Leaflet TAMIFLU 6mg / ml powder for oral suspension
Indicated for: influenza
Route of administration: oral
Substance: oseltamivir (neuraminidase inhibitor)
ATC: J05AH02 (Antiinfectives for systemic use | Direct acting antivirals | Neuraminidase inhibitors)
Use during breastfeeding only on medical advice.
Use during pregnancy only on medical advice.
Oseltamivir is an antiviral medication used for the treatment and prevention of influenza caused by influenza A and B viruses. It is most effective when taken within the first 48 hours of symptom onset.
Oseltamivir works by inhibiting neuraminidase, an enzyme essential for the replication and spread of the influenza virus in the body. By blocking this enzyme, the medication reduces the severity of symptoms, the duration of the illness, and the risk of complications such as pneumonia.
It is indicated for both the treatment of influenza in adults and children (including infants over 2 weeks old) and for the prevention of influenza in individuals exposed to the virus (e.g., through contact with an infected person).
Common side effects include nausea, vomiting, headache, and abdominal discomfort. These reactions are usually mild and temporary. In rare cases, severe allergic reactions or neuropsychiatric disturbances, such as confusion, hallucinations, or abnormal behavior, may occur, particularly in children and adolescents.
Patients should strictly follow their doctor’s instructions regarding dosage and duration of treatment. Oseltamivir does not replace influenza vaccination, which remains the most effective method of preventing the flu. It is important to consult a doctor before use, especially for pregnant women, individuals with kidney conditions, or those taking other medications.
General data about TAMIFLU 6mg / ml
- Substance: oseltamivir
- Date of latest medicines list: 01-01-2014
- Product code: W13634001
- Concentration: 6mg / ml
- Pharmaceutical form: powder for oral suspension
- Quantity: 1
- Product type: Original
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Pharmaceutical forms available for oseltamivir
Concentrations available for oseltamivir
- 30mg
- 45mg
- 6mg/ml
- 75mg
Leaflet TAMIFLU 6mg/ml
Contents of the package leaflet for the medicine TAMIFLU 6mg / ml powder for oral suspension
1. NAME OF THE MEDICINAL PRODUCT
Tamiflu 6 mg/ml powder for oral suspension
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of reconstituted suspension contains oseltamivir phosphate equivalent to 6 mg of oseltamivir.
One bottle of reconstituted suspension (65 ml) contains 390 mg of oseltamivir.
Excipients with known effect:5 ml oseltamivir suspension delivers 0.9 g of sorbitol and 2.5 mg of sodium benzoate.7.5 ml oseltamivir suspension delivers 1.3 g of sorbitol and 3.75 mg of sodium benzoate.10 ml oseltamivir suspension delivers 1.7 g of sorbitol and 5.0 mg of sodium benzoate.12.5 ml oseltamivir suspension delivers 2.1 g of sorbitol and 6.25 mg of sodium benzoate.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Powder for oral suspension
The powder is a granulate or clumped granulate with a white to light yellow colour.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of influenza
Tamiflu is indicated in adults and children including full term neonates who present with symptomstypical of influenza, when influenza virus is circulating in the community. Efficacy has beendemonstrated when treatment is initiated within two days of first onset of symptoms.
Prevention of influenza
- Post-exposure prevention in individuals 1 year of age or older following contact with aclinically 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 bycase basis by the circumstances and the population requiring protection. In exceptionalsituations (e.g. in case of a mismatch between the circulating and vaccine virus strains, and apandemic situation) seasonal prevention could be considered in individuals one year of age orolder.
- Tamiflu is indicated for post-exposure prevention of influenza in infants less than 1 year of ageduring 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 basisof official recommendations. Decisions regarding the use of oseltamivir for treatment and prophylaxisshould take into consideration what is known about the characteristics of the circulating influenzaviruses, available information on influenza drug susceptibility patterns for each season and the impactof the disease in different geographical areas and patient populations (see section 5.1).
4.2 Posology and method of administration
Tamiflu suspension and Tamiflu hard capsules are bioequivalent formulations. 75 mg doses can beadministered as either
- one 75 mg capsule or
- one 30 mg capsule plus one 45 mg capsule or
- by administering one 30 mg dose plus one 45 mg dose of suspension.
Adults, adolescents or children (> 40 kg) who are able to swallow capsules may receive appropriatedoses of Tamiflu capsules.
TreatmentTreatment should be initiated as soon as possible within the first two days of onset of symptoms ofinfluenza.
For adolescents (13 to 17 years of age) and adults: The recommended oral dose is 75 mg oseltamivirtwice daily for 5 days (or 10 days in immunocompromised patients).
Paediatric populationFor infants and children1 year of age or older: The recommended dose of Tamiflu 6 mg/ml oralsuspension is indicated in the table below. Tamiflu 30 mg and 45 mg capsules are available as analternative to the recommended dose of Tamiflu 6 mg/ml suspension.
The following weight-adjusted dosing regimens are recommended for infants and children 1 year ofage or older:
Recommended dose for10 days* Amount of oral
Recommended dose for Immunocompromised suspension to
Body weight 5 days Patients withdraw10 kg to 15 kg 30 mg twice daily 30 mg twice daily 5 ml twice daily> 15 kg to 23 kg 45 mg twice daily 45 mg twice daily 7.5 ml twice daily> 23 kg to 40 kg 60 mg twice daily 60 mg twice daily 10 ml twice daily> 40 kg 75 mg twice daily 75 mg twice daily 12.5 ml twice daily
*The recommended duration in immunocompromised patients (≥1 year old) is 10 days. See Special Populations,
Immunocompromised Patients for more information.
Children weighing > 40 kg and who are able to swallow capsules may receive treatment with the adultdosage of 75 mg capsules twice daily for 5 days as an alternative to the recommended dose of Tamiflususpension.
For infants less than 1 year of age: The recommended treatment dose for infants 0 - 12 months of ageis 3 mg/kg twice daily. This is based upon pharmacokinetic and safety data indicating that this dose ininfants 0 - 12 months provides plasma concentrations of the pro-drug and active metabolite that areanticipated to be clinically efficacious with a safety profile comparable to that seen in older childrenand adults (see section 5.2).
