 ml

10 kg

30 mg

5.0 ml

5.0 ml twice daily

5.0 ml once daily

5.0 ml

 

 

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)

Body Weight

(rounded to the nearest 0.5 kg)

Dose

(mg)

Volume

per dose

(6 mg/ml)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

Dispenser size

to use

(grading 0.1 ml)

3 kg

6 mg

1.0 ml

1.0 ml twice daily

1.0 ml once daily

1.0 ml (or 2.0 ml)

3.5 kg

7 mg

1.2 ml

1.2 ml twice daily

1.2 ml once daily

2.0 ml

4 kg

8 mg

1.3 ml

1.3 ml twice daily

1.3 ml once daily

2.0 ml

4.5 kg

9 mg

1.5 ml

1.5 ml twice daily

1.5 ml once daily

2.0 ml

 

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)

Body Weight

(rounded to the nearest 0.5 kg)

Dose

(mg)

Volume

per dose

(6 mg/ml)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

Dispenser size

to use

(grading 0.1 ml)

4 kg

10 mg

1.7 ml

1.7 ml twice daily

1.7 ml once daily

2.0 ml (or 3.0 ml)

4.5 kg

11.25 mg

1.9 ml

1.9 ml twice daily

1.9 ml once daily

2.0 ml (or 3.0 ml)

5 kg

12.5 mg

2.1 ml

2.1 ml twice daily

2.1 ml once daily

3.0 ml

5.5 kg

13.75 mg

2.3 ml

2.3 ml twice daily

2.3 ml once daily

3.0 ml

6 kg

15 mg

2.5 ml

2.5 ml twice daily

2.5 ml once daily

3.0 ml

6.5 kg

16.25 mg

2.7 ml

2.7 ml twice daily

2.7 ml once daily

3.0 ml

 

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)

Body Weight
(rounded to the nearest 0.5 kg)

Dose

(mg)

Volume

per dose

(6 mg/ml)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

Dispenser size

to use

(grading 0.1 ml)

6 kg

18 mg

3.0 ml

3.0 ml twice daily

3.0 ml once daily

3.0 ml (or 5.0 ml)

6.5 kg

19.5 mg

3.3 ml

3.3 ml twice daily

3.3 ml once daily

5.0 ml

7 kg

21 mg

3.5 ml

3.5ml twice daily

3.5 ml once daily

5.0 ml

7.5 kg

22.5 mg

3.8 ml

3.8 ml twice daily

3.8 ml once daily

5.0 ml

8 kg

24 mg

4.0 ml

4.0 ml twice daily

4.0 ml once daily

5.0 ml

8.5 kg

25.5 mg

4.3 ml

4.3 ml twice daily

4.3 ml once daily

5.0 ml

9 kg

27 mg

4.5 ml

4.5 ml twice daily

4.5 ml once daily

5.0 ml

9.5 kg

28.5 mg

4.8 ml

4.8 ml twice daily

4.8 ml once daily

5.0 ml

10 kg

30 mg

5.0 ml

5.0 ml twice daily

5.0 ml once daily

5.0 ml

 

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

 




[...][...][...][...][...][...][...][...][...][...][...][...][...]

Updated on 21 May 2015

Reasons for updating

  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

 







Updated on 15 May 2015

File name

PIL_9360_302.pdf

Reasons for updating

  • New PIL for new product

Updated on 15 May 2015

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.5 - Nature and contents of container
  • Change to section 10 - Date of revision of the text

Legal category:Product subject to medical prescription which may not be renewed (A)

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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:

 

Body weight*

Recommended dose for 5 days

3 kg

9 mg twice daily

4 kg

12 mg twice daily

5 kg

15 mg twice daily

6 kg

18 mg twice daily

7 kg

21 mg twice daily

8 kg

24 mg twice daily

9 kg

27 mg twice daily

10 kg

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 of age, 3 mg/kg should be used to determine dose regardless of the weight of the patient.

 

Age

Recommended dose for 5 days

0 to 1 month*

2 mg/kg twice daily

> 1 month to 3 months

2.5 mg/kg twice daily

> 3 months to 12 months

3 mg/kg twice daily

*          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:

 

Age

Recommended dose for 10 days

0 to 1 month*

2 mg/kg once daily

> 1 month to 3 months

2.5 mg/kg once daily

> 3 months to0 -  12 months

3 mg/kg once daily

*          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

 

5 May 2015

 








Updated on 15 May 2015

Reasons for updating

  • Change to packaging
  • Change to side-effects
  • Change to date of revision
  • Change to dosage and administration
  • Changes to therapeutic indications

Updated on 20 May 2014

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

4.2       Posology and method of administration

[…]

ElderlyOlder people

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

[…]

4.8    Undesirable effects

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

5.2       Pharmacokinetic properties

[…]

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

 

 

 

Updated on 19 May 2014

Reasons for updating

  • Change to date of revision
  • Addition of information on reporting a side effect.

Updated on 27 November 2013

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 6.3 - Shelf life
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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.

 

Body Weight

Recommended dose for 5 days

> 40 kg

75 mg twice daily

 

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

> 40 kg

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.

 

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:

 

Age

Recommended dose for 5 days

0 to 1 month*

2 mg/kg twice daily

> 3 months to 12 months

3 mg/kg twice daily

> 1 month to 3 months

2.5 mg/kg twice daily

> 3 months to 12 months

3 mg/kg twice daily

0 to 1 month*

2 mg/kg twice daily

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

 

[…]

 

 

Age

Recommended dose for 10 days

0 to 1 month*

2 mg/kg once daily

> 3 months to 12 months

3 mg/kg once daily

> 1 month to 3 months

2.5 mg/kg once daily

> 3 months to 12 months

3 mg/kg once daily

0 to 1 month*

2 mg/kg once daily

 

 

[…]

 

 

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.

 

[…]

 

Pharmacy compounding

 

Pharmacy compounded 156 mg/ml suspension prepared from capsules

 

Adults, adolescents and infants and children 1 year of age or older who are unable to swallow intact capsules

This procedure describes the preparation of a 156 mg/ml suspension that will provide one patient with enough medicine for a 5-day course of treatment or a 10-day course of prophylaxis.

 

The pharmacist may compound a 156 mg/ml suspension from Tamiflu 30 mg, 45 mg or 75 mg capsules using water containing 0.10.05 % w/v sodium benzoate added as a preservative.

 

First, calculate the total volume needed to be compounded and dispensed to provide a 5-day course of treatment or a 10-day course of prophylaxis for the patient. The total volume required is determined by the weight of the patient according to the recommendation in the table below:. To allow for accurate volume withdrawal of up to 10 doses (2 withdrawals per daily treatment dose for 5 days), the column indicating measurement loss is to be considered for compounding.

 

Volume of pharmacy compounded 156 mg/ml suspension prepared based upon the patient’s weight

Body weight
(kg)

Total volume to compound
per patient weight
(ml)

Measurement loss not considered

Total volume to compound
per patient weight
(ml)

Measurement loss considered

10 kg to 15 kg

3050 ml

60 ml or 75 ml*

> 15 kg to 23 kg

4075 ml

90 ml or 100 ml*

> 23 kg to 40 kg

50100 ml

125 ml

> 40 kg

60125 ml

137.5 ml (or 150 ml)*

*          Depending on the capsule strength used.

 

Second, determine the number of capsules and the amount of vehicle (water containing 0.10.05 % w/v sodium benzoate added as a preservative) that is needed to prepare the total volume (calculated from the table above: 3050 ml, 4075 ml, 50100 ml or 60125 ml) of pharmacy compounded 156 mg/ml suspension as shown in the table below:

 

Number of capsules and amount of vehicle needed to prepare the total volume of a pharmacy compounded 156 mg/ml suspension

Total volume
of compounded suspension
to be prepared

Required number of Tamiflu capsules
(mg of oseltamivir)

Required volume
of vehicle

75 mg

45 mg

30 mg

3050 ml

6 4 capsules

(450 300 mg)

10 capsules

(450 mg) Please use alternative capsule strength*

1510 capsules

(450 300 mg)

2949.5 ml

60 ml

Please use alternative capsule strength*

8 capsules

(360 mg)

12 capsules

(360 mg)

59.5 ml

4075 ml

86 capsules

(600 450 mg)

Please use alternative capsule strength*10 capsules

(450 mg)

20 15 capsules

(600 450 mg)

38.574 ml

90 ml

Please use alternative capsule strength*

12 capsules

(540 mg)

18 capsules

(540 mg)

89 ml

50100 ml

10 8 capsules

(750 600 mg)

Please use alternative capsule strength*

25 20 capsules

(750 600 mg)

4898.5 ml

60125 ml

12 10 capsules

(900 750 mg)

20 capsules

(900 mg)Please use alternative capsule strength*

30 capsules

(900 mg)Please use alternative capsule strength*

25 capsules

(750 mg)

57123.5 ml

137.5 ml

11 capsules

(825 mg)

Please use alternative capsule strength*

Please use alternative capsule strength*

136 ml

*          No integral number of capsules There is no combination of this capsule strength that can be used to achieve the target concentration; therefore, please use either the 30 mg or 75 mg capsulesan alternative capsule strength.

 

Third, follow the procedure below for compounding the 156 mg/ml suspension from Tamiflu capsules:

1.       Carefully separate the capsule body and cap and transfer the contents of the required number of Tamiflu capsules into a clean mortar.In a glass beaker of suitable size place the stated amount of water containing 0.05 % w/v sodium benzoate added as a preservative.

2.       Triturate the granules to a fine powder.Open the stated amount of Tamiflu capsules and transfer the content of each capsule directly to the preserved water in the glass beaker.

3.       Add one-third (1/3) of the specified amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) and triturate the powder until a uniform suspension is achieved.With a suitable stirring device, stir for 2 minutes.

          (Note: The drug substance, oseltamivir phosphate, readily dissolves in water. The suspension is caused by some of the excipients of Tamiflu capsules, which are insoluble.)

4.       Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle. A funnel may be used to eliminate any spillage.

5.       Add another one-third (1/3) of the vehicle to the mortar, rinse the pestle and mortar by a triturating motion and transfer the vehicle into the bottle.

6.       Repeat the rinsing (Step 5) with the remainder of the vehicle.

75.     Close the bottle using a child-resistant cap.

8.       Shake well to completely dissolve the active substance and to ensure homogeneous distribution of the dissolved active substance in the resulting suspension.

(Note: Undissolved residue may be visible but is comprised of inert ingredients of Tamiflu capsules, which are insoluble. However, the active substance, oseltamivir phosphate, readily dissolves in the specified vehicle and therefore forms a uniform solution.)

96.     Put an ancillary label on the bottle indicating Shake Gently Before Use.

          (Note: This compounded suspension should be gently shaken prior to administration to minimize the tendency for air entrapment.)

107.   Instruct the parent or caregiver that after the patient has completed the full course of therapy any remaining solution material following completion of therapy must be discarded. It is recommended that this information be provided by either affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions.

118.   Place an appropriate expiration date label according to storage condition (see section 6.3).

 

Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, use by date, name of medicinal product and any other required information to be in compliance with local pharmacy regulations. Refer to the table below for the proper dosing instructions.

 

Dosing chart for pharmacy-compounded 156 mg/ml suspension prepared from Tamiflu capsules for infants and children 1 year of age or older

Body weight
(kg)

Dose
(mg)

Volume per dose
156 mg/ml

Treatment dose
(for 5 days)

Prophylaxis dose
(for 10 days)

10 kg to 15 kg

30 mg

25 ml

25 ml twice daily

25 ml once daily

> 15 kg to 23 kg

45 mg

37.5 ml

37.5 ml twice daily

37.5 ml once daily

> 23 kg to 40 kg

60 mg

410 ml

410 ml twice daily

410 ml once daily

> 40 kg

75 mg

512.5 ml

512.5 ml twice daily

512.5 ml once daily

Note: This compounding procedure results in a 15 mg/ml suspension, which is different from the commercially available Tamiflu powder for oral suspension.

 

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 (2 ml, 3 ml, 4 ml or 5 mlaccording to the dosing table 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.

 

Pharmacy compounded 106 mg/ml suspension prepared from capsules

 

Infants less than 1 year of age

This procedure describes the preparation of a 106 mg/ml suspension that will provide one patient with enough medication for a 5-day course of treatment or a 10-day course of prophylaxis.

 

The pharmacist may compound a 106 mg/ml suspension from Tamiflu 30 mg, 45 mg or 75 mg capsules using water containing 0.10.05 % w/v sodium benzoate added as a preservative.

 

First, calculate the total volume needed to be compounded and dispensed for each patient. The total volume required is determined by the weight of the patient according to the recommendation in the table below:. To allow for accurate volume withdrawal of up to 10 doses (2 withdrawals per daily treatment dose for 5 days), the column indicating measurement loss is to be considered for compounding.

 

Volume of pharmacy compounded 106 mg/ml suspension prepared based upon the patient’s weight

Body weight
(kg)

Total volume to compound
per patient weight
(ml)

Measurement loss not considered

Total volume to compound
per patient weight
(ml)

Measurement loss considered

£ 7 kg

30up to 40 ml

50 ml

> 7 kg to 12 10 kg

4550 ml

50 mgml, 60 ml or 75 ml*

*          Depending on the capsule strength used.

 

Second, determine the number of capsules and the amount of vehicle (water containing 0.10.05 % w/v sodium benzoate added as a preservative) that is needed to prepare the total volume (calculated from the table above: 30 ml, 4550 ml) of pharmacy compounded 106 mg/ml suspension as shown in the table below:

 

Number of capsules and amount of vehicle needed to prepare the total volume of a pharmacy compounded 106 mg/ml suspension

Total volume
of compounded suspension
to be prepared

Required number of Tamiflu capsules
(mg of oseltamivir)

Required volume
of vehicle

75 mg

45 mg

30 mg

30 ml

4 capsules

(300 mg)Please use alternative capsule strength*

Please use alternative capsule strength*4 capsules

(180 mg)

10 6 capsules

(300 180 mg)

29.5 ml

4550 ml

64 capsules

(450 300 mg)

10 capsules

(450 mg)Please use alternative capsule strength*

15 10 capsules

(450 300 mg)

4449.5 ml

60 ml

Please use alternative capsule strength*

8 capsules

(360 mg)

12 capsules

(360 mg)

59.5 ml

75 ml

6 capsules

(450 mg)

10 capsules

(450 mg)

15 capsules

(450 mg)

74 ml

*          No integral number of capsules There is no combination of this capsule strength that can be used to achieve the target concentration; therefore, please use either the 30 mg or 75 mg capsulesan alternative capsule strength.

 

Third, follow the procedure below for compounding the 156 mg/ml suspension from Tamiflu capsules:

1.       Carefully separate the capsule body and cap and transfer the contents of the required number of Tamiflu capsules into a clean mortar.In a glass beaker of suitable size place the stated amount of water containing 0.05 % w/v sodium benzoate added as a preservative.

2.       Triturate the granules to a fine powder.Open the stated amount of Tamiflu capsules and transfer the content of each capsule directly to the preserved water in the glass beaker.

3.       Add one-third (1/3) of the specified amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) and triturate the powder until a uniform suspension is achieved.With a suitable stirring device, stir for 2 minutes.

          (Note: The drug substance, oseltamivir phosphate, readily dissolves in water. The suspension is caused by some of the excipients of Tamiflu capsules, which are insoluble.)

4.       Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle. A funnel may be used to eliminate any spillage.

5.       Add another one-third (1/3) of the vehicle to the mortar, rinse the pestle and mortar by a triturating motion and transfer the vehicle into the bottle.

6.       Repeat the rinsing (Step 5) with the remainder of the vehicle.

75.     Close the bottle using a child-resistant cap.

8.       Shake well to completely dissolve the active substance and to ensure homogeneous distribution of the dissolved active substance in the resulting suspension.

(Note: Undissolved residue may be visible but is comprised of inert ingredients of Tamiflu capsules, which are insoluble. However, the active substance, oseltamivir phosphate, readily dissolves in the specified vehicle and therefore forms a uniform solution.)

96.     Put an ancillary label on the bottle indicating Shake Gently Before Use.

          (Note: This compounded suspension should be gently shaken prior to administration to minimize the tendency for air entrapment.)

107.   Instruct the parent or caregiver that after the patient has completed the full course of therapy any remaining solution material following completion of therapy must be discarded. It is recommended that this information be provided by either affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions.

118.   Place an appropriate expiration date label according to storage condition (see section 6.3).

 

Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, use by date, name of medicinal product and any other required information to be in compliance with local pharmacy regulations. Refer to the table below for the proper dosing instructions.

