Roche Products Limited

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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

^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 studies^{a, b} investigating Tamiflu for treatment and prevention of influenza in children

^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

^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.

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4.2      Posology and method of administration

Tamiflu suspension and Tamiflu capsules are bioequivalent formulations. 75 mg doses can be administered as either

-           one 75 mg capsule or

-           one 30 mg capsule plus one 45 mg capsule or

-           by administering one 30 mg dose plus one 45 mg dose of suspension.

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

For infants below 12 months of age: This formulation is not suitable for dosing in infants less than 12 months of age.  For details, see sections below.

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: The recommended dose of Tamiflu oral suspension is indicated in the table below. Tamiflu 30 mg and 45 mg capsules are available as an alternative to the recommended dose of Tamiflu suspension.

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

For dosing, an oral dispenser with 30 mg, 45 mg and 60 mg graduations is provided in the box. For accurate dosing, the oral dispenser supplied should be used exclusively (a syringe with ml markings cannot be used).

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

Ø  For infants below 1 year of age: This formulation (Tamiflu 12 mg/ml powder for oral suspension) is unsuitable since the syringe provided in the pack (with mg markings) does not allow for appropriate dose adjustments and the use of syringes with ml markings may lead to unacceptable dosing inaccuracies. In the absence of a suitable formulation, the pharmacy compounded preparation should preferentially be used. Please refer to the SmPC for the 30 mg. 45 mg and 75 mg capsules (section 4.2).

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 are available as an alternative to the recommended dose of Tamiflu suspension.

The recommended post-exposure prevention dose of Tamiflu is:

For dosing, an oral dispenser with 30 mg, 45 mg and 60 mg graduations is provided in the box. For accurate dosing, the oral dispenser supplied should be used exclusively (a syringe with ml markings cannot be used).

It is recommended that Tamiflu powder for oral suspension be constituted by a pharmacist prior to dispensing to the patient (see section 6.6).

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

Ø            For infants below 1 year of age:  This formulation (Tamiflu 12 mg/ml powder for oral suspension) is unsuitable since the syringe provided in the pack (with mg markings) does not allow for appropriate dose adjustments and the use of syringes with ml markings may lead to unacceptable dosing inaccuracies. In the absence of a suitable formulation, the pharmacy compounded preparation should preferentially be used. Please refer to the SmPC for the 30 mg. 45 mg and 75 mg capsules (section 4.2).

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.

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.

* 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.

* 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).

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2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

1 g of powder for oral suspension contains oseltamivir phosphate equivalent to 30 mg of oseltamivir.

After reconstitution, each ml of suspension contains 12 mg oseltamivir.

One bottle of reconstituted suspension (75 ml) contains 900 mg of active substance (oseltamivir).

A bottle of 30 g Tamiflu powder for oral suspension contains 25.713 g of sorbitol

. One dose of 45 mg oseltamivir administered twice daily delivers 2.6 g of sorbitol.

30 mg oseltamivir suspension delivers 0.9 g of sorbitol.

45 mg oseltamivir suspension delivers 1.3 g of sorbitol.

60 mg oseltamivir suspension delivers 1.7 g of sorbitol.

75 mg oseltamivir suspension delivers 2.1 g of sorbitol.

For a full list of excipients, see section 6.1.

4.2     Posology and method of administration

Tamiflu suspension and Tamiflu capsules are bioequivalent formulations. 75 mg doses can be administered as either

-        one 75 mg capsule or

-        one 30 mg capsule plus one 45 mg capsule or

-        by administering one 30 mg dose plus one 45 mg dose of suspension.

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

For infants below 12 months of age: This formulation is not suitable for dosing in infants less than 12 months of age.  For details, see sections below.

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: The recommended dose of Tamiflu oral suspension is indicated in the table below. Tamiflu 30 mg and 45 mg capsules are available as an alternative to the recommended dose of Tamiflu suspension.

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

For dosing, an oral dispenser with 30 mg, 45 mg and 60 mg graduations is provided in the box. For accurate dosing, the oral dispenser supplied should be used exclusively (a syringe with ml markings cannot be used).

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

Ø  For infants below  1 year12 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:

*          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 functionsThis formulation(Tamiflu 12 mg/ml powder for oral suspension) is unsuitable since the syringe provided in the pack (with mg markings) does not allow for appropriate dose adjustments and the use of syringes with ml markings may lead to unacceptable dosing inaccuracies. In the absence of a suitable formulation, the pharmacy compounded preparation should preferentially be used. Please refer to the SmPC for the 30 mg. 45 mg and 75 mg capsules (section 4.2).

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 are available as an alternative to the recommended dose of Tamiflu suspension.

The recommended post-exposure prevention dose of Tamiflu is:

For dosing, an oral dispenser with 30 mg, 45 mg and 60 mg graduations is provided in the box. For accurate dosing, the oral dispenser supplied should be used exclusively a syringe with ml markings cannot be used).

It is recommended that Tamiflu powder for oral suspension be constituted by a pharmacist prior to dispensing to the patient (see section 6.6).

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

Ø  For infants below 1 year 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:

*          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 This formulation (Tamiflu 12 mg/ml powder for oral suspension) is unsuitable since the syringe provided in the pack (with mg markings) does not allow for appropriate dose adjustments and the use of syringes with ml markings may lead to unacceptable dosing inaccuracies. In the absence of a suitable formulation, the pharmacy compounded preparation should preferentially be used. Please refer to the SmPC for the 30 mg. 45 mg and 75 mg capsules (section 4.2).

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.

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.

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

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

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 inby 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).

This medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Sorbitol can have a mild laxative effect.

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.

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 and other handling

It is recommended that Tamiflu oral suspension should be reconstituted by the pharmacist prior to its dispensing to the patient.

Only the syringe included in the package with doses indicated in mg should be used. It cannot be replaced by a syringe with ml markings.

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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.

* 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.

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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]).

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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.

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4.1     Therapeutic indications

Tamiflu is indicated for the treatment of children 6 toinfants below 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 children 6 toinfants 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

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 providesØ 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 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

*          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:

*          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.

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 dose. 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.

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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.

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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).

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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.