A 3 ml oral dispenser (graduated in 0.1 ml steps) should be used for dosing children 0 - 12 months ofage requiring 1 ml to 3 ml of Tamiflu 6 mg/ml oral suspension. For higher doses the 10 ml syringeshould be used. The following dosing regimen is recommended for treatment of infants below 1 yearof age:
Dosing table of oseltamivir for children less than 1 year of age : 3 mg/kg twice daily
Body Recommended dose Recommended dose for Amount of oral Dispenser size
Weight* for 5 days 10 days** suspension to to use
Immunocompromised withdrawpatients3 kg 9 mg twice daily 9 mg twice daily 1.5 ml twice daily 3 ml3.5 kg 10.5 mg twice daily 10.5 mg twice daily 1.8 ml twice daily 3 ml4 kg 12 mg twice daily 12 mg twice daily 2.0 ml twice daily 3 ml4.5 kg 13.5 mg twice daily 13.5 mg twice daily 2.3 ml twice daily 3 ml5 kg 15 mg twice daily 15 mg twice daily 2.5 ml twice daily 3 ml5.5 kg 16.5 mg twice daily 16.5 mg twice daily 2.8 ml twice daily 3 ml6 kg 18 mg twice daily 18 mg twice daily 3.0 ml twice daily 3 ml> 6 - 7 kg 21 mg twice daily 21 mg twice daily 3.5 ml twice daily 10 ml> 7 - 8 kg 24 mg twice daily 24 mg twice daily 4.0 ml twice daily 10 ml> 8 - 9 kg 27 mg twice daily 27 mg twice daily 4.5 ml twice daily 10 ml> 9 - 10 kg 30 mg twice daily 30 mg twice daily 5.0 ml twice daily 10 ml
* This table is not intended to contain all possible weights for this population.
**The recommended duration in immunocompromised infants (0-12 months old) is 10 days. See Special Populations,
Immunocompromised Patients for more information.
This dosing recommendation is not intended for premature infants, i.e. those with a post-conceptualage less than 36 weeks. Insufficient data are available for these patients, in whom different dosing maybe required due to the immaturity of physiological functions.
PreventionPost-exposure prevention
For adolescents (13 to 17 years of age) and adults: The recommended dose for prevention of influenzafollowing 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 and children 1 year of age or older: Tamiflu 30 mg and 45 mg capsules are available as analternative to the recommended dose of Tamiflu 6 mg/ml suspension.
The recommended post-exposure prevention dose of Tamiflu is:
Body weight Recommended dose for Immunocompromised Amount of oral10 days Patients suspension to withdraw
Recommended dose for10 days10 kg to 15 kg 30 mg once daily 30 mg once daily 5 ml once daily> 15 kg to 23 kg 45 mg once daily 45 mg once daily 7.5 ml once daily> 23 kg to 40 kg 60 mg once daily 60 mg once daily 10 ml once daily> 40 kg 75 mg once daily 75 mg once daily 12.5 ml once daily
Children weighing > 40 kg and who are able to swallow capsules may receive prophylaxis with a75 mg capsule once daily for 10 days as an alternative to the recommended dose of Tamiflususpension.
For infants less than 1 year of age: The recommended prophylaxis dose for infants less than 12 monthsduring a pandemic influenza outbreak is half of the daily treatment dose. This is based upon clinicaldata in children > 1 year of age and adults showing that a prophylaxis dose equivalent to half the dailytreatment dose is clinically efficacious for the prevention of influenza (see Section 5.2 for exposuresimulation).
In case of a pandemic, a 3 ml oral dispenser (graduated in 0.1 ml steps) should be used for dosingchildren below 1 year of age requiring 1 ml to 3 ml of Tamiflu 6 mg/ml oral suspension. For higherdoses the 10 ml syringe should be used.
The following dosing regimen is recommended for infants less than 1 year of age:
Dosing table of oseltamivir for children below one year of age: 3 mg/kg once daily
Body Recommended dose Immunocompromised Amount of oral Dispenser size
Weight* for 10 days Patients suspension to to use
Recommended dose for 10 withdrawdays3 kg 9 mg once daily 9 mg once daily 1.5 ml once daily 3 ml3.5 kg 10.5 mg once daily 10.5 mg once daily 1.8 ml once daily 3 ml4 kg 12 mg once daily 12 mg once daily 2.0 ml once daily 3 ml4.5 kg 13.5 mg once daily 13.5 mg once daily 2.3 ml once daily 3 ml5 kg 15 mg once daily 15 mg once daily 2.5 ml once daily 3 ml5.5 kg 16.5 mg once daily 16.5 mg once daily 2.8 ml once daily 3 ml6 kg 18 mg once daily 18 mg once daily 3.0 ml once daily 3 ml> 6 - 7 kg 21 mg once daily 21 mg once daily 3.5 ml once daily 10 ml> 7 - 8 kg 24 mg once daily 24 mg once daily 4.0 ml once daily 10 ml> 8 - 9 kg 27 mg once daily 27 mg once daily 4.5 ml once daily 10 ml> 9 - 10 kg 30 mg once daily 30 mg once daily 5.0 ml once daily 10 ml
* This table is not intended to contain all possible weights for this population.
This dosing recommendation is not intended for premature infants, i.e. those with a post-conceptualage less than 36 weeks. Insufficient data are available for these patients, in whom different dosing maybe required due to the immaturity of physiological functions.
Prevention during an influenza epidemic in the community
Prevention during an influenza epidemic has not been studied in children below 12 years of age. Therecommended dose for adults and adolescents for prevention of influenza during a communityoutbreak is 75 mg oseltamivir once daily for up to 6 weeks (or up to 12 weeks inimmunocompromised patients).
Special populationsHepatic impairment
No dose adjustment is required either for treatment or for prevention in patients with hepaticdysfunction. No studies have been carried out in paediatric patients with hepatic disorder.
Renal impairmentTreatment of influenza: Dose adjustment is recommended for adults and adolescents (13 to 17 years ofage) with moderate or severe renal impairment. Recommended doses are detailed in the table below.
Creatinine clearance Recommended dose for treatment> 60 (ml/min) 75 mg twice daily> 30 to 60 (ml/min) 30 mg (suspension or capsules) twice daily> 10 to 30 (ml/min) 30 mg (suspension or capsules) once daily≤ 10 (ml/min) Not recommended (no data available)
Haemodialysis patients 30 mg after each haemodialysis session
Peritoneal dialysis patients* 30 mg (suspension or capsules) single dose
* Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients; the clearance ofoseltamivir carboxylate is expected to be higher when automated peritoneal dialysis (APD) mode is used.