 

Dosing chart for pharmacy compounded 106 mg/ml suspension prepared from Tamiflu capsules for infants 0 to 30 days of age (less than one month of age)

Body Weight

(rounded to the nearest 0.5 kg)

Dose

(mg)

Volume

per dose

(106 mg/ml)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

Dispenser size

to use

(grading 0.1 ml)

3 kg

6 mg

0.601.0 ml

0.601.0 ml twice daily

0.601.0 ml once daily

121.0 ml (or 232.0 ml)

3.5 kg

7 mg

0.701.2 ml

0.701.2 ml twice daily

0.701.2 ml once daily

12.0 ml (or 23 ml)

4 kg

8 mg

0.801.3 ml

0.801.3 ml twice daily

0.801.3 ml once daily

12.0 ml (or 23 ml)

4.5 kg

9 mg

0.901.5 ml

0.901.5 ml twice daily

0.901.5 ml once daily

12.0 ml (or 23 ml)

 

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)

Body Weight

(rounded to the nearest 0.5 kg)

Dose

(mg)

Volume

per dose

(6 mg/ml)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

Dispenser size

to use

(grading 0.1 ml)

4 kg

10 mg

1.7 ml

1.7 ml twice daily

1.7 ml once daily

2.0 ml (or 3.0 ml)

4.5 kg

11.25 mg

1.9 ml

1.9 ml twice daily

1.9 ml once daily

2.0 ml (or 3.0 ml)

5 kg

12.5 mg

2.1 ml

2.1 ml twice daily

2.1 ml once daily

3.0 ml

5.5 kg

13.75 mg

2.3 ml

2.3 ml twice daily

2.3 ml once daily

3.0 ml

6 kg

15 mg

2.5 ml

2.5 ml twice daily

2.5 ml once daily

3.0 ml

6.5 kg

16.25 mg

2.7 ml

2.7 ml twice daily

2.7 ml once daily

3.0 ml

 

Dosing chart for pharmacy compounded 106 mg/ml suspension prepared from Tamiflu capsules for infants one to twelve 91 to less than 365 days of age (more than three months to twelve months of age)

Body Weight
(rounded to the nearest 0.5 kg)

Dose

(mg)

Volume

per dose

(106 mg/ml)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

Dispenser size

to use

(grading 0.1 ml)

4 kg

10 mg

1.00 ml

1.00 ml twice daily

1.00 ml once daily

2 ml (or 3 ml)

4.5 kg

11.25 mg

1.10 ml

1.10 ml twice daily

1.10 ml once daily

2 ml (or 3 ml)

5 kg

12.5 mg

1.30 ml

1.30 ml twice daily

1.30 ml once daily

2 ml (or 3 ml)

5.5 kg

13.75 mg

1.40 ml

1.40 ml twice daily

1.40 ml once daily

2 ml (or 3 ml)

6 kg

15 18 mg

1.50 3.0 ml

1.503.0 ml twice daily

1.503.0 ml once daily

2 ml (or 3.0 ml) (or 5.0 ml)

6.5 kg

19.5 mg

3.3 ml

3.3 ml twice daily

3.3 ml once daily

5.0 ml

7 kg

21 mg

2.103.5 ml

2.10 3.5ml twice daily

2.10 3.5 ml once daily

35.0 ml

7.5 kg

22.5 mg

3.8 ml

3.8 ml twice daily

3.8 ml once daily

5.0 ml

8 kg

24 mg

2.404.0 ml

2.40 4.0 ml twice daily

2.40 4.0 ml once daily

35.0 ml

8.5 kg

25.5 mg

4.3 ml

4.3 ml twice daily

4.3 ml once daily

5.0 ml

9 kg

27 mg

2.70 4.5 ml

2.70 4.5 ml twice daily

2.70 4.5 ml once daily

35.0 ml

9.5 kg

28.5 mg

4.8 ml

4.8 ml twice daily

4.8 ml once daily

5.0 ml

³ 10 kg

30 mg

3.00 5.0 ml

3.00 5.0 ml twice daily

3.00 5.0 ml once daily

3 ml (or 5.0 ml)

 

Note:    This compounding procedure results in a 10 mg/ml suspension, which is different from the commercially available Tamiflu powder for oral suspension.

 

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.

 

[…]

 

10.     DATE OF REVISION OF THE TEXT

 

24 October 2013

 

 

 

 

Updated on 22 November 2013

Reasons for updating

  • Change to, or new use for medicine
  • Change to side-effects
  • Change to further information section
  • Change to date of revision

Updated on 21 December 2012

Reasons for updating

  • Change to section 4.9 - Overdose
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Underlined text = new text

 

Strike through text = deleted text

 

 

4.9     Overdose

 

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.

 

There is no experience with overdose. However, the anticipated manifestations of acute overdose would be nausea, with or without accompanying vomiting, and dizziness. Patients should discontinue the treatment in the event of overdose. 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.

 

 

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 20 June 2002

Date of last renewal: 20 June 20072012

 

10.     DATE OF REVISION OF THE TEXT

 

15 November 2012

 

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Updated on 13 December 2012

Reasons for updating

  • Change to instructions about overdose
  • Change to date of revision

Updated on 26 September 2012

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company



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


 

4.8     Undesirable effects

 

Summary of the safety profile

The overall safety profile of Tamiflu is based on data from 46246049 adult/adolescent and1480 1473 paediatric patients treated with Tamiflu or placebo for influenza, and on data from3533 3990 adult/adolescent and148 253 paediatric patients receiving Tamiflu or placebo/no treatment for the prophylaxis of influenza in clinical trials. In addition, 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 vomitingand headache in the treatment studies, and nausea , vomiting, headache and pain 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 reactions were was vomiting. , nausea, dyspepsia, abdominal pain and headache. In the majority of patients, these ARs did not lead to discontinuation of Tamiflu.

 

The following serious clinically important 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 summary list of adverse reactions

The ARs listed in the tables below fall into the following categories: Very common (³ 1/10), common (³ 1/100 to < 1/10), uncommon (³ 1/1,000 to < 1/100), rare (³ 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 prophylaxis prevention studies, ARs that occurred the most frequently (³ 1 %) 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,

Influenza,

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,

Nasal congestion,

Sore throat,

Rhinorrhea

 

 

Gastrointestinal disorders

Nausea

Vomiting

Abdominal pain (incl. upper abdominal pain), Diarrhoea, Dyspepsia

 

Gastrointestinal bleedings, Hemorrhagic 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

Musculoskeletal and connective tissue disorders

 

Arthralgia,

Back pain,

Myalgia

 

 

Reproductive system and breast disorders

 

Dysmenorrhea

 

 

General disorders and administration site conditions

 

Pain

Dizziness (incl. vertigo),

Fatigue,

Pyrexia ,

Pain in limb

Influenza like illness

 

 

Below is a list of commonly occurring ARs from treatment studies (n = 2,647) and prophylaxis studies (n = 1,945). These events occurred either more frequently in patients on placebo compared to patients on oseltamivir, or the difference in frequency between the two arms was less than 1 %. Commonly occurring ARs are those which occur with a frequency of greater than 1 per 100 patients, and less than 1 per 10 patients.

 

·        Infections and infestations: Bronchitis, herpes simplex, influenza, nasopharyngitis, upper respiratory tract infections, sinusitis

 

·        Nervous system disorders: Insomnia

 

·        Respiratory, thoracic and mediastinal disorders: Cough, nasal congestion, sore throat, rhinorrhea

 

·        Gastrointestinal disorders: Abdominal pain (incl. upper abdominal pain), diarrhoea, dyspepsia

 

·        Musculoskeletal and connective tissue disorders: Arthralgia, back pain, myalgia

 

·        Reproductive system and breast disorders: Dysmenorrhea

 

·        General disorders: Dizziness (incl. vertigo), fatigue, influenza like illness, pain in limb, pyrexia

 

Treatment and prevention of influenza in children:

 

A total of 14801473 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, 858851 children received treatment with oseltamivir suspension. A total of 148 158 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).

and in a separate 6-week paediatric prophylaxis study (n = 49).

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

 

Bronchitis,

Nasopharyngitis,

Otitis media,

Pneumonia,

Sinusitis,

Upper respiratory tract infection

 

 

Blood and lymphatic system disorders

 

 

Lymphadenopathy

 

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

Asthma (including aggravated asthma),

Epistaxis,

Rhinorrhoea

 

 

Gastrointestinal disorders

Vomiting

Abdominal pain (incl. upper abdominal pain), Dyspepsia,

Nausea

Diarrhoea

 

 

Skin and subcutaneous tissue disorders

 

 

Dermatitis (including allergic and atopic dermatitis)

 

General disorders

 

Pyrexia

 

 

 

Below is a list of commonly occurring ARs from treatment studies (n = 858) and prophylaxis studies (n = 148). These events occurred either more frequently in patients on placebo/no prophylaxis compared to patients on oseltamivir, or the difference in frequency between the two groups was less than 1 %. Commonly occurring ARs are those which occur with a frequency of greater than 1 per 100 patients, and less than 1 per 10 patients.

 

·        Infections and infestations: Bronchitis, nasopharyngitis, otitis media, pneumonia, sinusitis, upper respiratory tract infection

 

·        Eye disorders: Conjunctivitis (including red eyes, eye discharge and eye pain)

 

·        Ear and labyrinth disorders: Earache

 

·        Respiratory, thoracic and mediastinal disorders: Asthma (including aggravated asthma), cough, epistaxis, nasal congestion, rhinorrhoea

 

·        Gastrointestinal disorders: Diarrhoea

 

·        Skin and subcutaneous tissue disorders: Dermatitis (including allergic and atopic dermatitis)

 

·        General disorders: Pyrexia

 

The following additional Uncommon (frequency > 1/1,000 to < 1/100) ARs were reported in the paediatric treatment studies. These ARs previously qualified as Common (frequency > 1/100 to < 1/10) but in the larger datasets no longer fulfil the criteria to be included in the previous section.

 

·        Blood and lymphatic system disorders: Lymphadenopathy

 

·        Ear and labyrinth disorders: Tympanic membrane disorder

 

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)

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 patients 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 patients 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

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.

10.     DATE OF REVISION OF THE TEXT

 

 

 

 

 

 

Updated on 14 September 2012

Reasons for updating

  • Change to side-effects
  • Correction of spelling/typing errors

Updated on 08 June 2012

Reasons for updating

  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

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1.       NAME OF THE MEDICINAL PRODUCT

 

Tamiflu 30 mg hard capsules.

Tamiflu 45 mg hard capsules.

 

 

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

[…]

 

For a the full list of excipients, see section 6.1.

 

 

3.       PHARMACEUTICAL form

 

Hard capsule (capsule)

 

[…]

 

 

4.       Clinical particulars

 

4.1     Therapeutic indications

 

[…]

 

Tamiflu is indicated for the treatment of infants below 12 months 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.

 

Prevention of influenza

-        Post-exposure prevention in individuals one 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 below 12 months less than 1 year of age during a pandemic influenza outbreak (see section 5.2).

 

 […]

 

Based on limited pharmacokinetic and safety data, Tamiflu can be used in infants below 12 months of age for treatment during a pandemic influenza outbreak. 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.

 

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.

 

Adolescents (13 to 17 years of age) and adults

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 older than 1 year of age and children 1 year of age or older 2 to 12 years of age


Tamiflu 30 mg, 45 mg and 75 mg capsules
and
oral suspension are available for infants older than 1 year of age and for children 1  year of age or older. 2 to 12 years of age


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

Body Weight

Recommended dose for 5 days

10 kg to ≤ 15 kg

30 mg twice daily

> 15 kg to 23 kg

45 mg twice daily

> 23 kg to 40 kg

60 mg twice daily

> 40 kg

75 mg twice daily


Treatment should be 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

10 kg to ≤ 15 kg

30 mg once daily

> 15 kg to 23 kg

45 mg once daily

> 23 kg to 40 kg

60 mg once daily

> 40 kg

75 mg once daily


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


For infants below 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 below section 4.2 6.6).

 

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


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


Ø  For infants older than 1 year of age and for children 2 to 12 years of age: Tamiflu 30 mg and 45 mg capsules and oral suspension are available.


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

 

Body Weight

Recommended dose for 5 days

≤ 15 kg

30 mg twice daily

> 15 kg to 23 kg

45 mg twice daily

> 23 kg to 40 kg

60 mg twice daily

> 40 kg

75 mg twice daily

Children who are able to swallow capsules may receive treatment with Tamiflu capsules (30 mg, 45 mg, 75 mg) twice daily for 5 days as an alternative to the recommended dose of Tamiflu suspension.


Ø  For infants below 12 months of age: The recommended treatment dose for infants less than 12 months 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 weightage-adjusted dosing regimens are recommended for treatment of infants below 1 year of age:

 

Age

Recommended dose for 5 days

> 3 months to 12 months

3 mg/kg twice daily

> 1 month to 3 months

2.5 mg/kg twice daily

0 to 1 month*

2 mg/kg twice daily

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

 

Administration of Tamiflu to infants less than one year of age should be based upon the judgment of the physician after considering the potential benefit of treatment versus any potential risk to the infant.

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

 

These age-based dosing recommendations are not intended for premature infants, i.e. those with a postmenstrual age less than 37 weeks. Insufficient data are available for these patients, in whom different dosing may be required due to the immaturity of physiological functions.

 

Prevention of influenza

Body Weight

Recommended dose for 10 days

≤ 15 kg

30 mg once daily

> 15 kg to 23 kg

45 mg once daily

> 23 kg to 40 kg

60 mg once daily

> 40 kg

75 mg once daily

Post-exposure prevention:

Children who are able to swallow capsules may receive prevention Tamiflu capsules (30 mg, 45 mg, 75 mg) once daily for 10 days as an alternative to the recommended dose of Tamiflu suspension.


Ø  For infants below 12 months of age: The recommended prophylaxis dose for infants less than 12 months 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 weightage-adjusted dosing prophylaxis regimens are recommended for infants below 1 year of age:

 

Age

Recommended dose for 10 days

> 3 months to 12 months

3 mg/kg once daily

> 1 month to 3 months

2.5 mg/kg once daily

0 to 1 month*

2 mg/kg once daily

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

 

Administration of Tamiflu to infants less than one year of age should be based upon the judgment of the physician after considering the potential benefit of prophylaxis versus any potential risk to the infant.


[…]

 

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


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.


Extemporaneous formulation

When Tamiflu powder for oral suspension is not available

When commercially manufactured Tamiflu powder for oral suspension is not available, patients who are unable to swallow capsules may receive appropriate doses of Tamiflu prepared in a pharmacy or prepared at home.

For infants below 12 months, the pharmacy preparation should be preferred to home preparation. Detailed information on the home preparation can be found in section 3 of the package leaflet of Tamiflu capsules.


Pharmacy compounding

Ø  Adults and children greater than 1 year who are unable to swallow intact capsules

This procedure describes the preparation of a 15 mg/ml solution that will provide one patient with enough medication for a 5-day course of treatment or a 10-day course of prophylaxis.


The pharmacist may compound a suspension (15 mg/ml) from Tamiflu 30 mg, 45 mg or 75 mg capsules using water containing 0.1% w/v sodium benzoate added as a preservative.


First, calculate the Total Volume needed to be compounded and dispensed to provide a 5-day course of treatment or a 10=day course of prophylaxis for the patient. The Total Volume required is determined by the weight of the patient according to the recommendation in the table below:


Volume of Compounded Suspension (15 mg/ml) Prepared Based Upon the Patient’s Weight

Body Weight
(kg)

Total Volume to Compound per Patient Weight
(ml)

10 to 15 kg

30 ml

> 15 to 23 kg

40 ml

> 23 to 40 kg

50 ml

> 40 kg

60 ml


Second, determine the number of capsules and the amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) that is needed to prepare the Total Volume (calculated from the table above: 30 ml, 40 ml, 50 ml or 60 ml) of compounded suspension (15 mg/ml) as shown in the table below:


Number of Capsules and Amount of Vehicle Needed to Prepare the Total Volume of a Compounded Suspension (15 mg/ml)

Total Volume
of Compounded Suspension
to be Prepared

Required Number of Tamiflu Capsules
(mg of oseltamivir)

Required Volume
of Vehicle

75 mg

45 mg

30 mg

30 ml

6 capsules

(450 mg)

10 capsules

(450 mg)

15 capsules

(450 mg)

29 ml

40 ml

8 capsules

(600 mg)

Please use alternative capsule strength*

20 capsules

(600 mg)

38.5 ml

50 ml

10 capsules

(750 mg)

Please use alternative capsule strength*

25 capsules

(750 mg)

48 ml

60 ml

12 capsules

(900 mg)

20 capsules

(900 mg)

30 capsules

(900 mg)

57 ml

*          No integral number of capsules can be used to achieve the target concentration; therefore, please use either the 30 mg or 75 mg capsules.


Third, follow the procedure below for compounding the suspension (15 mg/ml) from Tamiflu capsules:

1.       Carefully separate the capsule body and cap and transfer the contents of the required number of Tamiflu capsules into a clean mortar.

2.       Triturate the granules to a fine powder.

3.       Add one-third (1/3) of the specified amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) and triturate the powder until a uniform suspension is achieved.

4.       Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle. A funnel may be used to eliminate any spillage.

5.       Add another one-third (1/3) of the vehicle to the mortar, rinse the pestle and mortar by a triturating motion and transfer the vehicle into the bottle.

6.       Repeat the rinsing (Step 5) with the remainder of the vehicle.

7.       Close the bottle using a child-resistant cap.

8.       Shake well to completely dissolve the active drug and to ensure homogeneous distribution of the dissolved drug in the resulting suspension.

(Note: Undissolved residue may be visible but is comprised of inert ingredients of Tamiflu capsules, which are insoluble. However, the active drug, oseltamivir phosphate, readily dissolves in the specified vehicle and therefore forms a uniform solution.)

9.       Put an ancillary label on the bottle indicating Shake Gently Before Use.

10.     Instruct the parent or caregiver that after the patient has completed the full course of therapy any remaining solution must be discarded. It is recommended that this information be provided by affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions.

11.     Place an appropriate expiration date label according to storage condition (see below).


Storage of the pharmacy-compounded suspension (15 mg/ml)

Room temperature storage conditions: Stable for 3 weeks (21 days) when stored at room temperature “do not store above 25 °C”.

Refrigerated storage conditions: Stable for 6 weeks when stored at 2 °C - 8 °C.


Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, use by date, drug name and any other required information to be in compliance with local pharmacy regulations. Refer to the table below for the proper dosing instructions.


Dosing Chart for Pharmacy-Compounded Suspension from Tamiflu Capsules for Children One Year of Age or Older

Body Weight
(kg)

Dose
(mg)

Volume per Dose
15 mg/ml

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

10 kg to 15 kg

30 mg

2 ml

2 ml twice daily

2 ml once daily

> 15 to 23 kg

45 mg

3 ml

3 ml twice daily

3 ml once daily

> 23 to 40 kg

60 mg

4 ml

4 ml twice daily

4 ml once daily

> 40 kg

75 mg

5 ml

5 ml twice daily

5 ml once daily

Note: This compounding procedure results in a 15 mg/ml suspension, which is different from the commercially available Tamiflu powder for oral suspension.

