Tamiflu 75 mg hard capsule.

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

For a full list of excipients, see section 6.1.

Hard capsule

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.

Treatment of influenza

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 below 12 months of age during a pandemic influenza outbreak (see section 5.2).

Prevention of influenza

- Post-exposure prevention in individuals one 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 of age during a pandemic influenza outbreak (see section 5.2).

Tamiflu is not a substitute for influenza vaccination.

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

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.

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

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

• 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.

For recommended treatment dose of Tamiflu for infants older than 1 year of age and for children 2 to 12 years of age, see SmPC of Tamiflu suspension and Tamiflu 30 and 45 mg capsules.

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.

• 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:

* 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

Post-exposure prevention

• 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.

• 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.

For recommended post-exposure prevention dose of Tamiflu for infants older than 1 year of age and for children of 2 to 12 years of age, see SmPC of Tamiflu suspension and Tamiflu 30 mg and 45 mg capsules.

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.

• 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.

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.

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

• 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

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)

* 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

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.

• 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

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)

* 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

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

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 itter 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.

* 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 patients (see sections 4.4, 4.8 and 5.1).

Hypersensitivity to the active substance or to any of the excipients.

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. 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).

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, acetylsalicylic acid, cimetidine, antacids (magnesium and aluminium hydroxides and calcium carbonates), rimantadine or warfarin (in subjects stable on warfarin and without influenza).

While no controlled clinical trials 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.

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

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

The overall safety profile of Tamiflu is based on data from 4624 adult/adolescent and 1480 paediatric patients treated with Tamiflu or placebo for influenza, and on data from 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 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.

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

Treatment and prevention of influenza in adults and adolescents:

In adult/adolescent treatment and prophylaxis studies, ARs that occurred the most frequently ( 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 Reactions ( 1 % in the oseltamivir group) in studies investigating Tamiflu for treatment and prevention of influenza in adults and adolescents or through post-marketing surveillance

^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 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 ( 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 (30 mg to 75 mg od).

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 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.

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.

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 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 was consistent with 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.

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.

Pharmacotherapeutic group: Antiviral ATC code: J05AH02

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

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

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

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

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.

* 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 proportional 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.

Adults and adolescents 13 years of age and older: Patients were eligible if they reported within 36 hours of onset of symptoms, had fever 37.8 °C, accompanied by at least one respiratory symptom (cough, nasal symptoms or sore throat) and at least one systemic symptom (myalgia, chills/sweats, malaise, fatigue or headache). In a pooled analysis of all influenza-positive adults and adolescents (N = 2413) enrolled into treatment studies, oseltamivir 75 mg twice daily for 5 days reduced the median duration of influenza illness by approximately one day from 5.2 days (95 % CI 4.9 – 5.5 days) in the placebo group to 4.2 days (95 % CI 4.0 – 4.4 days; p 0.0001).

The proportion of subjects who developed specified lower respiratory tract complications (mainly bronchitis) treated with antibiotics was reduced from 12.7 % (135/1063) in the placebo group to 8.6 % (116/1350) in the oseltamivir treated population (p = 0.0012).

Treatment of influenza in high risk populations: The median duration of influenza illness in elderly 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 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).

In influenza-positive patients with chronic cardiac and/or respiratory disease, the combined incidence of lower respiratory tract complications (mainly bronchitis) treated with antibiotics was 17 % (22/133) in the placebo group and 14 % (16/118) in the oseltamivir treated population (p = 0.5976).

Treatment of influenza in children: In a study of otherwise healthy children (65 % influenza-positive) aged 1 to 12 years (mean age 5.3 years) who had fever ( 37.8 °C) plus either cough or coryza, 67 % of influenza-positive patients were infected with influenza A and 33 % with influenza B. Oseltamivir treatment, started within 48 hours of onset of symptoms, significantly reduced the time to freedom from illness (defined as the simultaneous return to normal health and activity and alleviation of fever, cough and coryza) by 1.5 days (95 % CI 0.6 – 2.2 days; p < 0.0001) compared to placebo. Oseltamivir reduced the incidence of acute otitis media from 26.5 % (53/200) in the placebo group to 16 % (29/183) in the oseltamivir treated children (p = 0.013).

A second study was completed in 334 asthmatic children aged 6 to 12 years old of which 53.6 % were influenza-positive. In the oseltamivir treated group, the median duration of illness was not reduced significantly. By day 6 (the last day of treatment) FEV₁ had increased by 10.8 % in the oseltamivir treated group compared to 4.7 % on placebo (p = 0.0148) in this population.

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.

Treatment of influenza B infection: Overall, 15 % of the influenza-positive population were infected by influenza B, proportions ranging from 1 to 33 % in individual studies. The median duration of illness in influenza B infected subjects did not differ significantly between the treatment groups in individual studies. Data from 504 influenza B infected subjects were pooled across all studies for analysis. Oseltamivir reduced the time to alleviation of all symptoms by 0.7 days (95 % CI 0.1 – 1.6 days; p = 0.022) and the duration of fever ( 37.8 °C), cough and coryza by one day (95 % CI 0.4 – 1.7 days; p < 0.001) compared to placebo.

Prevention of influenza

The efficacy of oseltamivir in preventing naturally occurring influenza illness has been demonstrated in a post-exposure prevention study in households and two seasonal prevention studies. The primary efficacy parameter for all of these studies was the incidence of laboratory-confirmed influenza. The virulence of influenza epidemics is not predictable and varies within a region and from season to season, therefore the number needed to treat (NNT) in order to prevent one case of influenza illness varies.