Treatment mode can be switched from APD to CAPD if considered necessary by a nephrologist.
Prevention of influenza: Dose adjustment is recommended for adults and adolescents (13 to 17 yearsof age) with moderate or severe renal impairment as detailed in the table below.
Creatinine clearance Recommended dose for prevention> 60 (ml/min) 75 mg once daily> 30 to 60 (ml/min) 30 mg (suspension or capsules) once daily> 10 to 30 (ml/min) 30 mg (suspension or capsules) every second day≤ 10 (ml/min) Not recommended (no data available)
Haemodialysis patients 30 mg after every second haemodialysis session
Peritoneal dialysis patients* 30 mg (suspension or capsules) once weekly
* Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients; the clearance ofoseltamivir carboxylate is expected to be higher when automated peritoneal dialysis (APD) mode is used.
Treatment mode can be switched from APD to CAPD if considered necessary by a nephrologist.
There is insufficient clinical data available in infants and children (12 years of age and younger) withrenal impairment to be able to make any dosing recommendation.
ElderlyNo dose adjustment is required, unless there is evidence of moderate or severe renal impairment.
Immunocompromised patientsTreatment: For treatment of influenza, the recommended duration for immunocompromised patientsis 10 days (see sections 4.4, pct. 4.8, 5.1). No dose adjustment is necessary. Treatment should be initiatedas soon as possible within the first two days of onset of symptoms of influenza.
Seasonal prophylaxis: Longer duration of seasonal prophylaxis up to 12 weeks has been evaluated inimmunocompromised patients (see sections 4.4, pct. 4.8 and 5.1).
Method of administrationFor dosing, a 3 ml and 10 ml oral dispenser is provided in the box.
It is recommended that Tamiflu powder for oral suspension be constituted by a pharmacist prior todispensing to the patient (see section 6.6).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Oseltamivir is effective only against illness caused by influenza viruses. There is no evidence forefficacy of oseltamivir in any illness caused by agents other than influenza viruses (see section 5.1).
Tamiflu is not a substitute for influenza vaccination. Use of Tamiflu must not affect the evaluation ofindividuals 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 onlywhen 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 availableon oseltamivir susceptibility patterns of the currently circulating viruses when deciding whether to use
Tamiflu.
Severe concomitant condition
No information is available regarding the safety and efficacy of oseltamivir in patients with anymedical condition sufficiently severe or unstable to be considered at imminent risk of requiringhospitalisation.
Immunocompromised patientsThe efficacy of oseltamivir in either treatment or prophylaxis of influenza in immunocompromisedpatients has not been firmly established(see section 5.1).
Cardiac/respiratory disease
Efficacy of oseltamivir in the treatment of subjects with chronic cardiac disease and/or respiratorydisease has not been established. No difference in the incidence of complications was observedbetween the treatment and placebo groups in this population (see section 5.1).
Paediatric populationNo data allowing a dose recommendation for premature children (<36 weeks post-conceptual age) arecurrently available.
Severe renal impairmentDose adjustment is recommended for both treatment and prevention in adolescents (13 to 17 years ofage) and adults with severe renal impairment. There is insufficient clinical data available in infants andchildren (1 year of age or older) with renal impairment to be able to make any dosing recommendation(see sections 4.2 and 5.2).
Neuropsychiatric events
Neuropsychiatric events have been reported during administration of Tamiflu in patients withinfluenza, especially in children and adolescents. These events are also experienced by patients withinfluenza without oseltamivir administration. Patients should be closely monitored for behaviouralchanges, and the benefits and risks of continuing treatment should be carefully evaluated for eachpatient (see section 4.8).
ExcipientsThis medicinal product contains sorbitol. Patients with hereditary fructose intolerance (HFI) shouldnot take this medicinal product.
Sorbitol may cause gastrointestinal discomfort and mild laxative effect.
This medicinal product contains sodium benzoate. Sodium benzoate (E211) may increase jaundice innewborn babies (up to 4 weeks old).
4.5 Interaction with other medicinal products and other forms of interaction
Pharmacokinetic properties of oseltamivir, such as low protein binding and metabolism independent ofthe CYP450 and glucuronidase systems (see section 5.2), suggest that clinically significant druginteractions via these mechanisms are unlikely.
ProbenecidNo dose adjustment is required when co-administering with probenecid in patients with normal renalfunction. Co-administration of probenecid, a potent inhibitor of the anionic pathway of renal tubularsecretion, results in an approximate 2-fold increase in exposure to the active metabolite of oseltamivir.
Amoxicillin
Oseltamivir has no kinetic interaction with amoxicillin, which is eliminated via the same pathway,suggesting that oseltamivir interaction with this pathway is weak.
Renal elimination
Clinically important drug interactions involving competition for renal tubular secretion are unlikely,due to the known safety margin for most of these substances, the elimination characteristics of theactive metabolite (glomerular filtration and anionic tubular secretion) and the excretion capacity ofthese pathways. However, care should be taken when prescribing oseltamivir in subjects when takingco-excreted agents with a narrow therapeutic margin (e.g. chlorpropamide, methotrexate,phenylbutazone).
Additional informationNo pharmacokinetic interactions between oseltamivir or its major metabolite have been observedwhen co-administering oseltamivir with paracetamol, acetylsalicylic acid, cimetidine, antacids(magnesium and aluminium hydroxides and calcium carbonates), rimantadine or warfarin (in subjectsstable on warfarin and without influenza).
4.6 Fertility, pregnancy and lactation
Influenza is associated with adverse pregnancy and foetal outcomes, with a risk of major congenitalmalformations, including congenital heart defects. A large amount of data on oseltamivir exposure ofpregnant women from post-marketing reports and observational studies (more than 1000 exposedoutcomes during the first trimester) indicate no malformative nor feto/neonatal toxicity by oseltamivir.
However, in one observational study, while the overall malformation risk was not increased, theresults for major congenital heart defects diagnosed within 12 months of birth were not conclusive. Inthis study, the rate of major congenital heart defects following oseltamivir exposure during the firsttrimester was 1.76% (7 infants out of 397 pregnancies) compared to 1.01% in unexposed pregnanciesfrom the general population (Odds Ratio 1.75, 95% Confidence Interval 0.51 to 5.98). The clinicalsignificance of this finding is not clear, as the study had limited power. Additionally, this study wastoo small to reliably assess individual types of major malformations; moreover women exposed tooseltamivir and women unexposed could not be made fully comparable, in particular whether or notthey had influenza.