Dispense the suspension with a graduated oral syringe for measuring small amounts of suspension. If possible, mark or highlight the graduation corresponding to the appropriate dose (2 ml, 3 ml, 4 ml or 5 ml) 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.


Ø  Infants less than 1 year of age

This procedure describes the preparation of a 10 mg/ml solution that will provide one patient with enough medication for a 5-day course of treatment or a 10-day course of prophylaxis.


The pharmacist may compound a suspension (10 mg/ml) from Tamiflu 30 mg, 45 mg or 75 mg capsules using water containing 0.1% w/v sodium benzoate added as a preservative.


First, calculate the Total Volume needed to be compounded and dispensed for each patient. The Total Volume required is determined by the weight of the patient according to the recommendation in the table below:


Volume of Compounded Suspension (10 mg/ml) Prepared Based Upon the Patient’s Weight

Body Weight
(kg)

Total Volume to Compound per Patient Weight
(ml)

£ 7 kg

30 ml

> 7 to 12 kg

45 ml


Second, determine the number of capsules and the amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) that is needed to prepare the Total Volume (calculated from the table above: 30 ml, 45 ml) of compounded suspension (10 mg/ml) as shown in the table below:


Number of Capsules and Amount of Vehicle Needed to Prepare the Total Volume of a Compounded Suspension (10 mg/ml)

Total Volume
of Compounded Suspension
to be Prepared

Required Number of Tamiflu Capsules
(mg of oseltamivir)

Required Volume
of Vehicle

75 mg

45 mg

30 mg

30 ml

4 capsules

(300 mg)

Please use alternative capsule strength*

10 capsules

(300 mg)

29.5 ml

45 ml

6 capsules

(450 mg)

10 capsules

(450 mg)

15 capsules

(450 mg)

44 ml

*          No integral number of capsules can be used to achieve the target concentration; therefore, please use either the 30 mg or 75 mg capsules.


Third, follow the procedure below for compounding the suspension (10 mg/ml) from Tamiflu capsules:

1.       Carefully separate the capsule body and cap and transfer the contents of the required number of Tamiflu capsules into a clean mortar.

2.       Triturate the granules to a fine powder.

3.       Add one-third (1/3) of the specified amount of vehicle and triturate the powder until a uniform suspension is achieved.

4.       Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle. A funnel may be used to eliminate any spillage.

5.       Add another one-third (1/3) of the vehicle to the mortar, rinse the pestle and mortar by a triturating motion and transfer the vehicle into the bottle.

6.       Repeat the rinsing (Step 5) with the remainder of the vehicle.

7.       Close the bottle using a child-resistant cap.

8.       Shake well to completely dissolve the active drug and to ensure homogeneous distribution of the dissolved drug in the resulting suspension.
(Note: Undissolved residue may be visible but is comprised of inert ingredients of Tamiflu capsules, which are insoluble. However, the active drug, oseltamivir phosphate, readily dissolves in the specified vehicle and therefore forms a uniform solution.)

9.       Put an ancillary label on the bottle indicating “Shake Gently Before Use”.

10.     Instruct the parent or caregiver that after the patient has completed the full course of therapy any remaining solution must be discarded. It is recommended that this information be provided by affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions.

11.     Place an appropriate expiration date label according to storage condition (see below).


Storage of the pharmacy-compounded suspension (10 mg/ml)

Room temperature storage conditions: Stable for 3 weeks (21 days) when stored at room temperature “do not store above 25 °C”.

Refrigerated storage conditions: Stable for 6 weeks when stored at 2 °C - 8 °C.


Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, use by date, drug name and any other required information to be in compliance with local pharmacy regulations. Refer to the table below for the proper dosing instructions.


Dosing Chart for Pharmacy-Compounded Suspension (10 mg/ml) from Tamiflu Capsules for Infants Less Than One Month of Age

Body Weight
(rounded to the nearest 0.5 kg)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

3 kg

0.60 ml twice daily

0.60 ml once daily

3.5 kg

0.70 ml twice daily

0.70 ml once daily

4 kg

0.80 ml twice daily

0.80 ml once daily

4.5 kg

0.90 ml twice daily

0.90 ml once daily


Dosing Chart for Pharmacy-Compounded Suspension (10 mg/ml) from Tamiflu Capsules for Infants One to Twelve Months of Age

Body Weight
(rounded to the nearest 0.5 kg)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

4 kg

1.00 ml twice daily

1.00 ml once daily

4.5 kg

1.10 ml twice daily

1.10 ml once daily

5 kg

1.30 ml twice daily

1.30 ml once daily

5.5 kg

1.40 ml twice daily

1.40 ml once daily

6 kg

1.50 ml twice daily

1.50 ml once daily

7 kg

2.10 ml twice daily

2.10 ml once daily

8 kg

2.40 ml twice daily

2.40 ml once daily

9 kg

2.70 ml twice daily

2.70 ml once daily

³ 10 kg

3.00 ml twice daily

3.00 ml once daily


Note:    This compounding procedure results in a 10 mg/ml suspension, which is different from the commercially available Tamiflu powder for oral suspension.

Dispense the suspension with a graduated oral syringe for measuring small amounts of suspension. If possible, mark or highlight the graduation corresponding to the appropriate dose 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 preparation from Tamiflu capsules can be used (detailed instructions above in section 4.2). If the pharmacy preparation is not available either, Tamiflu doses may be prepared at home. The pharmacy preparation  is the preferred option in infants below 12 months of age.


When appropriate capsule strengths are available, 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 involves additional steps. Detailed instructions can be found in section 3 in the package leaflet of Tamiflu capsules.


Special populations

 

[…]

 

Renal impairment

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

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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) and adults with moderate or severe renal impairment as detailed in the table below.

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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 1 year of age or older (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.

 

Children

There is insufficient clinical data available in children with renal impairment to be able to make any dosing recommendation.


[…]

 

Method of administration

Capsules for Oral administration use.

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


4.3     Contraindications

 

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

 

4.4     Special warnings and precautions for use

 

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 (< 37 weeks post-menstrual age*) are currently available.

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

 

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 renal impairment

Dose adjustment is recommended for both treatment and prevention in adolescents (13 to 17 years of age) and adults with severe renal  insufficiencyimpairment. 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).

 

4.5     Interaction with other medicinal products and other forms of interaction

 

[…]


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).

 

4.6     Fertility, pregnancy and lactation

 

Pregnancy

While no controlled clinical trials 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.

 

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 lactating breastfeeding woman, administration of oseltamivir may be considered, where there are clear potential benefits to lactating 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).

 

4.8     Undesirable effects

 

Summary of the safety profile

The overall safety profile of Tamiflu is based on data from 4,624 adult/adolescent and 1,480 paediatric patients treated with Tamiflu or placebo for influenza, and on data from 3,533 adult/adolescent and 148 paediatric patients receiving Tamiflu or placebo for the prophylaxis of influenza in clinical trials studies. In addition, 475 immunocompromised patients (including 18 children) received Tamiflu or placebo for the prophylaxis of influenza.

In adults/adolescents, the most commonly reported adverse reactions (ARs) were nausea, vomiting and headache in the treatment studies, and nausea, vomiting, headache and pain 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 reactions were vomiting, nausea, dyspepsia, abdominal pain and headache. In the majority of patients, these ARs did not lead to discontinuation of Tamiflu.

 

Tabulated summary of adverse reactions

The ARs listed in the tables below fall into the following categories: Very Ccommon (³ 1/10), common (³ 1/100 to < 1/10), uncommon (³ 1/1,000 to < 1/100), rare (³ 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 trials studies.

 

[…]

 

Table 1       Most Frequent Adverse Rreactions (³ 1 % in the oseltamivir group) in studies investigating Tamiflu for treatment and prevention of influenza in adults and adolescents or through post-marketing surveillance

System Organ Class (SOC)

Adverse Rreactions according to frequency

Very common

Common

Uncommon

Rare

Blood and lymphatic system disorders

 

 

 

Thrombocytopeniaa

Immune system disorders

 

 

Hypersensitivity reactiona

Anaphylactic reactionsb, Anaphylactoid reactionsb

Psychiatric disorders

 

 

 

Agitationa,
Abnormal behaviourb, Anxietya,
Confusiona, Delusionsb, Deliriumb, Hallucinationa, Nightmaresa,
Self-injurya

Nervous system disorders

Headache

 

Altered level of consciousnessa, Convulsiona

 

Eye disorders

 

 

 

Visual disturbancea

Cardiac disorders

 

 

Cardiac arrhythmiaa

 

Gastrointestinal disorders

Nausea

Vomiting

 

Gastrointestinal bleedingsa, Hemorrhagic colitisa

Hepatobiliary disorders

 

 

Elevated liver enzymesa

Fulminant hepatitisb, Hepatic failurec, Hepatitisb

Skin and subcutaneous tissue disorders

 

 

Eczemaa, Dermatitisa, Rasha,
Urticariaa

Angioneurotic oedemaa,
Erythema multiformeb, Stevens-Johnson syndromeb,
Toxic epidermal necrolysisb

General disorders and administration site conditions

 

Pain

 

 

a  These are adverse reactions identified during post-marketing surveillance. They were also reported in the pooled clinical studies at the incidence presented in the table above.

b b           As the adverse reaction has not been observed in the 5,598 subjects administered Tamiflu in the pooled clinical studies, the upper limit of the 95 % confidence interval for the point estimate is not higher than 3/5,598 (i.e. 1/1,866 or less = rare).

 

[…]

 

Treatment and prevention of influenza in children:

 

A total of 1,480 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, 858 children received treatment with oseltamivir suspension. A total of 148 children received the recommended dose of Tamiflu once daily in a post-exposure prophylaxis study in households (n = 99), and in a separate 6-week paediatric prophylaxis study (n = 49). Table 2 shows the most frequently reported AR from paediatric clinical trials studies.

Table 2       Most frequent Adverse Rreactions (³ 1 % in the oseltamivir group) in studies a, b investigating Tamiflu for treatment and prevention of influenza in children

System Organ Class (SOC)

Adverse Rreactions according to frequency

Very common

Common

Uncommon

Rare

Nervous system disorders

 

Headache

 

 

Gastrointestinal disorders

Vomiting

Abdominal pain (incl. upper abdominal pain), dDyspepsia,
Nausea

 

 

a  The prevention study did not contain a placebo arm, i.e. was an uncontrolled study.

b Unit dose = age/weight-based dosing (30 mg to 75 mg od/bid).

 

[…]

 

Additional information on Other special populations:

 

Paediatric population (Iinfants less than one year of age)

Safety information available on oseltamivir administered for treatment of influenza in infants less than one year of age from prospective and retrospective observational trials 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.

 

[…]

 

Immunocompromised patients

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 trials studies.

 

Children with pre-existing bronchial asthma

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

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

Pharmacotherapeutic group: Antiviral Antivirals for systemic use, Nneuraminidase Iinhibitors ATC code: J05AH02

 

[…]

 

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 trials studies.

 

Reduced sensitivity of viral neuraminidase

Clinical studies: The risk of emergence of influenza viruses with reduced susceptibility or frank resistance to oseltamivir has been examined during Roche-sponsored clinical studies. All patients who were found to carry oseltamivir-resistant virus did so transiently, cleared the virus normally and showed no clinical deterioration.


Patient Population

Patients with Resistance Mutations (%)

Phenotyping*

Geno- and Phenotyping*

Adults and adolescents

4/1245 (0.32%)

5/1245 (0.4%)

Children (1-12 years)

19/464 (4.1%)

25/464 (5.4%)

* Full genotyping was not performed in all studies.


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.


Clinical and surveillance data: Natural mutations associated with reduced susceptibility to oseltamivir in vitro have been detected in influenza A and B viruses isolated from patients without exposure to oseltamivir. Resistant strains selected during oseltamivir treatment have been isolated from both immunocompetent and immunocompromised patients. Immunocompromised patients and young children are at a higher risk of developing oseltamivir-resistant virus during treatment.


Oseltamivir-resistant viruses isolated from oseltamivir-treated patients and oseltamivir-resistant laboratory strains of influenza viruses have been found to contain mutations in N1 and N2 neuraminidases. Resistance mutations tend to be viral sub-type specific. Since 2007 resistance associated H275Y mutation in seasonal H1N1 strains has become widespread. The susceptibility to oseltamivir and the prevalence of such viruses appear to vary seasonally and geographically. In 2008, H275Y was found in > 99 % of circulating H1N1 influenza isolates in Europe. The 2009 H1N1 influenza (“swine flu”) was almost uniformly susceptible to oseltamivir, with only sporadic reports of resistance in connection with both therapeutic and prophylactic regimens.

Treatment of influenza infection

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 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.

 

[…]

 

Specific studies have not been conducted to assess of the reduction in the risk of complications.

 

Oseltamivir resistance

Clinical studies: The risk of emergence of influenza viruses with reduced susceptibility or frank resistance to oseltamivir has been examined during Roche-sponsored clinical studies. All patients who were found to carry oseltamivir-resistant virus did so transiently, cleared the virus normally and showed no clinical deterioration.


Patient Population

Patients with Resistance Mutations (%)

Phenotyping*

Geno- and Phenotyping*

Adults and adolescents

4/1,245 (0.32%)

5/1,245 (0.4%)

Children (1-12 years)

19/464 (4.1%)

25/464 (5.4%)

* Full genotyping was not performed in all studies.


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.


Clinical and surveillance data: Natural mutations associated with reduced susceptibility to oseltamivir in vitro have been detected in influenza A and B viruses isolated from patients without exposure to oseltamivir. Resistant strains selected during oseltamivir treatment have been isolated from both immunocompetent and immunocompromised patients. Immunocompromised patients and young children are at a higher risk of developing oseltamivir-resistant virus during treatment.


Oseltamivir-resistant viruses isolated from oseltamivir-treated patients and oseltamivir-resistant laboratory strains of influenza viruses have been found to contain mutations in N1 and N2 neuraminidases. Resistance mutations tend to be viral sub-type specific. Since 2007 resistance associated H275Y mutation in seasonal H1N1 strains has become widespread. The susceptibility to oseltamivir and the prevalence of such viruses appear to vary seasonally and geographically. In 2008, H275Y was found in > 99 % of circulating H1N1 influenza isolates in Europe. The 2009 H1N1 influenza (“swine flu”) was almost uniformly susceptible to oseltamivir, with only sporadic reports of resistance in connection with both therapeutic and prophylactic regimens.

 

5.2     Pharmacokinetic properties

 

General Information


[…]

 

MetabolismBiotransformation

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.

 

[…]


Renal impairment

Administration of 100 mg oseltamivir phosphate twice daily for 5 days to patients with various degrees of renal impairment showed that exposure to oseltamivir carboxylate is inversely proportional to declining renal function. For dosing, see section 4.2.


Hepatic impairment

In vitro studies have concluded that exposure to oseltamivir is not expected to be increased significantly nor is exposure to the active metabolite expected to be significantly decreased in patients with hepatic impairment (see section 4.2).


Elderly

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 severe renal impairment (creatinine clearance below 30 ml/min) (see section 4.2).

 

Special Ppopulations


Children

Infants below 12 months less than 1 year of age: Limited pharmacokinetic and safety data are available for infants less than 2 years 1 year of age. Pharmacokinetic modelling was undertaken using these data in addition to data from studies in adults and infants and children older than 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.


Infants and Cchildren 1 year of age and or older: The pharmacokinetics of oseltamivir have been evaluated in single-dose pharmacokinetic studies in infants, children and adolescents aged 1 to 16 years of age. Multiple-dose pharmacokinetics were studied in a small number of children enrolled in a clinical efficacy study. Younger children cleared both the pro-drug and its active metabolite faster than adults, resulting in a lower exposure for a given mg/kg dose. Doses of 2 mg/kg give oseltamivir carboxylate exposures comparable to those achieved in adults receiving a single 75 mg dose (approximately 1 mg/kg). The pharmacokinetics of oseltamivir in children and adolescents over 12 years of age or older are similar to those in adults.


Infants below 12 months of age: Limited pharmacokinetic and safety data are available for infants less than 2 years of age. Pharmacokinetic modeling was undertaken using these data in addition to data from studies in adults and children older than 1 year of age. 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 children > 1 year of age (see sections 4.1 and 4.2). There are currently no data available in infants less than 1 month of age using Tamiflu.


Elderly

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  3060 ml /min) (see section 4.2).


Renal impairment

Administration of 100 mg oseltamivir phosphate twice daily for 5 days to patients with various degrees of renal impairment showed that exposure to oseltamivir carboxylate is inversely proportional to declining renal function. For dosing, see section 4.2.


Hepatic impairment

In vitro studies have concluded that exposure to oseltamivir is not expected to be increased significantly nor is exposure to the active metabolite expected to be significantly decreased in patients with hepatic impairment (see section 4.2).


5.3     Preclinical safety data

 

[…]

 

Teratology studies have been conducted in rats and rabbits at doses of up to 1,500 mg/kg/day and 500 mg/kg/day, respectively. No effects on foetal development were observed. A rat fertility study up to a dose of 1,500 mg/kg/day demonstrated no adverse effects reactions on either sex. In pre- and post-natal rat studies, prolonged parturition was noted at 1,500 mg/kg/day: the safety margin between human exposure and the highest no-effect dose (500 mg/kg/day) in rats is 480-fold for oseltamivir and 44-fold for the active metabolite, respectively. Foetal exposure in the rats and rabbits was approximately 15 to 20 % of that of the mother.

 

[…]

 

A potential for skin sensitisation to oseltamivir was observed in a "maximisation" test in guinea pigs. Approximately 50 % of the animals treated with the unformulated active ingredient substance showed erythema after challenging the induced animals. Reversible irritancy of rabbits' eyes was detected.