Post-exposure prevention: In a study in contacts (12.6 % vaccinated against influenza) of an index case of influenza, oseltamivir 75 mg once daily was started within 2 days of onset of symptoms in the index case and continued for seven days. Influenza was confirmed in 163 out of 377 index cases. Oseltamivir significantly reduced the incidence of clinical influenza illness occurring in the contacts of confirmed influenza cases from 24/200 (12 %) in the placebo group to 2/205 (1 %) in the oseltamivir group (92 % reduction [95 % CI 6 – 16; p 0.0001]). The number needed to treat (NNT) in contacts of true influenza cases was 10 (95 % CI 9 – 12) and was 16 (95 % CI 15 – 19) in the whole population (ITT) regardless of infection status in the index case.

The efficacy of oseltamivir in preventing naturally occurring influenza illness has been demonstrated in a post-exposure prevention study in households that included adults, adolescents, and children aged 1 to 12 years, both as index cases and as family contacts. The primary efficacy parameter for this study was the incidence of laboratory-confirmed clinical influenza in the households. Oseltamivir prophylaxis lasted for 10 days. In the total population, there was a reduction in the incidence of laboratory-confirmed clinical influenza in households from 20 % (27/136) in the group not receiving prevention to 7 % (10/135) in the group receiving prevention (62.7 % reduction [95 % CI 26.0 – 81.2; p = 0.0042]). In households of influenza-infected index cases, there was a reduction in the incidence of influenza from 26 % (23/89) in the group not receiving prevention to 11 % (9/84) in the group receiving prevention (58.5 % reduction [95 % CI 15.6 – 79.6; p = 0.0114]).

According to subgroup analysis in children at 1 to 12 years of age, the incidence of laboratory-confirmed clinical influenza among children was significantly reduced from 19 % (21/111) in the group not receiving prevention to 7 % (7/104) in the group receiving prevention (64.4 % reduction [95 % CI 15.8 – 85.0; p = 0.0188]). Among children who were not already shedding virus at baseline, the incidence of laboratory-confirmed clinical influenza was reduced from 21 % (15/70) in the group not receiving prevention to 4 % (2/47) in the group receiving prevention (80.1 % reduction [95 % CI 22.0 – 94.9; p = 0.0206]). The NNT for the total paediatric population was 9 (95 % CI 7 – 24) and 8 (95 % CI 6, upper limit not estimable) in the whole population (ITT) and in paediatric contacts of infected index cases (ITTII), respectively.

Prevention during an influenza epidemic in the community: In a pooled analysis of two other studies conducted in unvaccinated otherwise healthy adults, oseltamivir 75 mg once daily given for 6 weeks significantly reduced the incidence of clinical influenza illness from 25/519 (4.8 %) in the placebo group to 6/520 (1.2 %) in the oseltamivir group (76 % reduction [95 % CI 1.6 – 5.7; p = 0.0006]) during a community outbreak of influenza. The NNT in this study was 28 (95 % CI 24 – 50).

A study in elderly residents of nursing homes, where 80 % of participants received vaccine in the season of the study, oseltamivir 75 mg once daily given for 6 weeks significantly reduced the incidence of clinical influenza illness from 12/272 (4.4 %) in the placebo group to 1/276 (0.4 %) in the oseltamivir group (92 % reduction [95 % CI 1.5 – 6.6; p = 0.0015]). The NNT in this study was 25 (95 % CI 23 – 62).

Prophylaxis of influenza in immunocompromised patients: A double-blind, placebo-controlled, randomised study was conducted for seasonal prophylaxis of influenza in 475 immunocompromised patients(388 patients with solid organ transplantation [195 placebo; 193 oseltamivir], 87 patients with hemopoetic stem cell transplantation [43 placebo; 44 oseltamivir], no patient with other immunosuppressant conditions), including 18 children 1 to 12 years of age. 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 2.9 % (7/238) in the placebo group and 2.1 % (5/237) in the oseltamivir group (95 % CI -2.3 % – 4.1 %; p = 0.772).

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

Absorption

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

Distribution

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

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

Metabolism

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

Elimination

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

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).

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.

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.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity and genotoxicity. Results of the conventional rodent carcinogenicity studies showed a trend towards a dose-dependent increase in the incidence of some tumours that are typical for the rodent strains used. Considering the margins of exposure in relation to the expected exposure in the human use, these findings do not change the benefit-risk of Tamiflu in its adopted therapeutic indications.

Teratology studies have been conducted in rats and rabbits at doses of up to 1500 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 1500 mg/kg/day demonstrated no adverse effects on either sex. In pre- and post-natal rat studies, prolonged parturition was noted at 1500 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.

In lactating rats, oseltamivir and the active metabolite are excreted in the milk. Limited data indicate that oseltamivir and the active metabolite are excreted in human milk. Extrapolation of the animal data provides estimates of 0.01 mg/day and 0.3 mg/day for the respective compounds.

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 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 (1310 mg/kg), had no adverse effects 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).

Capsule core:

Pregelatinized 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)

Not applicable.

7 years

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.

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

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.

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

EU/1/02/222/001

Date of first authorisation: 20 June 2002

Date of last renewal: 20 June 2007

3 November 2011

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