Animal studies do not indicate reproductive toxicity (see section 5.3).
The use of Tamiflu may be considered during pregnancy if necessary and after considering theavailable safety and benefit information (for data on benefit in pregnant women please refer to section5.1 “Treatment of influenza in pregnant women”), and the pathogenicity of the circulating influenzavirus strain.
BreastfeedingIn lactating rats, oseltamivir and the active metabolite are excreted in milk. Very limited information isavailable on children breast-fed by mothers taking oseltamivir and on excretion of oseltamivir inbreast milk. Limited data demonstrated that oseltamivir and the active metabolite were detected inbreast 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 theunderlying condition of the breastfeeding woman, administration of oseltamivir may be considered,where there are clear potential benefits to breastfeeding mothers.
FertilityBased on preclinical data, there is no evidence that Tamiflu has an effect on male or female fertility(see section 5.3).
4.7 Effects on ability to drive and use machines
Tamiflu has no influence on the ability to drive and use machines.
4.8 Undesirable effects
The overall safety profile of Tamiflu is based on data from 6049 adult/adolescent and 1473 paediatricpatients treated with Tamiflu or placebo for influenza, and on data from 3990 adult/adolescent and 253paediatric patients receiving Tamiflu or placebo/no treatment for the prophylaxis of influenza inclinical trials. In addition, 245 immunocompromised patients (including 7 adolescents and 39 children)received Tamiflu for the treatment of influenza and 475 immunocompromised patients (including 18children, of these 10 Tamiflu and 8 placebo) received Tamiflu or placebo for the prophylaxis ofinfluenza.
In adults/adolescents, the most commonly reported adverse reactions (ARs) were nausea and vomitingin the treatment studies, and nausea in the prevention studies. The majority of these ARs were reportedon a single occasion on either the first or second treatment day and resolved spontaneously within 1-2days. In children, the most commonly reported adverse reaction was vomiting. In the majority ofpatients, these ARs did not lead to discontinuation of Tamiflu.
The following serious adverse reactions have been rarely reported since oseltamivir has beenmarketed: Anaphylactic and anaphylactoid reactions, hepatic disorders (fulminant hepatitis, hepaticfunction disorder and jaundice), angioneurotic oedema, Stevens-Johnson syndrome and toxicepidermal necrolysis, gastrointestinal bleeding and neuropsychiatric disorders.(Regarding neuropsychiatric disorders, see section 4.4.)
Tabulated list of adverse reactionsThe 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 analysisfrom clinical studies.
Treatment and prevention of influenza in adults and adolescents:
In adult/adolescent treatment and prevention studies, ARs that occurred the most frequently at therecommended dose (75 mg bid for 5 days for treatment and 75 mg od for up to 6 weeks forprophylaxis) are shown in Table 1.
The safety profile reported in subjects who received the recommended dose of Tamiflu for prophylaxis(75 mg once daily for up to 6 weeks) was qualitatively similar to that seen in the treatment studies,despite a longer duration of dosing in the prophylaxis studies.
Table 1 Adverse reactions in studies investigating Tamiflu for treatment and prevention ofinfluenza in adults and adolescents or through post-marketing surveillance
System Organ Adverse reactions according to frequency
Class (SOC) Very common Common Uncommon Rare
Infections and Bronchitis,infestations Herpes simplex,
Nasopharyngitis,
Upper respiratorytract infections,
Sinusitis
Blood and Thrombocytopenialymphaticsystem disorders
Immune system Hypersensitivity Anaphylacticdisorders reaction reactions,
Anaphylactoidreactions
Psychiatric Agitation,disorders Abnormalbehaviour, Anxiety,
Confusion,
Delusions,
Delirium,
Hallucination,
Nightmares,
Self-injury
Nervous system Headache Insomnia Altered level ofdisorders consciousness,
Convulsion
Eye disorders Visual disturbance
Cardiac Cardiacdisorders arrhythmia
Respiratory, Cough,thoracic and Sore throat,mediastinal Rhinorrheadisorders
Gastrointestinal Nausea Vomiting Gastrointestinaldisorders Abdominal pain bleedings,(incl. upper Haemorrhagicabdominal pain), colitis
Dyspepsia
Hepatobiliary Elevated liver Fulminant hepatitis,disorders enzymes Hepatic failure,
Hepatitis
Skin and Eczema, Angioneuroticsubcutaneous Dermatitis, oedema,tissue disorders Rash, Erythema
Urticaria multiforme,
Stevens-Johnsonsyndrome,
Toxic epidermalnecrolysis
General Paindisorders and Dizziness (incl.
vertigo),administration Fatigue,site conditions Pyrexia,
System Organ Adverse reactions according to frequency
Class (SOC) Very common Common Uncommon Rare
Pain in limb
Treatment and prevention of influenza in children:
A total of 1473 children (including otherwise healthy children aged 1-12 years old and asthmaticchildren aged 6-12 years old) participated in clinical studies of oseltamivir given for the treatment ofinfluenza. Of those, 851 children received treatment with oseltamivir suspension. A total of 158children received the recommended dose of Tamiflu once daily in a post-exposure prophylaxis studyin households (n = 99), a 6-week paediatric seasonal prophylaxis study (n = 49) and a 12-weekpaediatric seasonal prophylaxis study in immunocompromised subjects (n = 10).
Table 2 shows the most frequently reported ARs from paediatric clinical trials.
Table 2 Adverse reactions in studies investigating Tamiflu for treatment and prevention ofinfluenza in children (age/weight-based dosing [30 mg to 75 mg o.d.])