Whereas very high oral single doses of oseltamivir phosphate salt, up to the highest dose tested (1,310 mg/kg), had no adverse effects reactions in adult rats, such doses resulted in toxicity in juvenile 7-day-old rat pups, including death. These effects reactions were seen at doses of 657 mg/kg and higher. At 500 mg/kg, no adverse effects reactions were seen, including upon chronic treatment (500 mg/kg/day administered from 7 to 21 days post partum).

 

 

6.       PHARMACEUTICAL PARTICULARS

 

6.3       Shelf life

 

7 years


Storage of the pharmacy-compounded suspension

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


Shelf life of 6 weeks at 2 °C 8 °C.

 

6.4     Special precautions for storage

 

Do not store above 25 °C.

 

For storage conditions of the pharmacy-compounded suspension, see section 6.3.

Storage of the pharmacy-compounded suspension:

Room temperature storage conditions: Stable for 3 weeks (21 days) when stored at room temperature “do not store above 25 °C”.


Refrigerated storage conditions: Stable for 6 weeks when stored at 2 °C - 8 °C.

 

6.5     Nature and contents of container

 

One box contains 10 capsules in a tTriplex blister pack (PVC/PE/PVDC, sealed with aluminium foil).

Pack-size 10 capsules.

 

6.6     Special precautions for disposal and other handling

 

No special requirements.

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

 

Special instructions for use, handling and disposal of extemporaneous formulation prepared for children less than one year of age


Extemporaneous formulation


When Tamiflu powder for oral suspension is not available

When commercially manufactured Tamiflu powder for oral suspension is not available, patients who are unable to swallow capsules may receive appropriate doses of Tamiflu prepared in a pharmacy or prepared at home.

 

For infants below 12 months less than 1 year of age, the pharmacy preparation should be preferred to home preparation. Detailed information on the pharmacy preparation can be found in section 4.2 and on the home preparation can be found in section 3 of the package leaflet of Tamiflu capsules under “Making Tamiflu liquid suspension at home”.

 

[…]


Pharmacy compounding


Pharmacy compounded 15 mg/ml suspension prepared from capsules


Ø         Adults, adolescents and infants and children greater than 1 year of age or older who are unable to swallow intact capsules

This procedure describes the preparation of a 15 mg/ml solution suspension that will provide one patient with enough medication medicine for a 5-day course of treatment or a 10-day course of prophylaxis.


The pharmacist may compound a 15 mg/ml suspension (15 mg/ml) from Tamiflu 30 mg, 45 mg or 75 mg capsules using water containing 0.1% w/v sodium benzoate added as a preservative.


First, calculate the Ttotal Vvolume needed to be compounded and dispensed to provide a 5-day course of treatment or a 10-day course of prophylaxis for the patient. The Ttotal Vvolume required is determined by the weight of the patient according to the recommendation in the table below:


Volume of pharmacy compounded 15 mg/ml suspension (15 mg/ml) prepared based upon the patient’s weight

Body Wweight
(kg)

Total Vvolume to Ccompound per Ppatient Wweight
(ml)

10 to 15 kg

30 ml

> 15 to 23 kg

40 ml

> 23 to 40 kg

50 ml

> 40 kg

60 ml


Second, determine the number of capsules and the amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) that is needed to prepare the Ttotal Vvolume (calculated from the table above: 30 ml, 40 ml, 50 ml or 60 ml) of pharmacy compounded 15 mg/ml suspension (15 mg/ml) as shown in the table below:


Number of capsules and amount of vehicle needed to prepare the total volume of a pharmacy compounded 15 mg/ml suspension (15 mg/ml)

Total Vvolume
of
C
compounded Ssuspension
to be
P
prepared

Required Nnumber of Tamiflu Ccapsules
(mg of oseltamivir)

Required Vvolume
of
V
vehicle

75 mg

45 mg

30 mg

30 ml

6 capsules

(450 mg)

10 capsules

(450 mg)

15 capsules

(450 mg)

29 ml

40 ml

8 capsules

(600 mg)

Please use alternative capsule strength*

20 capsules

(600 mg)

38.5 ml

50 ml

10 capsules

(750 mg)

Please use alternative capsule strength*

25 capsules

(750 mg)

48 ml

60 ml

12 capsules

(900 mg)

20 capsules

(900 mg)

30 capsules

(900 mg)

57 ml

*          No integral number of capsules can be used to achieve the target concentration; therefore, please use either the 30 mg or 75 mg capsules.


Third, follow the procedure below for compounding the 15 mg/ml suspension (15 mg/ml) from Tamiflu capsules:

1.       Carefully separate the capsule body and cap and transfer the contents of the required number of Tamiflu capsules into a clean mortar.

2.       Triturate the granules to a fine powder.

3.       Add one-third (1/3) of the specified amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) and triturate the powder until a uniform suspension is achieved.

4.       Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle. A funnel may be used to eliminate any spillage.

5.       Add another one-third (1/3) of the vehicle to the mortar, rinse the pestle and mortar by a triturating motion and transfer the vehicle into the bottle.

6.       Repeat the rinsing (Step 5) with the remainder of the vehicle.

7.       Close the bottle using a child-resistant cap.

8.       Shake well to completely dissolve the active drug substance and to ensure homogeneous distribution of the dissolved drug medicinal product active substance in the resulting suspension.

(Note: Undissolved residue may be visible but is comprised of inert ingredients of Tamiflu capsules, which are insoluble. However, the active drug substance, oseltamivir phosphate, readily dissolves in the specified vehicle and therefore forms a uniform solution.)

9.       Put an ancillary label on the bottle indicating Shake Gently Before Use.

10.     Instruct the parent or caregiver that after the patient has completed the full course of therapy any remaining solution must be discarded. It is recommended that this information be provided by affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions.

11.     Place an appropriate expiration date label according to storage condition (see belowsection 6.3).


Storage of the pharmacy-compounded suspension (15 mg/ml)

Room temperature storage conditions: Stable for 3 weeks (21 days) when stored at room temperature “do not store above 25 °C”.

Refrigerated storage conditions: Stable for 6 weeks when stored at 2 °C - 8 °C.


Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, use by date, drug name of medicinal product and any other required information to be in compliance with local pharmacy regulations. Refer to the table below for the proper dosing instructions.


Dosing chart for pharmacy-compounded 15 mg/ml suspension prepared from Tamiflu capsules for infants and children one 1 year of age or older

Body Wweight
(kg)

Dose
(mg)

Volume per Ddose
15 mg/ml

Treatment Ddose
(for 5 days)

Prophylaxis Ddose
(for 10 days)

10 kg to 15 kg

30 mg

2 ml

2 ml twice daily

2 ml once daily

> 15 to 23 kg

45 mg

3 ml

3 ml twice daily

3 ml once daily

> 23 to 40 kg

60 mg

4 ml

4 ml twice daily

4 ml once daily

> 40 kg

75 mg

5 ml

5 ml twice daily

5 ml once daily

Note: This compounding procedure results in a 15 mg/ml suspension, which is different from the commercially available Tamiflu powder for oral suspension.


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 (2 ml, 3 ml, 4 ml or 5 ml) 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.


Pharmacy compounded 10 mg/ml suspension prepared from capsules


Ø         Infants less than 1 year of age

This procedure describes the preparation of a 10 mg/ml solution suspension that will provide one patient with enough medication for a 5-day course of treatment or a 10-day course of prophylaxis.


The pharmacist may compound a 10 mg/ml suspension (10 mg/ml) from Tamiflu 30 mg, 45 mg or 75 mg capsules using water containing 0.1% w/v sodium benzoate added as a preservative.


First, calculate the Ttotal Vvolume needed to be compounded and dispensed for each patient. The Ttotal Vvolume required is determined by the weight of the patient according to the recommendation in the table below:


Volume of pharmacy compounded 10 mg/ml suspension (10 mg/ml) prepared based upon the patient’s weight

Body Wweight
(kg)

Total Vvolume to Ccompound per Ppatient Wweight
(ml)

£ 7 kg

30 ml

> 7 to 12 kg

45 ml


Second, determine the number of capsules and the amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) that is needed to prepare the Ttotal Vvolume (calculated from the table above: 30 ml, 45 ml) of pharmacy compounded 10 mg/ml suspension (10 mg/ml) as shown in the table below:


Number of capsules and amount of vehicle needed to prepare the total volume of a pharmacy compounded 10 mg/ml suspension (10 mg/ml)

Total Vvolume
of
C
compounded Ssuspension
to be
P
prepared

Required Nnumber of Tamiflu Ccapsules
(mg of oseltamivir)

Required Vvolume
of
V
vehicle

75 mg

45 mg

30 mg

30 ml

4 capsules

(300 mg)

Please use alternative capsule strength*

10 capsules

(300 mg)

29.5 ml

45 ml

6 capsules

(450 mg)

10 capsules

(450 mg)

15 capsules

(450 mg)

44 ml

*          No integral number of capsules can be used to achieve the target concentration; therefore, please use either the 30 mg or 75 mg capsules.


Third, follow the procedure below for compounding the 10 mg/ml suspension (10 mg/ml) from Tamiflu capsules:

1.       Carefully separate the capsule body and cap and transfer the contents of the required number of Tamiflu capsules into a clean mortar.

2.       Triturate the granules to a fine powder.

3.       Add one-third (1/3) of the specified amount of vehicle and triturate the powder until a uniform suspension is achieved.

4.       Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle. A funnel may be used to eliminate any spillage.

5.       Add another one-third (1/3) of the vehicle to the mortar, rinse the pestle and mortar by a triturating motion and transfer the vehicle into the bottle.

6.       Repeat the rinsing (Step 5) with the remainder of the vehicle.

7.       Close the bottle using a child-resistant cap.

8.       Shake well to completely dissolve the active drug substance and to ensure homogeneous distribution of the dissolved drug medicinal product active substance in the resulting suspension.
(Note: Undissolved residue may be visible but is comprised of inert ingredients of Tamiflu capsules, which are insoluble. However, the active
drug substance, oseltamivir phosphate, readily dissolves in the specified vehicle and therefore forms a uniform solution.)

9.       Put an ancillary label on the bottle indicating “Shake Gently Before Use”.

10.     Instruct the parent or caregiver that after the patient has completed the full course of therapy any remaining solution must be discarded. It is recommended that this information be provided by affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions.

11.     Place an appropriate expiration date label according to storage condition (see below section 6.3).


Storage of the pharmacy-compounded suspension (10 mg/ml)

Room temperature storage conditions: Stable for 3 weeks (21 days) when stored at room temperature “do not store above 25 °C”.

Refrigerated storage conditions: Stable for 6 weeks when stored at 2 °C - 8 °C.


Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, use by date, drug name of medicinal product and any other required information to be in compliance with local pharmacy regulations. Refer to the table below for the proper dosing instructions.


Dosing chart for pharmacy- compounded 10 mg/ml suspension (10 mg/ml) prepared from Tamiflu capsules for infants less than one month of age

Body Weight

(rounded to the nearest 0.5 kg)

Dose

(mg)

Volume

per dose

(10 mg/ml)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

Dispenser size

to use

(grading 0.1 ml)

3 kg

6 mg

0.60 ml

0.60 ml twice daily

0.60 ml once daily

1 ml (or 2 ml)

3.5 kg

7 mg

0.70 ml

0.70 ml twice daily

0.70 ml once daily

1 ml (or 2 ml)

4 kg

8 mg

0.80 ml

0.80 ml twice daily

0.80 ml once daily

1 ml (or 2 ml)

4.5 kg

9 mg

0.90 ml

0.90 ml twice daily

0.90 ml once daily

1 ml (or 2 ml)

 

Dosing chart for pharmacy- compounded 10 mg/ml suspension (10 mg/ml) prepared from Tamiflu capsules for infants one to twelve months of age

Body Weight
(rounded to the nearest 0.5 kg)

Dose

(mg)

Volume

per dose

(10 mg/ml)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

Dispenser size

to use

(grading 0.1 ml)

4 kg

10 mg

1.00 ml

1.00 ml twice daily

1.00 ml once daily

2 ml (or 3 ml)

4.5 kg

11.25 mg

1.10 ml

1.10 ml twice daily

1.10 ml once daily

2 ml (or 3 ml)

5 kg

12.5 mg

1.30 ml

1.30 ml twice daily

1.30 ml once daily

2 ml (or 3 ml)

5.5 kg

13.75 mg

1.40 ml

1.40 ml twice daily

1.40 ml once daily

2 ml (or 3 ml)

6 kg

15 mg

1.50 ml

1.50 ml twice daily

1.50 ml once daily

2 ml (or 3 ml)

7 kg

21 mg

2.10 ml

2.10 ml twice daily

2.10 ml once daily

3 ml

8 kg

24 mg

2.40 ml

2.40 ml twice daily

2.40 ml once daily

3 ml

9 kg

27 mg

2.70 ml

2.70 ml twice daily

2.70 ml once daily

3 ml

³ 10 kg

30 mg

3.00 ml

3.00 ml twice daily

3.00 ml once daily

3 ml (or 5 ml)


Note:    This compounding procedure results in a 10 mg/ml suspension, which is different from the commercially available Tamiflu powder for oral suspension.


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 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 preparation suspension prepared from Tamiflu capsules can be used (see detailed instructions above). If the pharmacy compounded preparation suspension is also not available either, Tamiflu doses suspension may be prepared at home. The pharmacy compounded preparation suspension is the preferred option in infants below 12 months 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 Tamiflu liquid suspension at home”.

 

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 20 June 2002

Date of last renewal: 20 June 2007 22 May 2012

 

 

10.     DATE OF REVISION OF THE TEXT

22 May 2012

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Updated on 01 June 2012

Reasons for updating

  • Change to improve clarity and readability

Updated on 17 November 2011

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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4.5      Interaction with other medicinal products and other forms of interaction

 

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.

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.

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

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).

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

 

4.8      Undesirable effects

The overall safety profile of Tamiflu is based on data from 2107 4624 adult/adolescent and 1032 1480 paediatric patients treated with Tamiflu or placebo for influenza, and on data from 2914 3533 adult/adolescent and 148 paediatric patients receiving Tamiflu or placebo for the prophylaxis of influenza in clinical trials. In addition, 475 immunocompromised patients (including 18 children) received Tamiflu or placebo for the prophylaxis of influenza.

In adults/adolescents, the most commonly reported adverse drug reactions (ADRs) were nausea, vomiting and nausea headache in the treatment studies, and nausea, vomiting,  and headache and pain in the prevention studies. The majority of these ADRs 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 drug reactions were was vomiting, nausea, dyspepsia, abdominal pain and headache. In the majority of patients, these ARs did not lead to discontinuation of Tamiflu.

The ADRs listed in the tables below fall into the following categories: Very Common (³ 1/10), cCommon (³ 1/100 to < 1/10), uUncommon (³ 1/1,000 to < 1/100), rRare (³ 1/10,000 to < 1/1,000), and vVery rare (< 1/10,000) and not known (cannot be estimated from the available data). ADRs are added to the appropriate category in the tables according to the pooled analysis from clinical trials. Within each frequency grouping ADRs are presented in the order of decreasing seriousness.

Treatment and prevention of influenza in adults and adolescents:

In adult/adolescent treatment and prophylaxis studies, ARs that occurred the most frequently (³ 1 %) 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          Most Frequent Adverse Drug Reactions (³ 1 % in the oseltamivir group) in sStudies iInvestigating Tamiflu for tTreatment and pPrevention of iInfluenza in aAdults and aAdolescents or Tthrough pPost-mMarketing sSurveillance

System Organ Class (SOC)

Adverse Reactions according to frequency

Very common

Common

Uncommon

Rare

Blood and lymphatic system disorders

 

 

 

Thrombocytopeniaa

Immune system disorders

 

 

Hypersensitivity reactiona

Anaphylactic reactionsb, Anaphylactoid reactionsb

Psychiatric disorders

 

 

 

Agitationa, Abnormal behaviourb, Anxietya, Confusiona, Delusionsb, Deliriumb, Hallucinationa, Nightmaresa, Self-injurya

Nervous system disorders

Headache

 

Altered level of consciousnessa, Convulsiona

 

Eye disorders

 

 

 

Visual disturbancea

Cardiac disorders

 

 

Cardiac arrhythmiaa

 

Gastrointestinal disorders

Nausea

Vomiting

 

Gastrointestinal bleedingsa, Hemorrhagic colitisa

Hepatobiliary disorders

 

 

Elevated liver enzymesa

Fulminant hepatitisb, Hepatic failurec, Hepatitisb

Skin and subcutaneous tissue disorders

 

 

Eczemaa, Dermatitisa, Rasha, Urticariaa

Angioneurotic oedemaa, Erythema multiformeb, Stevens-Johnson syndromeb, Toxic epidermal necrolysisb

General disorders and administration site conditions

 

Pain

 

 

a   These are events adverse reactions identified during post-marketing surveillance. They were also reported in the pooled clinical studies at the incidence presented in the table above.

b  Subjects who experienced nausea alone; excludes subjects who experienced nausea in association with vomiting.

c  The difference between the placebo and oseltamivir groups was statistically significant.

These adverse reactions may be related to the underlying influenza infection because they occurred either more frequently in patients on placebo compared to patients on Tamiflu, or the frequency was very similar in the two arms.

b  As the adverse drug reaction has not been observed in the 5598 subjects administered Tamiflu in the pooled clinical studies, the upper limit of the 95 % confidence interval for the point estimate is not higher than 3/5598 (i.e. 1/1866 or less = rare).

Below is a list of commonly occurring ARs from treatment studies (n = 2647) and prophylaxis studies (n = 1945). These events occurred either more frequently in patients on placebo compared to patients on oseltamivir, or the difference in frequency between the two arms was less than 1 %. Commonly occurring ARs are those which occur with a frequency of greater than 1 per 100 patients, and less than 1 per 10 patients.

