Roche Products Limited

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

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.

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

4.2      Posology and method of administration

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

-           one 75 mg capsule or

-              one 30 mg capsule plus one 45 mg capsule or

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

Adults, adolescents or children (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.

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

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

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

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

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

* 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

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

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

The recommended post-exposure prevention dose of Tamiflu is:

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

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

* 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

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

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

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

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

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

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.

Ø  Infants less than 1 year of age

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

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

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

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

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 bitter taste.

Home preparation

When commercially manufactured Tamiflu oral suspension is not available, a pharmacy preparation from Tamiflu capsules can be used (detailed instructions above in section 4.2). If the pharmacy preparation is not available either, Tamiflu doses may be prepared at home. The pharmacy preparation is the preferred option in infants below 12 months of age.

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

When only 75 mg capsules are available, and doses of 30 mg or 45 mg are needed, the preparation involves additional steps. Detailed instructions can be found in section 3 in the package leaflet of Tamiflu capsules.

Special populations

Hepatic impairment

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

Renal impairment

Treatment of influenza: Dose adjustment is recommended for adults with moderate or severe renal impairment. Recommended doses are detailed in the table below.

* 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).

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

4.2     Posology and method of administration

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

-        one 75 mg capsule or

-           one 30 mg capsule plus one 45 mg capsule or

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

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

For infants below 1 year of age: In the absence of a suitable formulation, a pharmacy compounded preparation should preferentially be used as the syringe provided in the Tamiflu 12 mg/ml powder for oral suspension pack (with mg markings) does not allow for appropriate dose adjustments and commercially available syringes (with ml markings) may lead to unacceptable dosing inaccuracies (see below 4.2).

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

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

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

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

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

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

*          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

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

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

The recommended post-exposure prevention dose of Tamiflu is:

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

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

*          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

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

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

Pharmacy compounding

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

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

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

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

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

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.

Ø  Infants less than 1 year of age

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

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

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

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

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