System Organ Adverse reactions according to frequency
Class (SOC) Very common Common Uncommon Rare
Infections and Otitis media,infestations
Nervous system Headachedisorders
Eye disorders: Conjunctivitis(including redeyes, eyedischarge and eyepain)
Ear and Earache Tympanic membranelabyrinth disorderdisorders:
Respiratory, Cough, Rhinorrhoeathoracic and Nasal congestionmediastinaldisorders
Gastrointestinal Vomiting Abdominal paindisorders (incl. upperabdominal pain),
Dyspepsia,
Nausea
Skin and Dermatitis (includingsubcutaneous allergic and atopictissue disorders dermatitis)
Description of selected adverse reactionsPsychiatric disorders and nervous system disorders
Influenza can be associated with a variety of neurologic and behavioural symptoms which can includeevents such as hallucinations, delirium, and abnormal behaviour, in some cases resulting in fataloutcomes. These events may occur in the setting of encephalitis or encephalopathy but can occurwithout obvious severe disease.
In patients with influenza who were receiving Tamiflu, there have been postmarketing reports ofconvulsions and delirium (including symptoms such as altered level of consciousness, confusion,abnormal behaviour, delusions, hallucinations, agitation, anxiety, nightmares), in a very few casesresulting in self-injury or fatal outcomes. These events were reported primarily among paediatric andadolescent patients and often had an abrupt onset and rapid resolution. The contribution of Tamiflu tothose events is unknown. Such neuropsychiatric events have also been reported in patients withinfluenza who were not taking Tamiflu.
Hepato-biliary disorders
Hepato-biliary system disorders, including hepatitis and elevated liver enzymes in patients withinfluenza-like illness. These cases include fatal fulminant hepatitis/hepatic failure.
Other special populationsPaediatric population (infants less than one year of age)
In two studies to characterise the pharmacokinetics, pharmacodynamics and safety profile ofoseltamivir therapy in 135 influenza infected children less than one year of age, the safety profile wassimilar among age cohorts with vomiting, diarrohea and diaper rash being the most frequently reportedadverse events (see section 5.2). Insufficient data are available for infants who have a post-conceptualage of less than 36 weeks.
Safety information available on oseltamivir administered for treatment of influenza in infants less thanone year of age from prospective and retrospective observational studies (comprising together morethan 2,400 infants of that age class), epidemiological databases research and postmarketing reportssuggest that the safety profile in infants less than one year of age is similar to the established safetyprofile of children aged one year and older.
Older people and patients with chronic cardiac and/or respiratory disease
The population included in the influenza treatment studies is comprised of otherwise healthyadults/adolescents and patients “at risk” (patients at higher risk of developing complications associatedwith influenza, e.g. older people and patients with chronic cardiac or respiratory disease). In general,the safety profile in the patients “at risk” was qualitatively similar to that in otherwise healthyadults/adolescents.
Immunocompromised patientsThe treatment of influenza in immunocompromised patients were evaluated in two studies receivingstandard dose or high dose regimens (double dose or triple dose) of Tamiflu (see section 5.1). Thesafety profile of Tamiflu observed in these studies was consistent with that observed in previousclinical trials where Tamiflu was administered for treatment of influenza in non-immunocompromisedpatients across all age groups (otherwise healthy patients or “at risk” patients [i.e., those withrespiratory and/or cardiac co-morbidities]). The most frequent adverse reaction reported inimmunocompromised children was vomiting (28%).
In a 12-week prophylaxis study in 475 immunocompromised patients, including 18 children 1 to12 years of age and older, the safety profile in the 238 patients who received oseltamivir wasconsistent with that previously observed in Tamiflu prophylaxis clinical studies.
Children with pre-existing bronchial asthma
In general, the adverse reaction profile in children with pre-existing bronchial asthma was qualitativelysimilar to that of otherwise healthy children.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
Reports of overdoses with Tamiflu have been received from clinical trials and during post-marketingexperience. In the majority of cases reporting overdose, no adverse events were reported.
Adverse events reported following overdose were similar in nature and distribution to those observedwith therapeutic doses of Tamiflu, described in section 4.8 Undesirable effects.
No specific antidote is known.
Paediatric populationOverdose has been reported more frequently for children than adults and adolescents. Caution shouldbe exercised when preparing Tamiflu oral suspension and when administering Tamiflu products tochildren.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antivirals for systemic use, neuraminidase inhibitors ATC code:
J05AH02
Oseltamivir phosphate is a pro-drug of the active metabolite (oseltamivir carboxylate). The activemetabolite is a selective inhibitor of influenza virus neuraminidase enzymes, which are glycoproteinsfound on the virion surface. Viral neuraminidase enzyme activity is important both for viral entry intouninfected cells and for the release of recently formed virus particles from infected cells, and for thefurther spread of infectious virus in the body.
Oseltamivir carboxylate inhibits influenza A and B neuraminidases in vitro. Oseltamivir phosphateinhibits influenza virus infection and replication in vitro. Oseltamivir given orally inhibits influenza Aand B virus replication and pathogenicity in vivo in animal models of influenza infection at antiviralexposures similar to that achieved in man with 75 mg twice daily.
Antiviral activity of oseltamivir was supported for influenza A and B by experimental challengestudies in healthy volunteers.
Neuraminidase enzyme IC50 values for oseltamivir for clinically isolated influenza A ranged from0.1 nM to 1.3 nM, and for influenza B was 2.6 nM. Higher IC50 values for influenza B, up to amedian of 8.5 nM, have been observed in published studies.
Clinical studies
Treatment of influenza infection
The indication is based on clinical studies of naturally occurring influenza in which the predominantinfection was influenza A.Oseltamivir is effective only against illnesses caused by influenza virus.
Statistical analyses are therefore presented only for influenza-infected subjects. In the pooledtreatment study population, which included both influenza-positive and -negative subjects (ITT),primary efficacy was reduced proportionally to the number of influenza-negative individuals. In theoverall treatment population, influenza infection was confirmed in 67 % (range 46 % to 74 %) of therecruited patients. Of the older subjects, 64 % were influenza-positive and of those with chroniccardiac 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 localcommunity.
Adults and adolescents 13 years of age and older: Patients were eligible if they reported within36 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 = 2,413) enrolled into treatment studies, oseltamivir 75 mg twice daily for 5 days reduced themedian 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 (mainlybronchitis) treated with antibiotics was reduced from 12.7 % (135/1,063) in the placebo group to8.6 % (116/1,350) in the oseltamivir treated population (p = 0.0012).