·          Infections and infestations: Bronchitis, herpes simplex, influenza, nasopharyngitis, upper respiratory tract infections, sinusitis,

·          Nervous system disorders: Insomnia

·          Respiratory, thoracic and mediastinal disorders: Cough, nasal congestion, sore throat, rhinorrhea

·          Gastrointestinal disorders: Abdominal pain (incl. upper abdominal pain), diarrhoea, dyspepsia

·          Musculoskeletal and connective tissue disorders: Arthralgia, back pain, myalgia

·          Reproductive system and breast disorders: Dysmenorrhea

·          General disorders: Dizziness (incl. vertigo), fatigue, influenza like illness, pain in limb, pyrexia

Treatment and prevention of influenza in children:

A total of 1480  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, 858  children received treatment with oseltamivir suspension. A total of 148  children received the recommended dose of Tamiflu once daily in a post-exposure prophylaxis study in households (n = 99), and in a separate 6-week paediatric prophylaxis study (n = 49). Table 2 shows the most frequently reported AR from paediatric clinical trials.

Table 2          Most frequent Adverse Reactions (³ 1 % in the oseltamivir group) in studiesa, b investigating Tamiflu for treatment and prevention of influenza in children

System Organ Class (SOC)

Adverse Reactions according to frequency

Very common

Common

Uncommon

Rare

Nervous system disorders

 

Headache

 

 

Gastrointestinal disorders

Vomiting

Abdominal pain (incl. upper abdominal pain), dyspepsia, Nausea

 

 

a   The prevention study did not contain a placebo arm, i.e. was an uncontrolled study.

b  Unit dose = age/weight-based dosing (see section 4.2) (30 mg to 75 mg od).

c  Patients experienced ear ache and ear pain.

c   These adverse reactions may be related to the underlying influenza infection because they occurred either more frequently in patients on placebo/no prophylaxis compared to patients on Tamiflu, or the frequency was very similar in the two arms.

d  These adverse reactions previously qualified as common (frequency > 1/100 to < 1/10) but in the larger clinical trials datasets had a reporting frequency of < 1% in the Tamiflu arm.

Below is a list of commonly occurring ARs from treatment studies (n = 858) and prophylaxis studies (n = 148). These events occurred either more frequently in patients on placebo/no prophylaxis compared to patients on oseltamivir, or the difference in frequency between the two groups was less than 1 %. Commonly occurring ARs are those which occur with a frequency of greater than 1 per 100 patients, and less than 1 per 10 patients.

·          Infections and infestations: Bronchitis, nasopharyngitis, otitis media, pneumonia, sinusitis, upper respiratory tract infection

·          Eye disorders: Conjunctivitis (including red eyes, eye discharge and eye pain)

·          Ear and labyrinth disorders: Earache

·          Respiratory, thoracic and mediastinal disorders: Asthma (including aggravated asthma), cough, epistaxis, nasal congestion, rhinorrhoea

·          Gastrointestinal disorders: Diarrhoea

·          Skin and subcutaneous tissue disorders: Dermatitis (including allergic and atopic dermatitis)

·               General disorders: Pyrexia

 

The following additional Uncommon (frequency > 1/1,000 to < 1/100) ARs were reported in the paediatric treatment studies. These ARs previously qualified as Common (frequency > 1/100 to < 1/10) but in the larger datasets no longer fulfil the criteria to be included in the previous section.

·          Blood and lymphatic system disorders: Lymphadenopathy

·          Ear and labyrinth disorders: Tympanic membrane disorder

The table below shows the most frequently reported ADRs from paediatric clinical trials.

Most Frequent Adverse Drug Reactions (³ 1 % in the oseltamivir group in the treatment studies and ³ 10 % in the oseltamivir group in the prophylaxis study) in Children

System Organ Class (SOC)

Frequency Category

Adverse Drug Reaction

Percentage of Patients Experiencing the ADR

Treatment

Treatment

Preventiona

Oseltamivir

2 mg/kg bid

(n = 515)

Placebo

 

(n = 517)

Oseltamivir

30 to 75 mgb

(n = 158)

Oseltamivir

30 to 75 mgb

(n = 148)

Infections and infestations

 

 

 

 

Common:

 

 

 

 

Pneumonia

2 %

3 %

0 %

0 %

Sinusitis

2 %

3 %

0 %

< 1 %

Bronchitis

2 %

2 %

2 %

0 %

Otitis media

9 %

11 %

1 %

2 %

Disorders of the blood and lymphatic system

 

 

 

 

Common:

 

 

 

 

Lymphadenopathy

1 %

2 %

< 1 %

0 %

Respiratory, thoracic and mediastinal disorders

 

 

 

 

Common:

 

 

 

 

Cough

1%

1%

3 %

12 %

Nasal Congestion

< 1 %

< 1 %

2 %

11 %

Asthma (incl. aggravated)

4 %

4 %

0 %

1 %

Epistaxis

3 %

3 %

1 %

< 1 %

Gastrointestinal disorder

 

 

 

 

Very Common:

 

 

 

 

Vomiting

15 %

9 %

20 %

8 %

Diarrhoea

10 %

11 %

3 %

< 1 %

Common:

 

 

 

 

Nausea

3 %

4 %

6 %

4 %

Abdominal pain

5 %

4 %

2 %

1 %

Disorders of the eye

 

 

 

 

Common:

 

 

 

 

Conjunctivitis

1 %

< 1 %

0 %

0 %

Disorders of the ear and labyrinth

 

 

 

 

Common:

 

 

 

 

Ear disorderc

2 %

1 %

0 %

< 1 %

Tympanic membrane disorder

1 %

1 %

0 %

0 %

Skin and subcutaneous tissue disorders

 

 

 

 

Common:

 

 

 

 

Dermatitis

1 %

2 %

< 1 %

0 %

a   The prevention study did not contain a placebo arm, i.e. was an uncontrolled study.

b  Unit dose = weight-based dosing (see section 4.2).

c  Patients experienced ear ache and ear pain.

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

Further post marketing surveillance data onDescription of  selected serious adverse drug reactions:

Immune system disorders

Frequency not known: hypersensitivity reactions, including anaphylactic/anaphylactoid reactions.

Psychiatric disorders and nervous system disorders

Frequency not known: iInfluenza 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 pediatric 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.

Eye disorders

Frequency not known: visual disturbance.

 

Cardiac disorders

Frequency not known: cardiac arrhythmia.

Blood and lymphatic system disorders

Frequency not known: thrombocytopenia.

Gastrointestinal disorders

Frequency not known: gastrointestinal bleedings and hemorrhagic colitis.

Hepato-biliary disorders

Frequency not known: hHepato-biliary system disorders, including hepatitis and elevated liver enzymes in patients with influenza-like illness. These cases include fatal fulminant hepatitis/hepatic failure.

Skin and subcutaneous tissue disorders

Frequency not known: severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme and angioneurotic oedema.

Additional information on special populations:

Infants less than one year of age

Safety information available on oseltamivir administered for treatment of influenza in infants less than one year of age from prospective and retrospective observational trials (comprising together more than 2400 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 patients and

There were no clinically relevant differences in the safety population of the elderly subjects who received oseltamivir or placebo compared with the adult population aged up to 65 years.

Ppatients 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 patients 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.

The adverse event profile in adolescents and patients with chronic cardiac and/or respiratory disease was qualitatively similar to those of healthy young adults.

 

Immunocompromised patients

The adverse reactions noted In a 12-week prophylaxis study in 475 immunocompromised subjects patients, including 18 children 1 to 12 13 years of age and older, who received oseltamivir during 12 weeks for the seasonal prophylaxis of influenza were the safety profile in the 238 patients who received oseltamivirwas consistent with those that previously observed in Tamiflu prophylaxis clinical trials.

Children with pre-existing bronchial asthma

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

The adverse reactions noted in immunocompromised subjects 13 years of age and older who received oseltamivir during 12 weeks for the seasonal prophylaxis of influenza were consistent with those previously observed in Tamiflu clinical trials.

 

Updated on 14 November 2011

Reasons for updating

  • Change to side-effects
  • Change to date of revision

Updated on 06 July 2011

Reasons for updating

  • Change to section 4.2 - Posology and method of administration

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4.2      Posology and method of administration

 

Tamiflu 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.

 

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

 

For infants below 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 below 4.2).

 

Treatment of influenza

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

 

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

 

Ø  For infants older than 1 year of age and for children 2 to 12 years of age: Tamiflu 30 mg and 45 mg capsules and oral suspension are available.

 

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

Body Weight

Recommended dose for 5 days

≤ 15 kg

30 mg twice daily

> 15 kg to 23 kg

45 mg twice daily

> 23 kg to 40 kg

60 mg twice daily

> 40 kg

75 mg twice daily

 

Children who are able to swallow capsules may receive treatment with Tamiflu capsules (30 mg, 45 mg, 75 mg) twice daily for 5 days as an alternative to the recommended dose of Tamiflu suspension.

 

Ø  For infants below 12 months of age: The recommended treatment dose for infants less than 12 months is between 2 mg/kg twice daily and 3 mg/kg twice daily during a pandemic influenza outbreak. This is based upon limited pharmacokinetic 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 weight‑adjusted dosing regimens are recommended for treatment of infants below 1 year of age:

 

Age

Recommended dose for 5 days

> 3 months to 12 months

3 mg/kg twice daily

> 1 month to 3 months

2.5 mg/kg twice daily

0 to 1 month*

2 mg/kg twice daily

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

 

Administration of Tamiflu to infants less than one year of age should be based upon the judgment of the physician after considering the potential benefit of treatment versus any potential risk to the infant.

 

These age-based dosing recommendations are not intended for premature infants, i.e. those with a postmenstrual age less than 37 weeks. Insufficient data are available for these patients, in whom different dosing may be required due to the immaturity of physiological functions

 

Prevention of influenza

Post-exposure prevention

Ø  For adolescents (13 to 17 years of age) and adults: The recommended dose for prevention of influenza following close contact with an infected individual is 75 mg oseltamivir once daily for 10 days. Therapy should begin as soon as possible within two days of exposure to an infected individual.

 

Ø  For infants older than 1 year of age and for children 2 to 12 years of age: Tamiflu 30 mg and 45 mg capsules and oral suspension are available.

 

The recommended post-exposure prevention dose of Tamiflu is:

Body Weight

Recommended dose for 10 days

≤ 15 kg

30 mg once daily

> 15 kg to 23 kg

45 mg once daily

> 23 kg to 40 kg

60 mg once daily

> 40 kg

75 mg once daily

 

Children who are able to swallow capsules may receive prevention with Tamiflu capsules (30 mg, 45 mg, 75 mg) once daily for 10 days as an alternative to the recommended dose of Tamiflu suspension.

 

Ø  For infants below 12 months of age: The recommended prophylaxis dose for infants less than 12 months during a pandemic influenza outbreak is half of the daily treatment dose. This is based upon clinical data in children > 1 year of age and adults showing that a prophylaxis dose equivalent to half the daily treatment dose is clinically efficacious for the prevention of influenza. The following weight‑adjusted dosing prophylaxis regimens are recommended for infants below 1 year of age:

 

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Age

Recommended dose for 10 days

> 3 months to 12 months

3 mg/kg once daily

> 1 month to 3 months

2.5 mg/kg once daily

0 to 1 month*

2 mg/kg once daily

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

 

Administration of Tamiflu to infants less than one year of age should be based upon the judgment of the physician after considering the potential benefit of prophylaxis versus any potential risk to the infant.

 

These age-based dosing recommendations are not intended for premature infants, i.e. those with a postmenstrual age less than 37 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

The recommended dose for prevention of influenza during a community outbreak is 75 mg oseltamivir once daily for up to 6 weeks.

 

Extemporaneous formulation

When Tamiflu powder for oral suspension is not available

When commercially manufactured Tamiflu powder for oral suspension is not available, patients who are unable to swallow capsules may receive appropriate doses of Tamiflu prepared in a pharmacy or prepared at home.

 

For infants below 12 months, the pharmacy preparation should be preferred to home preparation. Detailed information on the home preparation can be found in section 3 of the package leaflet of Tamiflu capsules.

 

Pharmacy compounding

Ø  Adults and children greater than 1 year who are unable to swallow intact capsules

This procedure describes the preparation of a 15 mg/ml solution that will provide one patient with enough medication for a 5-day course of treatment or a 10-day course of prophylaxis.

 

The pharmacist may compound a suspension (15 mg/ml) from Tamiflu 30 mg, 45 mg or 75 mg capsules using water containing 0.1% w/v sodium benzoate added as a preservative.

 

First, calculate the Total Volume needed to be compounded and dispensed to provide a 5-day course of treatment or a 10=day course of prophylaxis for the patient. The Total Volume required is determined by the weight of the patient according to the recommendation in the table below:

 

Volume of Compounded Suspension (15 mg/ml) Prepared Based Upon the Patient’s Weight

Body Weight
(kg)

Total Volume to Compound per Patient Weight
(ml)

10 to 15 kg

30 ml

> 15 to 23 kg

40 ml

> 23 to 40 kg

50 ml

> 40 kg

60 ml

 

Second, determine the number of capsules and the amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) that is needed to prepare the Total Volume (calculated from the table above: 30 ml, 40 ml, 50 ml or 60 ml) of compounded suspension (15 mg/ml) as shown in the table below:

 

Number of Capsules and Amount of Vehicle Needed to Prepare the Total Volume of a Compounded Suspension (15 mg/ml)

Total Volume
of Compounded Suspension
to be Prepared

Required Number of Tamiflu Capsules
(mg of oseltamivir)

Required Volume
of Vehicle

75 mg

45 mg

30 mg

30 ml

6 capsules

(450 mg)

10 capsules

(450 mg)

15 capsules

(450 mg)

29 ml

40 ml

8 capsules

(600 mg)

Please use alternative capsule strength*

20 capsules

(600 mg)

38.5 ml

50 ml

10 capsules

(750 mg)

Please use alternative capsule strength*

25 capsules

(750 mg)

48 ml

60 ml

12 capsules

(900 mg)

20 capsules

(900 mg)

30 capsules

(900 mg)

57 ml

* No integral number of capsules can be used to achieve the target concentration; therefore, please use either the 30 mg or 75 mg capsules.

 

Third, follow the procedure below for compounding the suspension (15 mg/ml) from Tamiflu capsules:

1.         Carefully separate the capsule body and cap and transfer the contents of the required number of Tamiflu capsules into a clean mortar.

2.         Triturate the granules to a fine powder.

3.         Add one-third (1/3) of the specified amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) and triturate the powder until a uniform suspension is achieved.

4.         Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle. A funnel may be used to eliminate any spillage.

5.         Add another one-third (1/3) of the vehicle to the mortar, rinse the pestle and mortar by a triturating motion and transfer the vehicle into the bottle.

6.         Repeat the rinsing (Step 5) with the remainder of the vehicle.

7.         Close the bottle using a child-resistant cap.

8.         Shake well to completely dissolve the active drug and to ensure homogeneous distribution of the dissolved drug in the resulting suspension.

(Note: Undissolved residue may be visible but is comprised of inert ingredients of Tamiflu capsules, which are insoluble. However, the active drug, oseltamivir phosphate, readily dissolves in the specified vehicle and therefore forms a uniform solution.)

9.         Put an ancillary label on the bottle indicating Shake Gently Before Use.

10.       Instruct the parent or caregiver that after the patient has completed the full course of therapy any remaining solution must be discarded. It is recommended that this information be provided by affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions.

11.       Place an appropriate expiration date label according to storage condition (see below).

 

Storage of the pharmacy-compounded suspension (15 mg/ml)

Room temperature storage conditions: Stable for 3 weeks (21 days) when stored at room temperature “do not store above 25 °C”.

Refrigerated storage conditions: Stable for 6 weeks when stored at 2 °C - 8 °C.

 

Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, use by date, drug name and any other required information to be in compliance with local pharmacy regulations. Refer to the table below for the proper dosing instructions.

 

Dosing Chart for Pharmacy-Compounded Suspension from Tamiflu Capsules for Children One Year of Age or Older

Body Weight
(kg)

Dose
(mg)

Volume per Dose
15 mg/ml

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

10 kg to 15 kg

30 mg

2 ml

2 ml twice daily

2 ml once daily

> 15 to 23 kg

45 mg

3 ml

3 ml twice daily

3 ml once daily

> 23 to 40 kg

60 mg

4 ml

4 ml twice daily

4 ml once daily

> 40 kg

75 mg

5 ml

5 ml twice daily

5 ml once daily

Note: This compounding procedure results in a 15 mg/ml suspension, which is different from the commercially available Tamiflu powder for oral suspension.

 

Dispense the suspension with a graduated oral syringe for measuring small amounts of suspension. If possible, mark or highlight the graduation corresponding to the appropriate dose (2 ml, 3 ml, 4 ml or 5 ml) 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.

 

Ø  Infants less than 1 year of age

This procedure describes the preparation of a 10 mg/ml solution that will provide one patient with enough medication for a 5-day course of treatment or a 10-day course of prophylaxis.

 

The pharmacist may compound a suspension (10 mg/ml) from Tamiflu 30 mg, 45 mg or 75 mg capsules using water containing 0.1% w/v sodium benzoate added as a preservative.

 

First, calculate the Total Volume needed to be compounded and dispensed for each patient. The Total Volume required is determined by the weight of the patient according to the recommendation in the table below:

 

Volume of Compounded Suspension (10 mg/ml) Prepared Based Upon the Patient’s Weight

Body Weight
(kg)

Total Volume to Compound per Patient Weight
(ml)

£ 7 kg

30 ml

> 7 to 12 kg

45 ml

 

Second, determine the number of capsules and the amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) that is needed to prepare the Total Volume (calculated from the table above: 30 ml, 45 ml) of compounded suspension (10 mg/ml) as shown in the table below:

 

Number of Capsules and Amount of Vehicle Needed to Prepare the Total Volume of a Compounded Suspension (10 mg/ml)

Total Volume
of Compounded Suspension
to be Prepared

Required Number of Tamiflu Capsules
(mg of oseltamivir)

Required Volume
of Vehicle

75 mg

45 mg

30 mg

30 ml

4 capsules

(300 mg)

Please use alternative capsule strength*

10 capsules

(300 mg)

29.5 ml

45 ml

6 capsules

(450 mg)

10 capsules

(450 mg)

15 capsules

(450 mg)

44 ml

* No integral number of capsules can be used to achieve the target concentration; therefore, please use either the 30 mg or 75 mg capsules.

 

Third, follow the procedure below for compounding the suspension (10 mg/ml) from Tamiflu capsules:

1.         Carefully separate the capsule body and cap and transfer the contents of the required number of Tamiflu capsules into a clean mortar.

2.         Triturate the granules to a fine powder.

3.         Add one-third (1/3) of the specified amount of vehicle and triturate the powder until a uniform suspension is achieved.

4.         Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle. A funnel may be used to eliminate any spillage.

5.         Add another one-third (1/3) of the vehicle to the mortar, rinse the pestle and mortar by a triturating motion and transfer the vehicle into the bottle.

6.         Repeat the rinsing (Step 5) with the remainder of the vehicle.

7.         Close the bottle using a child-resistant cap.

8.         Shake well to completely dissolve the active drug and to ensure homogeneous distribution of the dissolved drug in the resulting suspension.
(Note: Undissolved residue may be visible but is comprised of inert ingredients of Tamiflu capsules, which are insoluble. However, the active drug, oseltamivir phosphate, readily dissolves in the specified vehicle and therefore forms a uniform solution.)

9.         Put an ancillary label on the bottle indicating “Shake Gently Before Use”.

10.       Instruct the parent or caregiver that after the patient has completed the full course of therapy any remaining solution must be discarded. It is recommended that this information be provided by affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions.

11.       Place an appropriate expiration date label according to storage condition (see below).

 

Storage of the pharmacy-compounded suspension (10 mg/ml)

Room temperature storage conditions: Stable for 3 weeks (21 days) when stored at room temperature “do not store above 25 °C”.

Refrigerated storage conditions: Stable for 6 weeks when stored at 2 °C - 8 °C.

 

Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, use by date, drug name and any other required information to be in compliance with local pharmacy regulations. Refer to the table below for the proper dosing instructions.

 

Dosing Chart for Pharmacy-Compounded Suspension (10 mg/ml) from Tamiflu Capsules for Infants Less Than One Month of Age

Body Weight
(rounded to the nearest 0.5 kg)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

3 kg

0.60 ml twice daily

0.60 ml once daily

3.5 kg

0.70 ml twice daily

0.70 ml once daily

4 kg

0.80 ml twice daily

0.80 ml once daily

4.5 kg

0.90 ml twice daily

0.90 ml once daily

 

Dosing Chart for Pharmacy-Compounded Suspension (10 mg/ml) from Tamiflu Capsules for Infants One to Twelve Months of Age

Body Weight
(rounded to the nearest 0.5 kg)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

4 kg

1.00 ml twice daily

1.00 ml once daily

4.5 kg

1.10 ml twice daily

1.10 ml once daily

5 kg

1.30 ml twice daily

1.30 ml once daily

5.5 kg

1.40 ml twice daily

1.40 ml once daily

6 kg

1.50 ml twice daily

1.50 ml once daily

7 kg

2.10 ml twice daily

2.10 ml once daily

8 kg

2.40 ml twice daily

2.40 ml once daily

9 kg

2.70 ml twice daily

2.70 ml once daily

³ 10 kg

3.00 ml twice daily

3.00 ml once daily

 

Note:     This compounding procedure results in a 10 mg/ml suspension, which is different from the commercially available Tamiflu powder for oral suspension.

 

Dispense the suspension with a graduated oral syringe for measuring small amounts of suspension. If possible, mark or highlight the graduation corresponding to the appropriate dose 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 preparation from Tamiflu capsules can be used (detailed instructions above in section 4.2). If the pharmacy preparation is not available either, Tamiflu doses may be prepared at home. The pharmacy preparation is the preferred option in infants below 12 months of age.

 

When appropriate capsule strengths are available, 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 involves additional steps. Detailed instructions can be found in section 3 in the package leaflet of Tamiflu capsules.

 

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 with moderate or severe renal impairment. Recommended doses are detailed in the table below.

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Creatinine clearance

Recommended dose for treatment

3060 (ml/min)

75 mg twice daily

10 30 to £ 30 60 (ml/min)

75 mg once daily,
or
30 mg (suspension or capsules) twice daily
,
or 30 mg capsules twice daily

£> 10 to 30 (ml/min)

Not recommended30 mg (suspension or capsules) once daily

dialysis patients£ 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 with moderate or severe renal impairment as detailed in the table below.

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Creatinine clearance

Recommended dose for prevention

3060 (ml/min)

75 mg once daily

10 to £ 30 to 60 (ml/min)

75 mg every second day,
or
30 mg (suspension
once daily,
or 30 mg capsules) once daily

£> 10 to 30 (ml/min)

Not recommended30 mg (suspension or capsules) every second day

dialysis patients£ 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.

 

Elderly

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

 

Children

There is insufficient clinical data available in children with renal impairment to be able to make any dosing recommendation.

 

Immunocompromised patients

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

 

Updated on 01 March 2011

Reasons for updating

  • Change to section 4.8 - Undesirable effects

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.8 updated to add Thrombocytopenia for all patient groups

Updated on 28 February 2011

Reasons for updating

  • Change to side-effects

Updated on 18 January 2011

Reasons for updating

  • Change to section 10 - Date of revision of the text

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

This SPC replaces the previously published combined 30mg and 45mg SPC which was displaying on IPHA with errors in the dosing table in section 4.2 under the sub-heading 'For infants below 12 months of age'.

The SPC has been updated to change European Medicines Agency acronym to EMA with corresponding change to email address quoted and approval dates.

Updated on 18 January 2011

Reasons for updating

  • Change to dosage and administration

Updated on 21 December 2010

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 6.6 - Special precautions for disposal and other handling
  • SPC retired pending re-submission

Legal category:Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

 

4.2     Posology and method of administration

 

Tamiflu 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.

 

Adults, adolescents or children (> 40 kg) (1 year of age or older) who are unable to swallow capsules may receive appropriate doses of Tamiflu suspension.

 

For infants below 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 below 4.2).

 

 

Treatment of influenza

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

 

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

 

Ø  For infants older than 1 year of age and for children 2 to 12 years of age: Tamiflu 30 mg and 45 mg capsules and oral suspension are available.

 

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

Body Weight

Recommended dose for 5 days

≤ 15 kg

30 mg twice daily

> 15 kg to 23 kg

45 mg twice daily

> 23 kg to 40 kg

60 mg twice daily

> 40 kg

75 mg twice daily

 

Children weighing > 40 kg and who are able to swallow capsules may receive treatment with the adult dosage of 75 mg Tamiflu capsules (30 mg, 45 mg, 75 mg) twice daily for 5 days as an alternative to the recommended dose of Tamiflu suspension.

 

Ø  For infants below 12 months of age: The recommended treatment dose for infants less than 12 months is between 2 mg/kg twice daily and 3 mg/kg twice daily during a pandemic influenza outbreak. This is based upon limited pharmacokinetic 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 weight‑adjusted dosing regimens are recommended for treatment of infants below 1 year of age:

 

Age

Recommended dose for 5 days

> 3 months to 12 months

3 mg/kg twice daily

> 1 month to 3 months

2.5 mg/kg twice daily

0 to 1 month*

2 mg/kg twice daily

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

 

Administration of Tamiflu to infants less than one year of age should be based upon the judgment of the physician after considering the potential benefit of treatment versus any potential risk to the infant.

 

These age-based dosing recommendations are not intended for premature infants, i.e. those with a postmenstrual age less than 37 weeks. Insufficient data are available for these patients, in whom different dosing may be required due to the immaturity of physiological functions

 

Prevention of influenza

Post-exposure prevention

Ø  For adolescents (13 to 17 years of age) and adults: The recommended dose for prevention of influenza following close contact with an infected individual is 75 mg oseltamivir once daily for 10 days. Therapy should begin as soon as possible within two days of exposure to an infected individual.

 

Ø  For infants older than 1 year of age and for children 2 to 12 years of age: Tamiflu 30 mg and 45 mg capsules and oral suspension are available.

 

The recommended post-exposure prevention dose of Tamiflu is:

Body Weight

Recommended dose for 10 days

≤ 15 kg

30 mg once daily

> 15 kg to 23 kg

45 mg once daily

> 23 kg to 40 kg

60 mg once daily

> 40 kg

75 mg once daily

 

Children weighing > 40 kg and who are able to swallow capsules may receive prevention with a 75 mg Tamiflu capsules (30 mg, 45 mg, 75 mg) once daily for 10 days as an alternative to the recommended dose of Tamiflu suspension.

 

Ø  For infants below 12 months of age: The recommended prophylaxis dose for infants less than 12 months during a pandemic influenza outbreak is half of the daily treatment dose. This is based upon clinical data in children > 1 year of age and adults showing that a prophylaxis dose equivalent to half the daily treatment dose is clinically efficacious for the prevention of influenza. The following weight‑adjusted dosing prophylaxis regimens are recommended for infants below 1 year of age:

 

Age

Recommended dose for 10 days

> 3 months to 12 months

3 mg/kg once daily

> 1 month to 3 months

2.5 mg/kg once daily

0 to 1 month*

2 mg/kg once daily

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

 

Administration of Tamiflu to infants less than one year of age should be based upon the judgment of the physician after considering the potential benefit of prophylaxis versus any potential risk to the infant.

 

These age-based dosing recommendations are not intended for premature infants, i.e. those with a postmenstrual age less than 37 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

The recommended dose for prevention of influenza during a community outbreak is 75 mg oseltamivir once daily for up to 6 weeks.

 

Extemporaneous formulation

When Tamiflu powder for oral suspension is not available

During situations when commercially manufactured Tamiflu powder for oral suspension is not readily available, adults, adolescents or children who are unable to swallow capsules may receive appropriate doses of Tamiflu prepared by a pharmacist or prepared at home by parents or caregivers.When commercially manufactured Tamiflu powder for oral suspension is not available, patients who are unable to swallow capsules may receive appropriate doses of Tamiflu prepared in a pharmacy or prepared at home.

 

For infants below 12 months, the pharmacy preparation should be preferred to home preparation. Detailed information on the home preparation can be found in section 3 of the package leaflet of Tamiflu capsules.

 

Pharmacy compounding

Ø  Adults and children greater than 1 year who are unable to swallow intact capsules

This procedure describes the preparation of a 15 mg/ml solution that will provide one patient with enough medication for a 5-day course of treatment or a 10-day course of prophylaxis.

 

The pharmacist may compound a suspension (15 mg/ml) from Tamiflu 30 mg, 45 mg or 75 mg capsules using water containing 0.1% w/v sodium benzoate added as a preservative.

 

First, calculate the Total Volume needed to be compounded and dispensed to provide a 5-day course of treatment or a 10=day course of prophylaxis for the patient. The Total Volume required is determined by the weight of the patient according to the recommendation in the table below:

 

Volume of Compounded Suspension (15 mg/ml) Prepared Based Upon the Patient’s Weight

Body Weight
(kg)

Total Volume to Compound per Patient Weight
(ml)

10 to 15 kg

30 ml

> 15 to 23 kg

40 ml

> 23 to 40 kg

50 ml

> 40 kg

60 ml

 

Second, determine the number of capsules and the amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) that is needed to prepare the Total Volume (calculated from the table above: 30 ml, 40 ml, 50 ml or 60 ml) of compounded suspension (15 mg/ml) as shown in the table below:

 

Number of Capsules and Amount of Vehicle Needed to Prepare the Total Volume of a Compounded Suspension (15 mg/ml)

Total Volume
of Compounded Suspension
to be Prepared

Required Number of Tamiflu Capsules
(mg of oseltamivir)

Required Volume
of Vehicle

75 mg

45 mg

30 mg

30 ml

6 capsules

(450 mg)

10 capsules

(450 mg)

15 capsules

(450 mg)

29 ml

40 ml

8 capsules

(600 mg)

Please use alternative capsule strength*

20 capsules

(600 mg)

38.5 ml

50 ml

10 capsules

(750 mg)

Please use alternative capsule strength*

25 capsules

(750 mg)

48 ml

60 ml

12 capsules

(900 mg)

20 capsules

(900 mg)

30 capsules

(900 mg)

57 ml

*          No integral number of capsules can be used to achieve the target concentration; therefore, please use either the 30 mg or 75 mg capsules.

 

Third, follow the procedure below for compounding the suspension (15 mg/ml) from Tamiflu capsules:

1.       Carefully separate the capsule body and cap and transfer the contents of the required number of Tamiflu capsules into a clean mortar.

2.       Triturate the granules to a fine powder.

3.       Add one-third (1/3) of the specified amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) and triturate the powder until a uniform suspension is achieved.

4.       Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle. A funnel may be used to eliminate any spillage.

5.       Add another one-third (1/3) of the vehicle to the mortar, rinse the pestle and mortar by a triturating motion and transfer the vehicle into the bottle.

6.       Repeat the rinsing (Step 5) with the remainder of the vehicle.

7.       Close the bottle using a child-resistant cap.

8.       Shake well to completely dissolve the active drug and to ensure homogeneous distribution of the dissolved drug in the resulting suspension.

(Note: Undissolved residue may be visible but is comprised of inert ingredients of Tamiflu capsules, which are insoluble. However, the active drug, oseltamivir phosphate, readily dissolves in the specified vehicle and therefore forms a uniform solution.)

9.       Put an ancillary label on the bottle indicating Shake Gently Before Use.

10.     Instruct the parent or caregiver that after the patient has completed the full course of therapy any remaining solution must be discarded. It is recommended that this information be provided by affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions.

11.     Place an appropriate expiration date label according to storage condition (see below).

 

Storage of the pharmacy-compounded suspension (15 mg/ml)

Room temperature storage conditions: Stable for 3 weeks (21 days) when stored at room temperature “do not store above 25 °C”.

Refrigerated storage conditions: Stable for 6 weeks when stored at 2 °C - 8 °C.

 

Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, use by date, drug name and any other required information to be in compliance with local pharmacy regulations. Refer to the table below for the proper dosing instructions.

 

Dosing Chart for Pharmacy-Compounded Suspension from Tamiflu Capsules for Children One Year of Age or Older

Body Weight
(kg)

Dose
(mg)

Volume per Dose
15 mg/ml

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

10 kg to 15 kg

30 mg

2 ml

2 ml twice daily

2 ml once daily

> 15 to 23 kg

45 mg

3 ml

3 ml twice daily

3 ml once daily

> 23 to 40 kg

60 mg

4 ml

4 ml twice daily

4 ml once daily

> 40 kg

75 mg

5 ml

5 ml twice daily

5 ml once daily

Note: This compounding procedure results in a 15 mg/ml suspension, which is different from the commercially available Tamiflu powder for oral suspension.

 

Dispense the suspension with a graduated oral syringe for measuring small amounts of suspension. If possible, mark or highlight the graduation corresponding to the appropriate dose (2 ml, 3 ml, 4 ml or 5 ml) 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.

 

Ø  Infants less than 1 year of age

This procedure describes the preparation of a 10 mg/ml solution that will provide one patient with enough medication for a 5-day course of treatment or a 10-day course of prophylaxis.

 

The pharmacist may compound a suspension (10 mg/ml) from Tamiflu 30 mg, 45 mg or 75 mg capsules using water containing 0.1% w/v sodium benzoate added as a preservative.

 

First, calculate the Total Volume needed to be compounded and dispensed for each patient. The Total Volume required is determined by the weight of the patient according to the recommendation in the table below:

 

Volume of Compounded Suspension (10 mg/ml) Prepared Based Upon the Patient’s Weight

Body Weight
(kg)

Total Volume to Compound per Patient Weight
(ml)

£ 7 kg

30 ml

> 7 to 12 kg

45 ml

 

Second, determine the number of capsules and the amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) that is needed to prepare the Total Volume (calculated from the table above: 30 ml, 45 ml) of compounded suspension (10 mg/ml) as shown in the table below:

 

Number of Capsules and Amount of Vehicle Needed to Prepare the Total Volume of a Compounded Suspension (10 mg/ml)

Total Volume
of Compounded Suspension
to be Prepared

Required Number of Tamiflu Capsules
(mg of oseltamivir)

Required Volume
of Vehicle

75 mg

45 mg

30 mg

30 ml

4 capsules

(300 mg)

Please use alternative capsule strength*

10 capsules

(300 mg)

29.5 ml

45 ml

6 capsules

(450 mg)

10 capsules

(450 mg)

15 capsules

(450 mg)

44 ml

*          No integral number of capsules can be used to achieve the target concentration; therefore, please use either the 30 mg or 75 mg capsules.

 

Third, follow the procedure below for compounding the suspension (10 mg/ml) from Tamiflu capsules:

1.       Carefully separate the capsule body and cap and transfer the contents of the required number of Tamiflu capsules into a clean mortar.

2.       Triturate the granules to a fine powder.

3.       Add one-third (1/3) of the specified amount of vehicle and triturate the powder until a uniform suspension is achieved.

4.       Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle. A funnel may be used to eliminate any spillage.

5.       Add another one-third (1/3) of the vehicle to the mortar, rinse the pestle and mortar by a triturating motion and transfer the vehicle into the bottle.

6.       Repeat the rinsing (Step 5) with the remainder of the vehicle.

7.       Close the bottle using a child-resistant cap.

8.       Shake well to completely dissolve the active drug and to ensure homogeneous distribution of the dissolved drug in the resulting suspension.
(Note: Undissolved residue may be visible but is comprised of inert ingredients of Tamiflu capsules, which are insoluble. However, the active drug, oseltamivir phosphate, readily dissolves in the specified vehicle and therefore forms a uniform solution.)

9.       Put an ancillary label on the bottle indicating “Shake Gently Before Use”.

10.     Instruct the parent or caregiver that after the patient has completed the full course of therapy any remaining solution must be discarded. It is recommended that this information be provided by affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions.

11.     Place an appropriate expiration date label according to storage condition (see below).

 

Storage of the pharmacy-compounded suspension (10 mg/ml)

Room temperature storage conditions: Stable for 3 weeks (21 days) when stored at room temperature “do not store above 25 °C”.

Refrigerated storage conditions: Stable for 6 weeks when stored at 2 °C - 8 °C.

 

Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, use by date, drug name and any other required information to be in compliance with local pharmacy regulations. Refer to the table below for the proper dosing instructions.

 

Dosing Chart for Pharmacy-Compounded Suspension (10 mg/ml) from Tamiflu Capsules for Infants Less Than One Month of Age

Body Weight
(rounded to the nearest 0.5 kg)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

3 kg

0.60 ml twice daily

0.60 ml once daily

3.5 kg

0.70 ml twice daily

0.70 ml once daily

4 kg

0.80 ml twice daily

0.80 ml once daily

4.5 kg

0.90 ml twice daily

0.90 ml once daily

 

Dosing Chart for Pharmacy-Compounded Suspension (10 mg/ml) from Tamiflu Capsules for Infants One to Twelve Months of Age

Body Weight
(rounded to the nearest 0.5 kg)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

4 kg

1.00 ml twice daily

1.00 ml once daily

4.5 kg

1.10 ml twice daily

1.10 ml once daily

5 kg

1.30 ml twice daily

1.30 ml once daily

5.5 kg

1.40 ml twice daily

1.40 ml once daily

6 kg

1.50 ml twice daily

1.50 ml once daily

7 kg

2.10 ml twice daily

2.10 ml once daily

8 kg

2.40 ml twice daily

2.40 ml once daily

9 kg

2.70 ml twice daily

2.70 ml once daily

³ 10 kg

3.00 ml twice daily

3.00 ml once daily

 

Note:    This compounding procedure results in a 10 mg/ml suspension, which is different from the commercially available Tamiflu powder for oral suspension.

 

Dispense the suspension with a graduated oral syringe for measuring small amounts of suspension. If possible, mark or highlight the graduation corresponding to the appropriate dose 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

During situations when commercially manufactured Tamiflu oral suspension is not readily available, adults, adolescents or children who are unable to swallow capsules may receive appropriate doses of Tamiflu (see section 3 in Package Leaflet) by opening capsules and pouring the contents of capsules into a suitable, small amount (1 teaspoon maximum) of sweetened food product such as sugar water, chocolate syrup, cherry syrup, dessert toppings (like caramel or fudge sauce) to mask the bitter taste. The mixture should be stirred and the entire contents given to the patient. The mixture must be swallowed immediately after its preparation. When commercially manufactured Tamiflu oral suspension is not available, a pharmacy preparation from Tamiflu capsules can be used (detailed instructions above in section 4.2). If the pharmacy preparation is not available either, Tamiflu doses may be prepared at home. The pharmacy preparation  is the preferred option in infants below 12 months of age.

 

When appropriate capsule strengths are available, 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 involves additional steps. Detailed instructions can be found in section 3 in the package leaflet of Tamiflu capsules.

 

 

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 with severe renal impairment. Recommended doses are detailed in the table below.

Creatinine clearance

Recommended dose for treatment

> 30 (ml/min)

75 mg twice daily

> 10 to £ 30 (ml/min)

75 mg once daily,
or 30 mg suspension twice daily,
or 30 mg capsules twice daily

£ 10 (ml/min)

Not recommended

dialysis patients

Not recommended

 

Prevention of influenza: Dose adjustment is recommended for adults with severe renal impairment as detailed in the table below.

Creatinine clearance

Recommended dose for prevention

> 30 (ml/min)

75 mg once daily

> 10 to £ 30 (ml/min)

75 mg every second day,
or 30 mg suspension once daily,
or 30 mg capsules once daily

£ 10 (ml/min)

Not recommended

dialysis patients

Not recommended

 

Elderly

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

 

Children

There is insufficient clinical data available in children with renal impairment to be able to make any dosing recommendation.

 

Immunocompromised patients

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

 

4.4     Special warnings and precautions for use

 

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.

 

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.

 

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

 

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).

 

No data allowing a dose recommendation for premature children (< 37 weeks post-menstrual age*) are currently available.

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

 

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 renal impairment

Dose adjustment is recommended for both treatment and prevention in adults with severe renal insufficiency. There is insufficient clinical data available in children with renal impairment to be able to make any dosing recommendation.(see sections 4.2 and 5.2).

 

Neuropsychiatric events have been reported during administration of Tamiflu in patients with influenza, especially in children and adolescents (see section 4.8). These events are also experienced in by patients with influenza without Tamifluoseltamivir administration and no causal relationship to the treatment with Tamiflu has been established. Three separate large epidemiological studies confirmed that influenza infected patients receiving Tamiflu are at no higher risk of developing neuropsychiatric events in comparison to influenza infected patients not receiving antivirals.   Patients with influenza 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).

 

4.8     Undesirable effects

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 accidental self injury or fatal outcomes. These events were reported primarily among pediatric 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.

6.6     Special precautions for disposal

 

No special requirements.

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

 

Special instructions for use, handling and disposal of extemporaneous formulation prepared for children less than one year of age

 

Extemporaneous formulation

When commercially manufactured Tamiflu powder for oral suspension is not available, patients who are unable to swallow capsules may receive appropriate doses of Tamiflu prepared in a pharmacy or prepared at home.

 

For infants below 12 months, the pharmacy preparation should be preferred to home preparation. Detailed information on the pharmacy preparation can be found in section 4.2 and on the home preparation can be found in section 3 of the package leaflet of Tamiflu capsules.

 

Syringes of appropriate volume and grading should be provided for administering the pharmacy compounded suspension as well as for the procedures involved in the home preparation. In both cases, the correct volumes should preferably be marked on the syringes.

 

 

Updated on 17 December 2010

Reasons for updating

  • Change to side-effects
  • Change to dosage and administration

Updated on 20 July 2010

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties

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4.1     Therapeutic indications

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 antiviralsoseltamivir 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).

 

 

4.4     Special warnings and precautions for use

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.

 

 

5.1     Pharmacodynamic properties

Reduced sensitivity of viral neuraminidase

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 subjects. There was no resistance observed during a 12-week prophylaxis study in immunocompromised subjects.

 

Clinical studies: The risk of emergence of influenza viruses with reduced susceptibility or frank resistance to oseltamivir has been examined during Roche-sponsored clinical studies. All patients who were found to carry oseltamivir-resistant virus did so transiently, cleared the virus normally and showed no clinical deterioration.

 

Patient Population

Patients with Resistance Mutations (%)

Phenotyping*

Geno- and Phenotyping*

Adults and adolescents

4/1245 (0.32%)

5/1245 (0.4%)

Children (1-12 years)

19/464 (4.1%)

25/464 (5.4%)

* Full genotyping was not performed in all studies.

 

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 subjects. There was no resistance observed during a 12-week prophylaxis study in immunocompromised subjects.

 

The rate of emergence of resistance may be higher in the youngest age groups, and in immunocompromised patients. Oseltamivir-resistant viruses isolated from oseltamivir-treated patients and oseltamivir-resistant laboratory strains of influenza viruses have been found to contain mutations in N1 and N2 neuraminidases. Resistance mutations tend to be viral sub-type specific (including those found in H5N1 variants).

Clinical and surveillance data: Natural mutations associated with reduced susceptibility to oseltamivir in vitro have been detected in influenza A and B viruses isolated from patients without exposure to oseltamivir. Resistant strains selected during oseltamivir treatment have been isolated from both immunocompetent and immunocompromised patients. Immunocompromised patients and young children are at a higher risk of developing oseltamivir-resistant virus during treatment.

 

Oseltamivir-resistant viruses isolated from oseltamivir-treated patients and oseltamivir-resistant laboratory strains of influenza viruses have been found to contain mutations in N1 and N2 neuraminidases. Resistance mutations tend to be viral sub-type specific. Since 2007 resistance associated H275Y mutation in seasonal H1N1 strains has become widespread. The susceptibility to oseltamivir and the prevalence of such viruses appear to vary seasonally and geographically. In 2008, H275Y was found in > 99 % of circulating H1N1 influenza isolates in Europe. The 2009 H1N1 influenza (“swine flu”) was almost uniformly susceptible to oseltamivir, with only sporadic reports of resistance in connection with both therapeutic and prophylactic regimens.

 

Naturally occurring mutations in influenza A/H1N1 virus associated with reduced susceptibility to oseltamivir in vitro have been detected in patients who, based on the reported information, have not been exposed to oseltamivir. The extent of reduction in susceptibility to oseltamivir and the prevalence of such viruses appears to vary seasonally and geographically.

 

Updated on 19 July 2010

Reasons for updating

  • Change to how the medicine works

Updated on 25 March 2010

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

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4.2     Posology and method of administration

Immunocompromised patients

The recommended duration for the prevention of influenza in immunocompromised subjects 1 year of age and older during a community outbreak is for up to 12 weeks (see section 5.1). The safety profile of Tamiflu in the seasonal prophylaxis of influenza in immunocompromised in subjects 1 year of age and older has been shown to be similar to that in prophylactic studies with immunocompetent patients. Studies have been carried out up to 12 weeks. However, the efficacy of Tamiflu in preventing influenza in this population has not been firmly established (see section 5.1). No dose adjustment is necessary in subjects with normal creatinine clearance. Longer duration of seasonal prophylaxis up to 12 weeks has been evaluated in immunocompromised subjects (see sections 4.4, 4.8 and 5.1).

 

4.4     Special warnings and precautions for use

 

The safety and efficacy of oseltamivir in either treatment or preventionprophylaxis of influenza in immunocompromised patients havehas not been firmly established (see section 5.1).

 

4.8     Undesirable effects

 

The overall safety profile of Tamiflu is based on data from 2107 adult and 1032 paediatric patients treated with Tamiflu or placebo for influenza, and on data from 2914 adult and 99148 paediatric patients receiving Tamiflu or placebo for the prophylaxis of influenza in clinical trials. In addition, 475 immunocompromised patients (including 18 children) received Tamiflu or placebo for the prophylaxis of influenza.

 

Immunocompromised patients

The adverse reactions noted in immunocompromised subjects 113 years of age and older who received oseltamivir during 12 weeks for the seasonal prophylaxis of influenza were consistent with those previously observed in Tamiflu clinical trials.

 

5.1     Pharmacodynamic properties

Reduced sensitivity of viral neuraminidase

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 subjects. There was no resistance observed during a 12-week prophylaxis study in immunocompromised subjects. There have been post-marketing reports of oseltamivir resistance occurring in immunosuppressed patients receiving oseltamivir for prophylaxis of pandemic H1N1 2009 infection.

 

The European Medicines Agency has deferred the obligation to submit the results of studies with Tamiflu in one or more subsets of the paediatric population in influenza. See section 4.2 for information on paediatric use.

 

Prophylaxis of influenza in immunocompromised patients: A double-blind, placebo-controlled, randomised study was conducted for seasonal prophylaxis of influenza in 475 immunocompromised subjects (388 subjects with solid organ transplantation [195 placebo; 193 oseltamivir], 87 subjects with haemopoetic stem cell transplantation [43 placebo; 44 oseltamivir], no subject with other immunosuppressant conditions), including 18 children 1 to 12 years of age. Laboratory-confirmed clinical influenza, as defined by RT-PCR plus oral temperature 37.2 °C plus cough and/or coryza, all recorded within 24 hours, was evaluated. Among subjects who were not already shedding virus at baseline, Tamiflu reduced the incidence of laboratory-confirmed clinical influenza from 3.0% (7/231) in the group not receiving prophylaxis to 0.4% (1/232) in the group receiving prophylaxis.The primary endpoint in this study was the incidence of laboratory‑confirmed clinical influenza as determined by viral culture and/or a four-fold rise in HAI antibodies. The incidence of laboratory‑confirmed clinical influenza was reduced from2.9 % (7/238 (2.9 %) in the placebo group to 5/237 (2.1 %)and 2.1 % (5/237) in the oseltamivir group (28.3 % reduction [(95 % CI -2.3 % – 4.1 %; p = 0.772]).

When evaluating laboratory‑confirmed clinical influenza as determined by RT-PCR, the incidence was reduced from 7/238 (2.9 %) in the placebo group to 2/237 (0.8 %) in the oseltamivir group (71.3 % reduction [95 % CI -0.6 – 5.2; p = 0.176]). Among subjects who were not already shedding virus at baseline, the incidence was reduced from 7/231 (3.0 %) in the placebo group to 1/232 (0.4 %) in the oseltamivir group (85.8 % reduction [95 % CI 0.1 – 5.7; p = 0.037]).

 

Updated on 23 March 2010

Reasons for updating

  • Change to drug interactions

Updated on 02 February 2010

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use

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4.2     Posology and method of administration

 

These age-based dosing recommendations are not intended for premature infants, i.e. those with a postmenstrual age less than 37 weeks. Insufficient data are available for these patients, in whom different dosing may be required due to the immaturity of physiological functions.

 

4.4     Special warnings and precautions for use

 

No data allowing a dose recommendation for premature children (< 37 weeks post-menstrual age*) are currently available.

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

 

Updated on 04 November 2009

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.4 - Special precautions for storage

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4.1     Therapeutic indications

Tamiflu is indicated for the treatment of infants below children 6 to 12 months of age during a pandemic influenza outbreak. (see section 5.2).

 

-        Tamiflu is indicated for post-exposure prevention of influenza in infants below 12 months of age during a pandemic influenza outbreak (see section 5.2).

 

Based on limited pharmacokinetic and safety data, Tamiflu can be used in infants below children 6 to 12 months of age for treatment during a pandemic influenza outbreak. 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

During situations when commercially manufactured Tamiflu oral suspension is not readily available, adults, adolescents or children who are unable to swallow capsules may receive appropriate doses of Tamiflu (see section 3 in Package Leaflet) by opening capsules and pouring the contents of capsules into a suitable, small amount (1 teaspoon maximum) of sweetened food product such as regular or sugar-free chocolate syrup, honey (only for children two years or older), light brown or table sugar dissolved in water, dessert toppings, sweetened condensed milk, apple sauce or yogurt to mask the bitter taste. The mixture should be stirred and the entire contents given to the patient. The mixture must be swallowed immediately after its preparation.

For children 6 to 12 months of age: Depending on the pathogenicity of the circulating influenza virus strain, children between 6 and 12 months of age can be treated with Tamiflu during a pandemic influenza outbreak, although the available data are

Ø         For infants below 12 months of age: The recommended treatment dose for infants less than 12 months is between 2 mg/kg twice daily and 3 mg/kg twice daily during a pandemic influenza outbreak. This is based upon limited. Pharmacokinetic data indicatepharmacokinetic data indicating that a dosage of 3 mg/kg twice daily in children 6 to 12 months of age providesthese doses provide plasma drug exposures in the majority of patients similar to those shown to be clinically efficacious in children age one or older children and adults (see section 5.2). The following weight‑adjusted dosing regimens are recommended for treatment of infants below 1 year of age:

 

The recommended dose for treatment of children 6 to 12 months of age is 3 mg per kg body weight twice daily for 5 days for treatment

Age

Recommended dose for 5 days

> 3 months to 12 months

3 mg/kg twice daily

> 1 month to 3 months

2.5 mg/kg twice daily

0 to 1 month*

2 mg/kg twice daily

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

 

Administration of Tamiflu to infants less than one year of age should be based upon the judgment of the physician after considering the potential benefit of treatment versus any potential risk to the infant.

 

Ø  For infants below 12 months of age: The recommended prophylaxis dose for infants less than 12 months during a pandemic influenza outbreak is half of the daily treatment dose. This is based upon clinical data in children > 1 year of age and adults showing that a prophylaxis dose equivalent to half the daily treatment dose is clinically efficacious for the prevention of influenza. The following weight‑adjusted dosing prophylaxis regimens are recommended for infants below 1 year of age:

 

Age

Recommended dose for 10 days

> 3 months to 12 months

3 mg/kg once daily

> 1 month to 3 months

2.5 mg/kg once daily

0 to 1 month*

2 mg/kg once daily

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

 

Administration of Tamiflu to infants less than one year of age should be based upon the judgment of the physician after considering the potential benefit of prophylaxis versus any potential risk to the infant.

 

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.

 

Extemporaneous formulation

When Tamiflu powder for oral suspension is not available

During situations when commercially manufactured Tamiflu powder for oral suspension is not readily available, adults, adolescents or children who are unable to swallow capsules may receive appropriate doses of Tamiflu prepared by a pharmacist or prepared at home by parents or caregivers.

 

Pharmacy compounding

Ø  Adults and children greater than 1 year who are unable to swallow intact capsules

This procedure describes the preparation of a 15 mg/ml solution that will provide one patient with enough medication for a 5-day course of treatment or a 10-day course of prophylaxis.

 

The pharmacist may compound a suspension (15 mg/ml) from Tamiflu 30 mg, 45 mg or 75 mg capsules using water containing 0.1% w/v sodium benzoate added as a preservative.

 

First, calculate the Total Volume needed to be compounded and dispensed to provide a 5-day course of treatment or a 10=day course of prophylaxis for the patient. The Total Volume required is determined by the weight of the patient according to the recommendation in the table below:

 

Volume of Compounded Suspension (15 mg/ml) Prepared Based Upon the Patient’s Weight

Body Weight
(kg)

Total Volume to Compound per Patient Weight
(ml)

10 to 15 kg

30 ml

> 15 to 23 kg

40 ml

> 23 to 40 kg

50 ml

> 40 kg

60 ml

 

Second, determine the number of capsules and the amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) that is needed to prepare the Total Volume (calculated from the table above: 30 ml, 40 ml, 50 ml or 60 ml) of compounded suspension (15 mg/ml) as shown in the table below:

 

Number of Capsules and Amount of Vehicle Needed to Prepare the Total Volume of a Compounded Suspension (15 mg/ml)

Total Volume
of Compounded Suspension
to be Prepared

Required Number of Tamiflu Capsules
(mg of oseltamivir)

Required Volume
of Vehicle

75 mg

45 mg

30 mg

30 ml

6 capsules

(450 mg)

10 capsules

(450 mg)

15 capsules

(450 mg)

29 ml

40 ml

8 capsules

(600 mg)

Please use alternative capsule strength*

20 capsules

(600 mg)

38.5 ml

50 ml

10 capsules

(750 mg)

Please use alternative capsule strength*

25 capsules

(750 mg)

48 ml

60 ml

12 capsules

(900 mg)

20 capsules

(900 mg)

30 capsules

(900 mg)

57 ml

*          No integral number of capsules can be used to achieve the target concentration; therefore, please use either the 30 mg or 75 mg capsules.

 

Third, follow the procedure below for compounding the suspension (15 mg/ml) from Tamiflu capsules:

1.       Carefully separate the capsule body and cap and transfer the contents of the required number of Tamiflu capsules into a clean mortar.

2.       Triturate the granules to a fine powder.

3.       Add one-third (1/3) of the specified amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) and triturate the powder until a uniform suspension is achieved.

4.       Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle. A funnel may be used to eliminate any spillage.

5.       Add another one-third (1/3) of the vehicle to the mortar, rinse the pestle and mortar by a triturating motion and transfer the vehicle into the bottle.

6.       Repeat the rinsing (Step 5) with the remainder of the vehicle.

7.       Close the bottle using a child-resistant cap.

8.       Shake well to completely dissolve the active drug and to ensure homogeneous distribution of the dissolved drug in the resulting suspension.

(Note: Undissolved residue maybe visible but is comprised of inert ingredients of Tamiflu capsules, which are insoluble. However, the active drug, oseltamivir phosphate, readily dissolves in the specified vehicle and therefore forms a uniform solution.)

9.       Put an ancillary label on the bottle indicating Shake Gently Before Use.

10.     Instruct the parent or caregiver that after the patient has completed the full course of therapy any remaining solution must be discarded. It is recommended that this information be provided by affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions.

11.     Place an appropriate expiration date label according to storage condition (see below).

 

Storage of the pharmacy-compounded suspension (15 mg/ml)

Room temperature storage conditions: Stable for 3 weeks (21 days) when stored at room temperature “do not store above 25 °C”.

Refrigerated storage conditions: Stable for 6 weeks when stored at 2 °C - 8 °C.

 

Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, use by date, drug name and any other required information to be in compliance with local pharmacy regulations. Refer to the table below for the proper dosing instructions.

 

Dosing Chart for Pharmacy-Compounded Suspension from Tamiflu Capsules for Children One Year of Age or Older

Body Weight
(kg)

Dose
(mg)

Volume per Dose
15 mg/ml

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

10 kg to 15 kg

30 mg

2 ml

2 ml twice daily

2 ml once daily

> 15 to 23 kg

45 mg

3 ml

3 ml twice daily

3 ml once daily

> 23 to 40 kg

60 mg

4 ml

4 ml twice daily

4 ml once daily

> 40 kg

75 mg

5 ml

5 ml twice daily

5 ml once daily

Note: This compounding procedure results in a 15 mg/ml suspension, which is different from the commercially available Tamiflu powder for oral suspension.

 

Dispense the suspension with a graduated oral syringe for measuring small amounts of suspension. If possible, mark or highlight the graduation corresponding to the appropriate dose (2 ml, 3 ml, 4 ml or 5 ml) 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.

 

Ø  Infants less than 1 year of age

This procedure describes the preparation of a 10 mg/ml solution that will provide one patient with enough medication for a 5-day course of treatment or a 10-day course of prophylaxis.

 

The pharmacist may compound a suspension (10 mg/ml) from Tamiflu 30 mg, 45 mg or 75 mg capsules using water containing 0.1% w/v sodium benzoate added as a preservative.

 

First, calculate the Total Volume needed to be compounded and dispensed for each patient The Total Volume required is determined by the weight of the patient according to the recommendation in the table below:

 

Volume of Compounded Suspension (10 mg/ml) Prepared Based Upon the Patient’s Weight

Body Weight
(kg)

Total Volume to Compound per Patient Weight
(ml)

Up to 7 kg

30 ml

7 to 12 kg

45 ml

 

Second, determine the number of capsules and the amount of vehicle (water containing 0.1% w/v sodium benzoate added as a preservative) that is needed to prepare the Total Volume (calculated from the table above: 30 ml, 45 ml) of compounded suspension (10 mg/ml) as shown in the table below:

 

Number of Capsules and Amount of Vehicle Needed to Prepare the Total Volume of a Compounded Suspension (10 mg/ml)

Total Volume
of Compounded Suspension
to be Prepared

Required Number of Tamiflu Capsules
(mg of oseltamivir)

Required Volume
of Vehicle

75 mg

45 mg

30 mg

30 ml

4 capsules

(300 mg)

Please use alternative capsule strength*

10 capsules

(300 mg)

29.5 ml

45 ml

6 capsules

(450 mg)

10 capsules

(450 mg)

15 capsules

(450 mg)

44 ml

*          No integral number of capsules can be used to achieve the target concentration; therefore, please use either the 30 mg or 75 mg capsules.

 

Third, follow the procedure below for compounding the suspension (10 mg/mL) from Tamiflu capsules:

1.       Carefully separate the capsule body and cap and transfer the contents of the required number of Tamiflu capsules into a clean mortar.

2.       Triturate the granules to a fine powder.

3.       Add one-third (1/3) of the specified amount of vehicle and triturate the powder until a uniform suspension is achieved.

4.       Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle. A funnel may be used to eliminate any spillage.

5.       Add another one-third (1/3) of the vehicle to the mortar, rinse the pestle and mortar by a triturating motion and transfer the vehicle into the bottle.

6.       Repeat the rinsing (Step 5) with the remainder of the vehicle.

7.       Close the bottle using a child-resistant cap.

8.       Shake well to completely dissolve the active drug and to ensure homogeneous distribution of the dissolved drug in the resulting suspension.
(Note: Undissolved residue may be visible but is comprised of inert ingredients of Tamiflu capsules, which are insoluble. However, the active drug, oseltamivir phosphate, readily dissolves in the specified vehicle and therefore forms a uniform solution.)

9.       Put an ancillary label on the bottle indicating “Shake Gently Before Use”.

10.     Instruct the parent or caregiver that after the patient has completed the full course of therapy any remaining solution must be discarded. It is recommended that this information be provided by affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions.

11.     Place an appropriate expiration date label according to storage condition (see below).

 

Storage of the pharmacy-compounded suspension (10 mg/mL)

Room temperature storage conditions: Stable for 3 weeks (21 days) when stored at room temperature “do not store above 25 °C”.

Refrigerated storage conditions: Stable for 6 weeks when stored at 2 °C - 8 °C.

 

Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, use by date, drug name and any other required information to be in compliance with local pharmacy regulations. Refer to the table below for the proper dosing instructions.

 

Dosing Chart for Pharmacy-Compounded Suspension (10 mg/ml) from Tamiflu Capsules for Infants Less Than One Month of Age

Body Weight
(rounded to the nearest 0.5 kg)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

3 kg

0.60 ml twice daily

0.60 ml once daily

3.5 kg

0.70 ml twice daily

0.70 ml once daily

4 kg

0.80 ml twice daily

0.80 ml once daily

4.5 kg

0.90 ml twice daily

0.90 ml once daily

 

Dosing Chart for Pharmacy-Compounded Suspension (10 mg/ml) from Tamiflu Capsules for Children One to Twelve Months of Age

Body Weight
(rounded to the nearest 0.5 kg)

Treatment Dose
(for 5 days)

Prophylaxis Dose
(for 10 days)

4 kg

1.00 ml twice daily

1.00 ml once daily

4.5 kg

1.10 ml twice daily

1.10 ml once daily

5 kg

1.30 ml twice daily

1.30 ml once daily

5.5 kg

1.40 ml twice daily

1.40 ml once daily

6 kg

1.50 ml twice daily

1.50 ml once daily

7 kg

2.10 ml twice daily

2.10 ml once daily

8 kg

2.40 ml twice daily

2.40 ml once daily

9 kg

2.70 ml twice daily

2.70 ml once daily

³ 10 kg

3.00 ml twice daily

3.00 ml once daily

 

Note:    This compounding procedure results in a 10 mg/ml suspension, which is different from the commercially available Tamiflu powder for oral suspension.

 

Dispense the suspension with a graduated oral syringe for measuring small amounts of suspension. If possible, mark or highlight the graduation corresponding to the appropriate dose 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

During situations when commercially manufactured Tamiflu oral suspension is not readily available, adults, adolescents or children who are unable to swallow capsules may receive appropriate doses of Tamiflu (see section 3 in Package Leaflet) by opening capsules and pouring the contents of capsules into a suitable, small amount (1 teaspoon maximum) of sweetened food product such as sugar water, chocolate syrup, cherry syrup, dessert toppings (like caramel or fudge sauce) to mask the bitter taste. The mixture should be stirred and the entire contents given to the patient. The mixture must be swallowed immediately after its preparation.

 

4.8     Undesirable effects

Additional information on special populations:

 

Infants less than one year of age

Safety information available on oseltamivir administered for treatment of influenza in infants less than one year of age from prospective and retrospective observational trials (comprising together more than 2400 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 patients

There were no clinically relevant differences in the safety population of the elderly subjects who received oseltamivir or placebo compared with the adult population aged up to 65 years.

 

Patients with chronic cardiac and/or respiratory disease

The adverse event profile in adolescents and patients with chronic cardiac and/or respiratory disease was qualitatively similar to those of healthy young adults.

 

Safety information available on oseltamivir administered for treatment of influenza in children less than one year of age from prospective and retrospective observational trials (comprising together more than 2400 children of that age class), epidemiological databases research and postmarketing reports suggest that the safety profile in children less than one year of age is similar to the established safety profile of children aged one year and older.

 

5.2     Pharmacokinetic properties

Children 6 to Infants below 12 months of age: Limited exposure data from children 6 to 12 months of age from a pharmacodynamic, pharmacokinetic and safety study in influenza-infected children data are available for infants less than 2 years of age.  , suggest that for most children 6 to 12 months of age, the exposure following 3 mg/kg dosing is similar to the exposures seen in older children and adults using the approved dosePharmacokinetic modeling was undertaken using these data in addition to data from studies in adults and children older than 1 year of age. 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 children > 1 year of age (see sections 4.1 and 4.2). There are currently no data available in infants less than 1 month of age using Tamiflu.

 

6.4     Special precautions for storage

 

Do not store above 25 °C.

 

Storage of the pharmacy-compounded suspension:

Room temperature storage conditions: Stable for 3 weeks (21 days) when stored at room temperature “do not store above 25 °C”.

 

Refrigerated storage conditions: Stable for 6 weeks when stored at 2 °C - 8 °C.

 

Updated on 30 October 2009

Reasons for updating

  • Change to side-effects
  • Change to dosage and administration

Updated on 18 September 2009

Reasons for updating

  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use

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4.1     Therapeutic indications

Tamiflu is indicated for the treatment of children 6 to 12 months of age during a pandemic influenza outbreak.

 

Based on limited pharmacokinetic and safety data, Tamiflu can be used in children 6 to 12 months of age for treatment during a pandemic influenza outbreak. 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

Tamiflu is not recommended for use in children less than one year of age due to insufficient data on safety and efficacy (see section 5.3).

 

For children 6 to 12 months of age: Depending on the pathogenicity of the circulating influenza virus strain, children between 6 and 12 months of age can be treated with Tamiflu during a pandemic influenza outbreak, although the available data are limited. Pharmacokinetic data indicate that a dosage of 3 mg/kg twice daily in children 6 to 12 months of age provides plasma drug exposures in the majority of patients similar to those shown to be clinically efficacious in children age one or older and adults (see section 5.2).

 

The recommended dose for treatment of children 6 to 12 months of age is 3 mg per kg body weight twice daily for 5 days for treatment

 

4.4     Special warnings and precautions for use

The safety and efficacy of oseltamivir for the treatment and prevention of influenza in children of less than one year of age have not been established (see section 5.3).

 

4.6     Pregnancy and lactation

 

There areWhile no adequate data from controlled clinical trials have been conducted on the use of oseltamivir in pregnant women. Animal, 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). Oseltamivir should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the foetusPregnant 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.

 

In lactating rats, oseltamivir and the active metabolite are excreted in the milk. ItVery limited information is not known whetheravailable on children breast-fed by mothers taking oseltamivir orand on excretion of oseltamivir in breast milk. Limited data demonstrated that oseltamivir and the active metabolite are excretedwere detected in human milk. Oseltamivir should be used during breast-feeding only if milk, however the potential benefit for the mother justifies the potential risk for the breast-fed 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 lactating woman, administration of oseltamivir may be considered, where there are clear potential benefits to lactating mothers.

 

4.8     Undesirable effects

Children

Children 1 year of age and older: The pharmacokinetics of oseltamivir have been evaluated in single-dose pharmacokinetic studies in children aged 1 to 16 years. Multiple-dose pharmacokinetics were studied in a small number of children enrolled in a clinical efficacy study. Younger children cleared both the pro-drug and its active metabolite faster than adults, resulting in a lower exposure for a given mg/kg dose. Doses of 2 mg/kg give oseltamivir carboxylate exposures comparable to those achieved in adults receiving a single 75 mg dose (approximately 1 mg/kg). The pharmacokinetics of oseltamivir in children over 12 years of age are similar to those in adults.

 

Children 6 to 12 months of age: Limited exposure data from children 6 to 12 months of age from a pharmacodynamic, pharmacokinetic and safety study in influenza-infected children less than 2 years of age, suggest that for most children 6 to 12 months of age, the exposure following 3 mg/kg dosing is similar to the exposures seen in older children and adults using the approved dose.

 

5.3     Preclinical safety data

In lactating rats, oseltamivir and the active metabolite are excreted in the milk. It is not known whetherLimited data indicate that oseltamivir or and the active metabolite isare excreted in human milk, but extrapolation. Extrapolation of the animal data provides estimates of 0.01 mg/day and 0.3 mg/day for the respective compounds.

 

Updated on 15 September 2009

Reasons for updating

  • Change to side-effects
  • Change to information about pregnancy or lactation

Updated on 18 May 2009

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  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage

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Shelf life increased from 5 to  7 years

Do not store above 25 deg C

Updated on 14 May 2009

Reasons for updating

  • Change to storage instructions

Updated on 30 April 2009

Reasons for updating

  • Change to warnings or special precautions for use

Updated on 17 April 2009

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  • Change to section 5.3 - Preclinical safety data

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5.3     Preclinical safety data

In a two-week study in unweaned rats, a single dose of 1000 mg/kg oseltamivir phosphate given to 7‑day old pups resulted in deaths associated with unusually high exposure to the pro-drug. However, at 2000 mg/kg in 14-day old unweaned pups, there were no deaths or other significant effects. No adverse effects occurred at 500 mg/kg/day administered from 7 to 21 days post partum. In a single-dose investigatory study of this observation in 7-, 14- and 24-day old rats, a dose of 1000 mg/kg resulted in brain exposure to the pro-drug that suggested, respectively, 1500-, 650- and 2-fold the exposure found in the brain of adult (42-day old) rats.

Whereas very high oral single doses of oseltamivir phosphate had no effect in adult rats, such doses resulted in toxicity in juvenile 7-day-old rat pups, including death. These effects were seen at doses of 657 mg/kg and higher. At 500 mg/kg, no adverse effects were seen, including upon chronic treatment (500 mg/kg/day administered from 7 to 21 days post partum).

 

Updated on 17 November 2008

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  • Change to section 4.8 - Undesirable effects

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4.8     Undesirable effects

Psychiatric disorders and nervous system disorders

Frequency not known: 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 encelphalitis 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 accidental 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.

convulsions and psychiatric events such as depressed level of consciousness, abnormal behavior, hallucinations and deliriumIn rare cases, the delirium resulted in accidental injuryThe symptoms were mainly reported in children and adolescentsConvulsions and psychiatric symptoms have also been reported in patients with influenza not taking Tamiflu.

 

Updated on 23 September 2008

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  • Change to section 4.8 - Undesirable effects

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Eye disorders

Frequency not known: visual disturbance.

 

Cardiac disorders

Frequency not known: cardiac arrhythmia.

Updated on 23 September 2008

Reasons for updating

  • Change to side-effects

Updated on 26 August 2008

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

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change to section 4.1  - excessive change within this section
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Change to section 5.1 - excessive change within this section

Updated on 26 August 2008

Reasons for updating

  • Change to side-effects

Updated on 07 December 2007

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  • Change to section 4.8 - Undesirable effects

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4.8 Undesirable effects
 
In rare cases gastro-intestinal bleedings and haemorrhagic colitis were observed after the use of Tamiflu.

Updated on 07 December 2007

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  • Change to warnings or special precautions for use

Updated on 08 October 2007

Reasons for updating

  • New SPC for new product

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Updated on 08 October 2007

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects

Updated on 29 August 2007

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to information about driving or using machinery
  • Change to side-effects
  • Change to storage instructions
  • Change to further information section

Updated on 13 April 2007

Reasons for updating

  • Change to side-effects
  • Change to further information section
  • Change to date of revision

Updated on 28 February 2006

Reasons for updating

  • Change to marketing authorisation holder

Updated on 31 January 2005

Reasons for updating

  • New PIL for medicines.ie