Treatment of influenza in high risk populations: The median duration of influenza illness in oldersubjects (≥ 65 years) and in subjects with chronic cardiac and/or respiratory disease receivingoseltamivir 75 mg twice daily for 5 days was not reduced significantly. The total duration of fever wasreduced by one day in the groups treated with oseltamivir. In influenza-positive older people,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 incidenceof 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 pregnant women: No controlled clinical studies have been conducted on theuse of oseltamivir in pregnant women, however, there is evidence from post-marketing andretrospective observational studies showing benefit of the current dosing regimen in this patientpopulation in terms of lower morbidity/mortality. Results from pharmacokinetic analyses indicate alower exposure to the active metabolite, however dose adjustments are not recommended for pregnantwomen in the treatment or prophylaxis of influenza (see section 5.2, Pharmacokinetics, Special
Population).
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. Oseltamivirtreatment, started within 48 hours of onset of symptoms, significantly reduced the time to freedomfrom 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. Oseltamivirreduced 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 % wereinfluenza-positive. In the oseltamivir treated group, the median duration of illness was not reducedsignificantly. By day 6 (the last day of treatment) FEV1 had increased by 10.8 % in the oseltamivirtreated 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 forinformation on paediatric use.
The indication in infants below the age of 1 is based upon extrapolation of efficacy data from olderchildren and the recommended posology is based upon pharmacokinetic modelling data (see Section5.2).
Treatment of influenza B infection: Overall, 15 % of the influenza-positive population were infected byinfluenza B, proportions ranging from 1 to 33 % in individual studies. The median duration of illnessin influenza B infected subjects did not differ significantly between the treatment groups in individualstudies. 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.
Treatment of influenza in immunocompromised patients: A randomized, double blind study, toevaluate safety and characterize the effects of oseltamivir on the development of resistant influenzavirus (primary analysis) in influenza-infected immunocompromised patients, included 151 adultpatients, 7 adolescents and 9 children evaluable for efficacy of oseltamivir (secondary analysis, notpowered). The study included solid organ transplant [SOT] patients, haematopoietic stem celltransplant [HSCT] patients, HIV positive patients with a CD4+ cell count <500 cells/mm3, patients onsystemic immunosuppressive therapy, and those with haematological malignancy. These patients wererandomized to be treated, within 96 hours of symptoms onset for a duration of 10 days. The treatmentregimens were: standard dose (75mg or weight-adjusted dose for children) twice daily (73 adultpatients, 4 adolescent patients and 4 children) or double dose (150mg or weight-adjusted dose forchildren) twice daily (78 adult patients, 3 adolescent patients and 5 children) of oseltamivir.
The median time to resolution of symptoms (TTRS) for adults and adolescents was similar betweenthe standard dose group (103.4 hours [95% CI 75.4-122.7]) and double dose group (107.2 hours [95%
CI 63.9-140.0]). The TTRS for children was variable and the interpretation is limited by the smallsample size.The proportion of adult patients with secondary infections in the standard dose group anddouble dose group was comparable (8.2% vs 5.1%). For adolescents and children, only one patient (anadolescent) in the standard dose group experienced a secondary infection (bacterial sinusitis).
A pharmacokinetics and pharmacodynamics study was conducted in severely immunocompromisedchildren (≤12 years of age, n=30) receiving standard (75mg or weight adjusted twice daily) vs. tripledose (225mg or weight-adjusted dose twice daily) oseltamivir for an adaptive dosing period of 5 to 20days dependent on duration of viral shedding (mean treatment duration: 9 days). No patients in thestandard dose group and 2 patients in the triple dose group reported secondary bacterial infections(bronchitis and sinusitis).
Prevention of influenza
The efficacy of oseltamivir in preventing naturally occurring influenza illness has been demonstratedin a post-exposure prevention study in households and two seasonal prevention studies. The primaryefficacy parameter for all of these studies was the incidence of laboratory-confirmed influenza. Thevirulence of influenza epidemics is not predictable and varies within a region and from season toseason, therefore the number needed to treat (NNT) in order to prevent one case of influenza illnessvaries.
Post-exposure prevention: In a study in contacts (12.6 % vaccinated against influenza) of an indexcase of influenza, oseltamivir 75 mg once daily was started within 2 days of onset of symptoms in theindex 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 ofconfirmed influenza cases from 24/200 (12 %) in the placebo group to 2/205 (1 %) in the oseltamivirgroup (92 % reduction [95 % CI 6 - 16; p ≤ 0.0001]). The number needed to treat (NNT) in contactsof 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 demonstratedin a post-exposure prevention study in households that included adults, adolescents, and children aged1 to 12 years, both as index cases and as family contacts. The primary efficacy parameter for this studywas the incidence of laboratory-confirmed clinical influenza in the households. Oseltamivirprophylaxis lasted for 10 days. In the total population, there was a reduction in the incidence oflaboratory-confirmed clinical influenza in households from 20 % (27/136) in the group not receivingprevention 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 ofinfluenza from 26 % (23/89) in the group not receiving prevention to 11 % (9/84) in the groupreceiving 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 thegroup 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 groupnot receiving prevention to 4 % (2/47) in the group receiving prevention (80.1 % reduction [95 % CI22.0 - 94.9; p = 0.0206]). The NNT for the total paediatric population was 9 (95 % CI 7 - 24) and8 (95 % CI 6, upper limit not estimable) in the whole population (ITT) and in paediatric contacts ofinfected index cases (ITTII), respectively.
Post-exposure prevention of influenza in infants less than 1 year of age during a pandemic:
Prevention during an influenza pandemic has not been studied in controlled clinical studies in children0-12 months of age. See Section 5.2 for exposure simulation details.
Prevention during an influenza epidemic in the community: In a pooled analysis of two other studiesconducted in unvaccinated otherwise healthy adults, oseltamivir 75 mg once daily given for 6 weekssignificantly reduced the incidence of clinical influenza illness from 25/519 (4.8 %) in the placebogroup 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 older people in nursing homes, where 80 % of participants received vaccine in the seasonof the study, oseltamivir 75 mg once daily given for 6 weeks significantly reduced the incidence ofclinical influenza illness from 12/272 (4.4 %) in the placebo group to 1/276 (0.4 %) in the oseltamivirgroup (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 immunocompromisedpatients (388 patients with solid organ transplantation [195 placebo; 193 oseltamivir], 87 patients withhaemopoetic stem cell transplantation [43 placebo; 44 oseltamivir], no patient with otherimmunosuppressant conditions), including 18 children 1 to 12 years of age. The primary endpoint inthis study was the incidence of laboratory-confirmed clinical influenza as determined by viral cultureand/or a four-fold rise in HAI antibodies. The incidence of laboratory-confirmed clinical influenza was2.9 % (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 the reduction in the risk of complications.
Oseltamivir resistance
Clinical studies: The risk of emergence of influenza viruses with reduced susceptibility or frankresistance to oseltamivir has been examined during Roche-sponsored clinical studies. Developingoseltamivir-resistant virus during treatment was more frequent in children than adults, ranging fromless than 1% in adults to 18% in infants aged below 1 year. Children who were found to carryoseltamivir-resistant virus in general shed the virus for a prolonged period compared with subjectswith susceptible virus. However treatment-emergent resistance to oseltamivir did not affect treatmentresponse and caused no prolongation of influenza symptoms.
An overall higher incidence of oseltamivir resistance was observed in adult and adolescentimmunocompromised patients treated with standard dose or double dose of oseltamivir for a durationof 10 days [14.5% (10/69) in standard dose group and 2.7% (2/74) in double dose group], compared todata from studies with oseltamivir-treated otherwise healthy adult and adolescent patients. Themajority of adult patients that developed resistance were transplant recipients (8/10 patients in thestandard dose group and 2/2 patients in the double dose group). Most of the patients with oseltamivir-resistant virus were infected with influenza type A and had prolonged viral shedding.
The incidence of oseltamivir-resistance observed in immunocompromised children (≤12 years of age)treated with Tamiflu across the two studies and evaluated for resistance was 20.7% (6/29). Of the siximmunocompromised children found with treatment-emergent resistance to oseltamivir, 3 patientsreceived standard dose and 3 patients high dose (double or triple dose). The majority had acutelymphoid leukemia and were ≤ 5 years of age.
Incidence of Oseltamivir Resistance in Clinical Studies
Patients with Resistance Mutations (%)
Patient Population Phenotyping* Geno- and Phenotyping*
Adults and adolescents 0.88% (21/2382) 1.13% (27/2396)
Children (1-12 years) 4.11% (71/1726) 4.52% (78/1727)
Infant (<1 year) 18.31% (13/71) 18.31 (13/71)
* Full genotyping was not performed in all studies.
Prophylaxis of Influenza
There has been no evidence for emergence of drug resistance associated with the use of Tamiflu inclinical 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 noresistance observed during a 12-week prophylaxis study in immunocompromised patients.
Clinical and surveillance data: Natural mutations associated with reduced susceptibility to oseltamivirin vitro have been detected in influenza A and B viruses isolated from patients without exposure tooseltamivir. Resistant strains selected during oseltamivir treatment have been isolated from bothimmunocompetent and immunocompromised patients. Immunocompromised patients and youngchildren are at a higher risk of developing oseltamivir-resistant virus during treatment.
Oseltamivir-resistant viruses isolated from oseltamivir-treated patients and oseltamivir-resistantlaboratory strains of influenza viruses have been found to contain mutations in N1 and N2neuraminidases. Resistance mutations tend to be viral sub-type specific. Since 2007 naturallyoccurring resistance associated with the H275Y mutation in seasonal H1N1 strains has beensporadically detected. The susceptibility to oseltamivir and the prevalence of such viruses appear tovary seasonally and geographically. In 2008, H275Y was found in > 99 % of circulating H1N1influenza isolates in Europe. The 2009 H1N1 influenza (“swine flu”) was almost uniformlysusceptible to oseltamivir, with only sporadic reports of resistance in connection with both therapeuticand prophylactic regimens.
5.2 Pharmacokinetic properties
General Information
AbsorptionOseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivirphosphate (pro-drug) and is extensively converted by predominantly hepatic esterases to the activemetabolite (oseltamivir carboxylate). At least 75 % of an oral dose reaches the systemic circulation asthe 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 areunaffected by co-administration with food.
DistributionThe mean volume of distribution at steady state of the oseltamivir carboxylate is approximately23 litres in humans, a volume equivalent to extracellular body fluid. Since neuraminidase activity isextracellular, oseltamivir carboxylate distributes to all sites of influenza virus spread.
The binding of the oseltamivir carboxylate to human plasma protein is negligible (approximately 3 %).
BiotransformationOseltamivir is extensively converted to oseltamivir carboxylate by esterases located predominantly inthe liver. In vitro studies demonstrated that neither oseltamivir nor the active metabolite is a substratefor, or an inhibitor of, the major cytochrome P450 isoforms. No phase 2 conjugates of eithercompound have been identified in vivo.
EliminationAbsorbed oseltamivir is primarily (> 90 %) eliminated by conversion to oseltamivir carboxylate. It isnot further metabolised and is eliminated in the urine. Peak plasma concentrations of oseltamivircarboxylate decline with a half-life of 6 to 10 hours in most subjects. The active metabolite iseliminated 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 % ofan oral radiolabelled dose is eliminated in faeces.
Other special populationsPaediatric population
Infants less than 1 year of age: The pharmacokinetics, pharmacodynamics and safety of Tamiflu havebeen evaluated in two uncontrolled open-label studies including influenza infected children less thanone year of age (n=135). The rate of clearance of the active metabolite, corrected for body-weight,decreases with ages below one year. Metabolite exposures are also more variable in the youngestinfants. The available data indicates that the exposure following a 3 mg/kg dose in infants 0-12 monthsof age provides pro-drug and metabolite exposures anticipated to be efficacious with a safety profilecomparable to that seen in older children and adults using the approved dose (see sections 4.1 and4.2).The reported adverse events were consistent with the established safety profile in older children.
There are no data available for infants below 1 year of age for post exposure prevention of influenza.
Prevention during an influenza epidemic in the community has not been studied in children below 12years of age.
Post-exposure prevention of influenza in infants less than 1 year of age during a pandemic:
Simulation of once daily dosing of 3mg/kg in infants <1 year shows an exposure in the same range orhigher than for once daily dosing of 75 mg in adults. Exposure does not exceed that for treatment ofinfants < 1 year (3 mg/kg twice daily) and is anticipated to result in a comparable safety profile (see
Section 4.8). No clinical studies of prophylaxis in infants aged <1 have been performed.
Infants and children 1 year of age or older: The pharmacokinetics of oseltamivir have been evaluatedin single-dose pharmacokinetic studies in infants, children and adolescents 1 to 16 years of age.
Multiple-dose pharmacokinetics were studied in a small number of children enrolled in a clinicalefficacy 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 carboxylateexposures comparable to those achieved in adults receiving a single 75 mg dose (approximately1 mg/kg). The pharmacokinetics of oseltamivir in children and adolescents 12 years of age or older aresimilar to those in adults.
ElderlyExposure to the active metabolite at steady state was 25 to 35 % higher in older people (age 65 to 78years) compared to adults less than 65 years of age given comparable doses of oseltamivir. Half-livesobserved in older people were similar to those seen in young adults. On the basis of drug exposure andtolerability, dosage adjustments are not required for older people unless there is evidence of moderateor severe renal impairment (creatinine clearance below 60 ml /min) (see section 4.2).
Renal impairmentAdministration of 100 mg oseltamivir phosphate twice daily for 5 days to patients with variousdegrees of renal impairment showed that exposure to oseltamivir carboxylate is inversely proportionalto declining renal function. For dosing, see section 4.2.
Hepatic impairmentIn vitro studies have concluded that exposure to oseltamivir is not expected to be increasedsignificantly nor is exposure to the active metabolite expected to be significantly decreased in patientswith hepatic impairment (see section 4.2).
Pregnant Women
A pooled population pharmacokinetic analysis indicates that the Tamiflu dosage regimen described in
Section 4.2 Posology and method of administration results in lower exposure (30% on average acrossall trimesters) to the active metabolite in pregnant women compared to non-pregnant women. Thelower predicted exposure however, remains above inhibitoy concentrations (IC95 values) and at atherapeutic level for a range of influenza virus strains. In addition, there is evidence fromobservational studies showing benefit of the current dosing regimen in this patient population.
Therefore, dose adjustments are not recommended for pregnant women in the treatmentor prophylaxis of influenza (see section 4.6 Fertility, pregnancy and lactation).
Immunocompromised Patients
Population pharmacokinetic analyses indicate that treatment of adult and paediatric (<18 years old)immunocompromised patients with oseltamivir (as described in Section 4.2. Posology and method ofadministration) results in an increased predicted exposure (from approximately 5% up to 50%) to theactive metabolite when compared to non-immunocompromised patients with comparable creatinineclearance. Due to the wide safety margin of the active metabolite, no dose adjustments are required inpatients due to their immunocompromised status. However, for immunocompromised patients withrenal impairment, doses should be adjusted as outlined in section 4.2. Posology and method ofadministration.
Pharmacokinetics and pharmacodynamics analyses from two studies in immunocompromised patientsindicated that there was no meaningful additional benefit in exposures higher than those achieved afterthe administration of the standard dose.
5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated-dose toxicity and genotoxicity. Results of the conventional rodentcarcinogenicity studies showed a trend towards a dose-dependent increase in the incidence of sometumours that are typical for the rodent strains used. Considering the margins of exposure in relation tothe expected exposure in the human use, these findings do not change the benefit-risk of Tamiflu in itsadopted therapeutic indications.
Teratology studies have been conducted in rats and rabbits at doses of up to 1,500 mg/kg/day and500 mg/kg/day, respectively. No effects on foetal development were observed. A rat fertility study upto a dose of 1,500 mg/kg/day demonstrated no adverse reactions on either sex. In pre- and post-natalrat studies, prolonged parturition was noted at 1,500 mg/kg/day: the safety margin between humanexposure and the highest no-effect dose (500 mg/kg/day) in rats is 480-fold for oseltamivir and 44-foldfor the active metabolite, respectively. Foetal exposure in the rats and rabbits was approximately 15 to20 % of that of the mother.
In lactating rats, oseltamivir and the active metabolite are excreted in the milk. Limited data indicatethat oseltamivir and the active metabolite are excreted in human milk. Extrapolation of the animal dataprovides 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 substance showed erythemaafter challenging the induced animals. Reversible irritancy of rabbits' eyes was detected.
Whereas very high oral single doses of oseltamivir phosphate salt, up to the highest dose tested(1,310 mg/kg), had no adverse reactions in adult rats, such doses resulted in toxicity in juvenile 7-day-old rat pups, including death. These reactions were seen at doses of 657 mg/kg and higher. At500 mg/kg, no adverse reactions were seen, including upon chronic treatment (500 mg/kg/dayadministered from 7 to 21 days post partum).
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sorbitol (E420),
Sodium dihydrogen citrate (E331[a])
Xanthan gum (E415)
Sodium benzoate (E211)
Saccharin sodium (E954)
Titanium dioxide (E171)
Tutti frutti flavour (including maltodextrins [maize], propylene glycol, arabic gum E414 and naturalidentical flavouring substances [mainly consisting of banana, pineapple and peach flavour]).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years
After reconstitution, store below 25 °C for 10 days.
6.4 Special precautions for storage
Do not store above 30°C.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
100 ml amber glass bottle (with child-resistant polypropylene screw cap, outer part: polyethylene;inner part: polypropylene; liner: polyethylene) with 13 g of powder for oral suspension, a plasticadapter (low density polyethylene) , plastic 3 ml oral dispenser (0.1 ml graduation) and 10 ml oraldispenser (0.5 ml graduation) (barrel and plunger: polypropylene, silicon based seal ring) and a plasticmeasuring cup (polypropylene).
Pack-size of one bottle.
6.6 Special precautions for disposal and other handling
It is recommended that Tamiflu oral suspension should be reconstituted by the pharmacist prior tobeing dispensed to the patient.
After reconstitution with 55 ml of water, the usable volume of oral suspension allows for the retrievalof a total of 10 doses of 30 mg oseltamivir.
Preparation of oral suspension1. Tap the closed bottle gently several times to loosen the powder.2. Measure 55 ml of water by filling the measuring cup to the indicated level (measuring cupincluded in the box).3. Add all 55 ml of water into the bottle, recap the bottle and shake the closed bottle well for 15seconds.4. Remove the cap and push the bottle adapter into the neck of the bottle.5. Close the bottle tightly with the cap (on the top of the bottle adapter). This will make sure thatthe bottle adapter fits in the bottle in the right position.
Tamiflu powder for suspension will appear as an opaque and white to light yellow suspension afterreconstitution.
Any unused product or waste material should be disposed of in accordance with local requirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu