EBILFUMIN 75mg capsules medication leaflet

Ebilfumin 30 mg hard capsules

Ebilfumin 45 mg hard capsules

Ebilfumin 75 mg hard capsules

Ebilfumin 30 mg hard capsules

Each hard capsule contains oseltamivir phosphate equivalent to 30 mg of oseltamivir.

For the full list of excipients, see section 6.1.

Ebilfumin 45 mg hard capsules

Each hard capsule contains oseltamivir phosphate equivalent to 45 mg of oseltamivir.

For the full list of excipients, see section 6.1.

Ebilfumin 75 mg hard capsules

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

For the full list of excipients, see section 6.1.

Ebilfumin 30 mg hard capsules

The hard capsule consists of a rich yellow body and cap bearing the black imprint “OS 30”. Capsulesize: 4

The capsule contains a white granulated powder.

Ebilfumin 45 mg hard capsules

The hard capsule consists of a white opaque body and cap bearing the black imprint “OS 45”. Capsulesize: 4

The capsule contains a white granulated powder.

Ebilfumin 75 mg hard capsules

The hard capsule consists of a white opaque body and a rich yellow cap bearing the black imprint “OS75”. Capsule size: 2

The capsule contains a white granulated powder.

Treatment of influenza

Ebilfumin 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 Ebilfumin for prevention of influenza should be determined on a caseby case 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.

- Ebilfumin is indicated for post-exposure prevention of influenza in infants less than 1 year ofage during a pandemic influenza outbreak (see section 5.2).

Ebilfumin is not a substitute for influenza vaccination.

The use of antivirals for the treatment and prevention of influenza should be determined on the basis ofofficial 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).

Ebilfumin hard capsules are bioequivalent formulations. 75 mg doses can be administered aseither:

- one 75 mg capsule or

- one 30 mg capsule plus one 45 mg capsule.

Commercially manufactured oseltamivir powder for oral suspension (6 mg/ml) is the preferred productfor paediatric and adult patients who have difficulties swallowing capsules or where lower doses areneeded.

Adults, and adolescents 13 years and over

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

Body Weight Recommended dose for 5 days Recommended dose for 10 days*

Immunocompromised Patients> 40 kg 75 mg twice daily 75 mg twice daily

* The recommended treatment duration in immunocompromised adults and adolescents is 10 days. See Special Populations,

Immunocompromised Patients for more information.

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

Post-exposure prevention: The recommended dose for prevention of influenza following close contactwith an infected individual is 75 mg oseltamivir once daily for 10 days for adolescents (13 to 17 yearsof age) and adults.

Body Weight Recommended dose for 10 days Recommended dose for 10 days

Immunocompromised Patients> 40 kg 75 mg once daily 75 mg once daily

Therapy should begin as soon as possible within two days of exposure to an infected individual.

Prevention during an influenza epidemic in the community: The recommended dose for prevention ofinfluenza during a community outbreak is 75 mg oseltamivir once daily for up to 6 weeks (or up to12 weeks in immunocompromised patients, see sections 4.4, pct. 4.8 and 5.1).

Children 1 to 12 years of age

Ebilfumin 30 mg, 45 mg and 75 mg capsules are available for infants and children 1 year of age orolder

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

Body Weight Recommended dose for 5 days Recommended dose for 10 days*

Immunocompromised Patients10 kg to 15 kg 30 mg twice daily 30 mg twice daily> 15 kg to 23 kg 45 mg twice daily 45 mg twice daily> 23 kg to 40 kg 60 mg twice daily 60 mg twice daily> 40 kg 75 mg twice daily 75 mg twice daily

*The recommended treatment duration in immunocompromised children (≥1 year old) is 10 days. See Special

Populations, Immunocompromised Patients for more information.

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

Post-exposure prevention: The recommended post-exposure prevention dose of Ebilfumin is:

Body Weight Recommended dose for 10 days Recommended dose for 10 days

For Immunocomprmised Patients10 kg to 15 kg 30 mg once daily 30 mg once daily> 15 kg to 23 kg 45 mg once daily 45 mg once daily> 23 kg to 40 kg 60 mg once daily 60 mg once daily> 40 kg 75 mg once daily 75 mg once daily

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

Infants 0 - 12 months of age

Treatment: The recommended treatment dose for infants 0 - 12 months of age is 3 mg/kg twice daily.

This is based upon pharmacokinetic and safety data indicating that this dose in infants 0 - 12 monthsprovides plasma concentrations of the pro-drug and active metabolite that are anticipated to beclinically efficacious with a safety profile comparable to that seen in older children and adults (seesection 5.2). The following dosing regimen is recommended for treatment of infants 0 - 12 months ofage:

Body weight* Recommended dose for 5 days Recommended dose for 10 days**

Immunocompromised Patients3 kg 9 mg twice daily 9 mg twice daily4 kg 12 mg twice daily 12 mg twice daily5 kg 15 mg twice daily 15 mg twice daily6 kg 18 mg twice daily 18 mg twice daily7 kg 21 mg twice daily 21 mg twice daily8 kg 24 mg twice daily 24 mg twice daily9 kg 27 mg twice daily 27 mg twice daily10 kg 30 mg twice daily 30 mg twice daily

* This table is not intended to contain all possible weights for this population. For all patients under the age of 1year, 3 mg/kg should be used to determine dose regardless of the weight of the patient.

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

** 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-conceptual age less than 36 weeks. Insufficient data are available for these patients, in whomdifferent dosing may be required due to the immaturity of physiological functions.

Post-exposure prevention: The recommended prophylaxis dose for infants less than 1 year of ageduring a pandemic influenza outbreak is half of the daily treatment dose. This is based upon clinicaldata in infants and children 1 year of age or older and adults showing that a prophylaxis doseequivalent to half the daily treatment dose is clinically efficacious for the prevention of influenza. Thefollowing age-adjusted dosing prophylaxis regimen is recommended for infants 0 - 12 months of age(see Section 5.2 for exposure simulation):

Age Recommended dose for 10 days Recommended dose for 10 days

Immunocompromised Patients0 - 12 months 3 mg/kg once daily 3 mg/kg once daily

This dosing recommendation is not intended for premature infants, i.e. those with a post-conceptual age less than 36 weeks. Insufficient data are available for these patients, in whomdifferent dosing may be required due to the immaturity of physiological functions.

Prevention during an influenza epidemic in the community: Prevention during an influenza epidemichas not been studied in children 0-12 months of age.

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

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.

Treatment 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 twice daily> 10 to 30 (ml/min) 30 mg once daily≤ 10 (ml/min) Not recommended (no data available)

Haemodialysis patients 30 mg after each haemodialysis session

Peritoneal dialysis patients* 30 mg 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 once daily> 10 to 30 (ml/min) 30 mg 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 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.

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

Treatment: For treatment of influenza, the recommended duration for immunocompromisedpatients is 10 days (see sections 4.4, pct. 4.8 and 5.1). No dose adjustment is necessary. Treatmentshould be initiated as soon as possible within the first two days of onset of symptoms of influenza.

Seasonal prophylaxis: Longer duration of seasonal prophylaxis up to 12 weeks has been evaluatedin immunocompromised patients (see sections 4.4, pct. 4.8 and 5.1).

Oral use.

Patients who are unable to swallow capsules may receive appropriate doses of an oseltamivirsuspension..

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

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).

Oseltamivir is not a substitute for influenza vaccination

Use of oseltamivir must not affect the evaluation of individuals for annual influenza vaccination. Theprotection against influenza lasts only as long as oseltamivir is administered. Oseltamivir should beused for the treatment and prevention of influenza only when reliable epidemiological data indicatethat influenza virus is circulating in the community. Susceptibility of circulating influenza virus strainsto oseltamivir has been shown to be highly variable (see section 5.1). Therefore, prescribers shouldtake into account the most recent information available on oseltamivir susceptibility patterns of thecurrently circulating viruses when deciding whether to use oseltamivir.

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.

The 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).

No data allowing a dose recommendation for premature children (< 36 weeks post-conceptual age) arecurrently available.

Dose 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 oseltamivir 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).

Excipient

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially‘sodium-free’.

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.

No 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).

No 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).

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 byoseltamivir.

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 oseltamivir 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.

In 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 in breastmilk. Limited data demonstrated that oseltamivir and the active metabolite were detected in breastmilk, 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.

Based on preclinical data, there is no evidence that oseltamivir has an effect on male or female fertility(see section 5.3).

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

The overall safety profile of oseltamivir is based on data from 6049 adult/adolescent and 1473paediatric patients treated with oseltamivir or placebo for influenza, and on data from 3990adult/adolescent and 253 paediatric patients receiving oseltamivir or placebo/no treatment for theprophylaxis of influenza in clinical trials. In addition, 245 immunocompromised patients (including 7adolescents and 39 children) received oseltamivir for the treatment of influenza and 475immunocompromised patients (including 18 children, of these 10 oseltamivir and 8 placebo) receivedoseltamivir or placebo for the prophylaxis of influenza.

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 oseltamivir.

The following serious adverse reactions have been rarely reported since oseltamivir has beenmarketed: Anaphylactic and anaphylactoid reactions, hepatic disorders (fulminant hepatitis,hepatic function disorder and jaundice), angioneurotic oedema, Stevens-Johnson syndrome andtoxic epidermal necrolysis, gastrointestinal bleeding and neuropsychiatric disorders.(Regarding neuropsychiatric disorders, see section 4.4.)

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

Treatment and prevention of influenza in adults and adolescents:

In adult/adolescent treatment and prevention studies, ARs that occurred the most frequently atthe recommended dose (75 mg bid for 5 days for treatment and 75 mg od for up to 6 weeksfor prophylaxis) are shown in Table 1.

The safety profile reported in subjects who received the recommended dose of oseltamivir forprophylaxis (75 mg once daily for up to 6 weeks) was qualitatively similar to that seen in thetreatment studies, despite a longer duration of dosing in the prophylaxis studies.

Table 1 Adverse reactions in studies investigating oseltamivir for treatment andprevention of influenza in adults and adolescents or through post-marketingsurveillance

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 Thrombocytopenialymphatic systemdisorders

Immune system Hypersensitivity Anaphylacticdisorders reaction reactions,

Anaphylactoidreactions

Psychiatric Agitation,Abnormaldisorders behaviour,

Anxiety,Confusion,

Delusions, Delirium,

Hallucination,

Nightmares,Self-injury

Nervous system Headache Insomnia Altered leveldisorders ofconsciousness,

Eye disorders Visual disturbance

Cardiac Cardiac arrhythmiadisorders

Respiratory, Cough,thoracic and Sore throat,mediastinal Rhinorrheadisorders

Gastrointestinal Nausea Vomiting Gastrointestinaldisorders Abdominal pain bleedings,(incl. upper Haemorrhagicabdominal pain), colitis

Dyspepsia

Hepatobiliary Elevated liver Fulminantdisorders enzymes hepatitis,

Hepatic failure,

Skin and Eczema, Angioneu roticsubcutaneous Dermatitis, Rash, oedema,tissue disorders Urticaria Erythemamultiforme,

Stevens-Johnsonsyndrome, Toxicepidermalnecrolysis

General Paindisorders and Dizziness (incl.administration vertigo),site conditions Fatigue,

Pyrexia ,

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 treatmentof influenza. Of those, 851 children received treatment with oseltamivir suspension. A total of 158children received the recommended dose of oseltamivir once daily in a post-exposure prophylaxisstudy in households (n = 99), a 6-week paediatric seasonal prophylaxis study (n = 49) and a 12-week paediatric seasonal prophylaxis study in immunocompromised subjects (n = 10).

Table 2 shows the most frequently reported ARs from paediatric clinical trials.

Table 2 Adverse reactions in studies investigating oseltamivir for treatment andprevention of influenza in children (age/weight-based dosing [30 mg to 75 mgo.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 Dermatitissubcutaneous (including allergictissue disorders and atopicdermatitis)

Psychiatric disorders and nervous system disorders

Influenza can be associated with a variety of neurologic and behavioural symptoms which caninclude events such as hallucinations, delirium, and abnormal behaviour, in some cases resulting infatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occurwithout obvious severe disease.

In patients with influenza who were receiving oseltamivir, 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 ofoseltamivir to those events is unknown. Such neuropsychiatric events have also been reported inpatients with influenza who were not taking oseltamivir.

Hepato-biliary disorders

Hepato-biliary system disorders, including hepatitis and elevated liver enzymes in patientswith influenza-like illness. These cases include fatal fulminant hepatitis/hepatic failure.

Paediatric 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 frequentlyreported adverse events (see section 5.2). Insufficient data are available for infants who have a post-conceptual age of less than 36 weeks.

Safety information available on oseltamivir administered for treatment of influenza in infants lessthan one year of age from prospective and retrospective observational studies (comprising togethermore than 2,400 infants of that age class), epidemiological databases research and postmarketingreports suggest that the safety profile in infants less than one year of age is similar to the establishedsafety profile 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.

The treatment of influenza in immunocompromised patients were evaluated in two studies receivingstandard dose or high dose regimens (double dose or triple dose) of oseltamivir (see section 5.1). Thesafety profile of oseltamivir observed in these studies was consistent with that observed in previousclinical trials where oseltamivir was administered for treatment of influenza in non-immunocompromised patients across all age groups (otherwise healthy patients or “at risk” patients[i.e., those with respiratory and/or cardiac co-morbidities]). The most frequent adverse reactionreported in immunocompromised children was vomiting (28%).

In a 12-week prophylaxis study in 475 immunocompromised patients, including 18 children 1 to 12years of age and older, the safety profile in the 238 patients who received oseltamivir was consistentwith that previously observed in oseltamivir 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 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.

Reports of overdoses with oseltamivir have been received from clinical trials and during post-marketing experience. In the majority of cases reporting overdose, no adverse events were reported.

Adverse events reported following overdose were similar in nature and distribution to those observedwith therapeutic doses of oseltamivir, described in section 4.8 Undesirable effects.

No specific antidote is known.

Overdose has been reported more frequently for children than adults and adolescents. Caution shouldbe exercised when preparing oseltamivir oral suspension and when administering oseltamivir productsto children.

Pharmacotherapeutic group: Antivirals for systemic use, neuraminidase inhibitors, ATCcode: 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 a medianof 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 aretherefore presented only for influenza-infected subjects. In the pooled treatment study population,which included both influenza-positive and -negative subjects (ITT), primary efficacy was reducedproportionally to the number of influenza-negative individuals. In the overall treatment population,influenza infection was confirmed in 67 % (range 46 % to 74 %) of the recruited patients. Of theolder subjects, 64 % were influenza-positive and of those with chronic cardiac and/or respiratorydisease 62 % were influenza-positive. In all phase III treatment studies, patients were recruitedonly during the period in which influenza was circulating in the local community.

Adults and adolescents 13 years of age and older: Patients were eligible if they reported within 36hours 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 the medianduration of influenza illness by approximately one day from 5.2 days (95 % CI 4.9 - 5.5 days) in theplacebo 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 withoseltamivir 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 fromolder children and the recommended posology is based upon pharmacokinetic modelling data(see Section 5.2).

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 (75 mg or weight adjusted dose for children) twice daily (73 adultpatients, 4 adolescent patients and 4 children) or double dose (150 mg 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 (75 mg or weight adjusted twice daily) vs. tripledose (225 mg or weight adjusted twice daily) oseltamivir for an adaptive dosing period of 5 to 20 daysdependant on duration of viral shedding (mean treatment duration: 9 days). No patients in the standarddose group and 2 patients in the triple dose group reported secondary bacterial infections (bronchitisand 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 thisstudy was 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 theincidence of influenza from 26 % (23/89) in the group not receiving prevention to 11 % (9/84) inthe group receiving prevention (58.5 % reduction [95 % CI 15.6 - 79.6; p = 0.0114]). According tosubgroup analysis in children at 1 to 12 years of age, the incidence of laboratory-confirmed clinicalinfluenza among children was significantly reduced from 19 % (21/111) in the group not receivingprevention 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 oflaboratory-confirmed clinical influenza was reduced from 21 % (15/70) in the group not receivingprevention to 4 % (2/47) in the group receiving prevention (80.1 % reduction [95 % CI 22.0 - 94.9;p = 0.0206]). The NNT for the total paediatric population was 9 (95 % CI 7 - 24) and 8 (95 % CI 6,upper limit not estimable) in the whole population (ITT) and in paediatric contacts of infected indexcases (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 inchildren 0-12 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). Astudy 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 theoseltamivir group (92 % reduction [95 % CI 1.5 - 6.6; p = 0.0015]). The NNT in this study was 25(95 % CI 23 - 62).

Prophylaxis of influenza in immunocompromised patients: A double-blind, placebo-controlled,randomised study was conducted for seasonal prophylaxis of influenza in 475 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 oseltamivir across the two studies and evaluated for resistance was 20.7% (6/29). Of thesix immunocompromised 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

Patient Population Patients with Resistance Mutations (%)

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)

Infants (<1year) 18.31% (13/71) 18.31% (13/71)

* Full genotyping was not performed in all studies.

Prophylaxis of Influenza

There has been no evidence for emergence of drug resistance associated with the use of oseltamivir 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 naturally occurringresistance associated with the H275Y mutation in seasonal H1N1 strains has been sporadically detected.

The susceptibility to oseltamivir and the prevalence of such viruses appear to vary seasonally andgeographically. In 2008, H275Y was found in > 99 % of circulating H1N1 influenza isolates in Europe.

The 2009 H1N1 influenza (“swine flu”) was almost uniformly susceptible to oseltamivir, with onlysporadic reports of resistance in connection with both therapeutic and prophylactic regimens.

General Information

Oseltamivir 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 circulationas the active metabolite. Exposure to the pro-drug is less than 5 % relative to the active metabolite.

Plasma concentrations of both pro-drug and active metabolite are proportional to dose and areunaffected by co-administration with food.

The mean volume of distribution at steady state of the oseltamivir carboxylate is approximately 23litres 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 %).

Oseltamivir 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.

Absorbed 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.

Infants less than 1 year of age: The pharmacokinetics, pharmacodynamics and safety of oseltamivirhave been evaluated in two uncontrolled open-label studies including influenza infected children lessthan one 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 theyoungest infants. The available data indicates that the exposure following a 3 mg/kg dose in infants 0 -12 months of age provides pro-drug and metabolite exposures anticipated to be efficacious with asafety profile comparable to that seen in older children and adults using the approved dose (seesections 4.1 and 4.2). The reported adverse events were consistent with the established safety profile inolder 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 (approximately 1mg/kg). The pharmacokinetics of oseltamivir in children and adolescents 12 years of age or older aresimilar to those in adults.

Exposure 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 exposureand tolerability, dosage adjustments are not required for older people unless there is evidence ofmoderate or severe renal impairment (creatinine clearance below 60 ml /min) (see section 4.2).

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

In 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 Ebilfumin dosage regimendescribed in Section 4.2 Posology and method of administration results in lower exposure (30% onaverage across all trimesters) to the active metabolite in pregnant women compared tonon-pregnant women. The lower predicted exposure however, remains above inhibitory concentrations(IC95 values) and at a therapeutic level for a range of influenza virus strains. In addition, there isevidence from observational studies showing benefit of the current dosing regimen in this patientpopulation. 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.

Pharmacokinetic and pharmacodynamic 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.

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 oseltamivir inits adopted therapeutic indications.

Teratology studies have been conducted in rats and rabbits at doses of up to 1,500 mg/kg/day and 500mg/kg/day, respectively. No effects on foetal development were observed. A rat fertility study up to adose of 1,500 mg/kg/day demonstrated no adverse reactions on either sex. In pre- and post-natal ratstudies, 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 (1,310mg/kg), had no adverse reactions in adult rats, such doses resulted in toxicity in juvenile 7-day- old ratpups, including death. These reactions were seen at doses of 657 mg/kg and higher. At 500 mg/kg, noadverse reactions were seen, including upon chronic treatment (500 mg/kg/day administered from 7 to21 days post partum).

Ebilfumin 30 mg hard capsules

Capsule core

Pregelatinised starch (derived from maize starch)

Talc

Povidone (K-29/32)

Croscarmellose sodium

Sodium stearyl fumarate

Gelatin

Yellow iron oxide (E172)

Titanium dioxide (E171)

Shellac Glaze-45% (20% esterified)

Black iron oxide (E172)

Propylene glycol (E1520)

Ammonium hydroxide 28% (E527)

Ebilfumin 45 mg hard capsules

Capsule core

Pregelatinised starch (derived from maize starch)

Talc

Povidone (K-29/32)

Croscarmellose sodium

Sodium stearyl fumarate

Gelatin

Titanium dioxide (E171)

Shellac Glaze-45% (20% esterified)

Black iron oxide (E172)

Propylene glycol (E1520)

Ammonium hydroxide 28% (E527)

Ebilfumin 75 mg hard capsules

Capsule core

Pregelatinised starch (derived from maize starch)

Talc

Povidone (K-29/32)

Croscarmellose sodium

Sodium stearyl fumarate

Cap:

Gelatin

Yellow iron oxide (E172)

Titanium dioxide (E171)

Body:

Gelatin

Titanium dioxide (E171)

Shellac Glaze-45% (20% esterified)

Black iron oxide (E172)

Propylene glycol (E1520)

Ammonium hydroxide 28% (E527)

Not applicable.

6 years

Storage of the pharmacy compounded suspension

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

Shelf life of 6 weeks at 2°C - 8°C.

Store below 25°C.

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

PVC/PE/PVdC/Al blisters or HDPE containers with LDPE lid (and a desiccant).

Pack-size 10 capsules.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Extemporaneous formulation

When oseltamivir powder for oral suspension is not available

Commercially manufactured oseltamivir powder for oral suspension (6 mg/ml) is the preferredproduct for paediatric and adult patients who have difficulties swallowing capsules or where lowerdoses are needed. In the event that commercially manufactured oseltamivir powder for oralsuspension is not available, the pharmacist may compound a suspension (6 mg/ml) from Ebilfumincapsules or patients can prepare the suspension from capsules at home.

The pharmacy preparation should be preferred to home preparation. Detailed information on the homepreparation can be found in the package leaflet of Ebilfumin capsules under “Making liquid Ebilfuminat home”.

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

Pharmacy compounding

Pharmacy compounded 6 mg/ml suspension prepared from capsules

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

This procedure describes the preparation of a 6 mg/ml suspension that will provide one patient withenough medicine for a 5-day course of treatment or a 10-day course of prophylaxis. Forimmunocompromised patients, a 10-day course of treatment is needed.

The pharmacist may compound a 6 mg/ml suspension from Ebilfumin 30 mg, 45 mg or 75 mgcapsules using water containing 0.05 % w/v sodium benzoate added as a preservative.

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

For immunocompromised patients, calculate the total volume needed to be compounded and dispensedto provide a 10-day course of treatment for the patient. The total volume needed is indicated in thetable below for immunocompromised patients and is determined by the patient’s weight. To allow foraccurate volume withdrawal of up to 20 doses (2 withdrawals per daily treatment dose for 10 days),the column indicating measurement loss is to be considered for compounding.

Volume of pharmacy compounded 6 mg/ml suspension prepared based upon the patient’sweight for 5-day treatment or 10-day prophylaxis course

Body weight Total volume to compound Total volume to compound(kg) per patient weight per patient weight(ml) (ml)

Measurement loss not considered Measurement loss considered10 kg to 15 kg 50 ml 60 ml or 75 ml*> 15 kg to 23 kg 75 ml 90 ml or 100 ml*> 23 kg to 40 kg 100 ml 125 ml> 40 kg 125 ml 137.5 ml (or 150 ml)*

*Depending on the capsule strength used.

Volume of pharmacy compounded 6 mg/ml suspension prepared based upon the patient’sweight for 10-days of treatment for immunocompromised patients

Body weight Total volume to compound Total volume to compound(kg) per patient weight per patient weight(ml) (ml)

Measurement loss not considered Measurement loss considered10 kg to 15 kg 100 ml 125 ml> 15 kg to 23 kg 150 ml 187.5 ml> 23 kg to 40 kg 200 ml 250 ml> 40 kg 250 ml 300 ml

Second, determine the number of capsules and the amount of vehicle (water containing 0.05 % w/vsodium benzoate added as a preservative) that is needed to prepare the total volume (calculated fromthe table above) of pharmacy compounded 6 mg/ml suspension as shown in the table below:

Number of capsules and amount of vehicle needed to prepare the total volume of a pharmacycompounded 6 mg/ml suspension (for 5 days of treatment or 10-days of prophylaxis)

Total volume Required number of Ebilfumin capsulesof compounded (mg of oseltamivir)suspension Required volumeto be prepared 75 mg 45 mg 30 mg of vehicle60 ml Please use 8 capsules 12 capsules 59.5 mlalternative (360 mg) (360 mg)capsulestrength*75 ml 6 capsules 10 capsules 15 capsules 74 ml(450 mg) (450 mg) (450 mg)90 ml Please use 12 capsules 18 capsules 89 mlalternative (540 mg) (540 mg)capsulestrength*100 ml 8 capsules Please use 20 capsules 98.5 ml(600 mg) alternative (600 mg)capsulestrength*125 ml 10 capsules Please use 25 capsules 123.5 ml(750 mg) alternative (750 mg)capsulestrength*137.5 ml 11 capsules Please use Please use 136 ml(825 mg) alternative alternativecapsule capsulestrength* strength*

* There is no combination of this capsule strength that can be used to achieve the target concentration; therefore,please use an alternative capsule strength.

Number of capsules and amount of vehicle needed to prepare the total volume of a pharmacycompounded 6 mg/ml suspension (for 10 days of treatment in immunocompromised patients)

Total volume Required number of Ebilfumin capsulesof compounded (mg of oseltamivir)suspension Required volumeto be prepared 75 mg 45 mg 30 mg of vehicle125ml 10 capsules Please use 25 capsules 123.5 ml(750 mg) alternative (750 mg)capsulestrength*187.5ml 15 capsules 25 capsules Please use 185 ml(1120 mg) (1120 mg) alternativecapsulestrength*250ml 20 capsules Please use 50 capsules 246.5 ml(1500 mg) alternative (1500 mg)capsulestrength*300ml 24 capsules 40 capsules 60 capsules 296 ml(1800 mg) (1800 mg) (1800 mg)

* There is no combination of this capsule strength that can be used to achieve the target concentration; therefore,please use an alternative capsule strength.

Third, follow the procedure below for compounding the 6 mg/ml suspension from Ebilfumin capsules:

1. In a glass beaker of suitable size place the stated amount of water containing 0.05 % w/vsodium benzoate added as a preservative.

2. Open the stated amount of Ebilfumin capsules and transfer the content of each capsule directlyto the preserved water in the glass beaker.

3. With a suitable stirring device, stir for 2 minutes.(Note: The drug substance, oseltamivir phosphate, readily dissolves in water. The suspension iscaused by some of the excipients of Ebilfumin capsules, which are insoluble.)4. Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle.

A funnel may be used to eliminate any spillage.5. Close the bottle using a child-resistant cap.6. Put an ancillary label on the bottle indicating “Shake Gently Before Use”.(Note: This compounded suspension should be gently shaken prior to administration tominimise the tendency for air entrapment.)7. Instruct the parent or caregiver that any remaining material following completion of therapymust be discarded. It is recommended that this information be provided by either affixing anancillary label to the bottle or adding a statement to the pharmacy label instructions.

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

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

Dosing chart for pharmacy-compounded 6 mg/ml suspension prepared from Ebilfumincapsules for patients 1 year of age or older

Treatment dose(for 10 days*)

Body Volume Immuno-weight Dose per dose Treatment dose compromised Prophylaxis dose(kg) (mg) 6 mg/ml (for 5 days) patients (for 10 days)10 kg to 15 30 mg 5 ml 5 ml twice daily 5 ml twice daily 5 ml once dailykg> 15 kg to 45 mg 7.5 ml 7.5 ml twice daily 7.5 ml twice daily 7.5 ml once daily23 kg> 23 kg to 60 mg 10 ml 10 ml twice daily 10 ml twice daily 10 ml once daily40 kg> 40 kg 75 mg 12.5 ml 12.5 ml twice daily 12.5 ml twice daily 12.5 ml once daily

*The recommended duration in immunocompromised patients (≥1 year of age) is 10 days. See Special

Populations, Immunocompromised Patients for more information.

Dispense the pharmacy compounded suspension with a graduated oral syringe for measuring smallamounts of suspension. If possible, mark or highlight the graduation corresponding to the appropriatedose (according to the dosing table above ) on the oral syringe for each patient.

The appropriate dose must be mixed by the caregiver with an equal quantity of sweet liquid food, suchas sugar water, chocolate syrup, cherry syrup, dessert toppings (like caramel or fudge sauce) to maskthe bitter taste.

Infants less than 1 year of age

This procedure describes the preparation of a 6 mg/ml suspension that will provide one patient withenough medication for a 5-day course of treatment or a 10-day course of prophylaxis. Forimmunocompromised patients, a 10-day course of treatment for the patient is needed.

The pharmacist may compound a 6 mg/ml suspension from Ebilfumin 30 mg, 45 mg or 75 mgcapsules using water containing 0.05 % w/v sodium benzoate added as a preservative.

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

For immunocompromised patients, calculate the total volume needed to be compounded and dispensedto provide a 10-day course of treatment for the patient. The total volume needed is indicated in thetable below and is determined by the patient’s weight. To allow for accurate volume withdrawal of upto 20 doses (2 withdrawals per daily treatment dose for 10 days), the column indicating measurementloss is to be considered for compounding.

Volume of pharmacy compounded 6 mg/ml suspension prepared based upon the patient’sweight (for 5 days of treatment or 10-days of prophylaxis)

Body weight Total volume to compound Total volume to compound(kg) per patient weight per patient weight(ml) (ml)

Measurement loss not considered Measurement loss considered≤ 7 kg up to 40 ml 50 ml> 7 kg to 10 kg 50 ml 60 ml or 75 ml*

* Depending on the capsule strength used.

Volume of pharmacy compounded 6 mg/ml suspension prepared based upon the patient’sweight (for 10-days of treatment in immunocompromised patients)

Body weight Total volume to compound Total volume to compound(kg) per patient weight per patient weight(ml) (ml)

Measurement loss not considered Measurement loss considered≤ 7 kg up to 80 ml 100 ml> 7 kg to 10 kg 100 ml 125 ml

Second, determine the number of capsules and the amount of vehicle (water containing 0.05 % w/vsodium benzoate added as a preservative) that is needed to prepare the total volume (calculatedfrom the table above) of pharmacy compounded 6 mg/ml suspension as shown in the table below:

Number of capsules and amount of vehicle needed to prepare the total volume of apharmacy compounded 6 mg/ml suspension (for 5 days of treatment or 10-days ofprophylaxis)

Total volume Required number of Ebilfumin capsulesof compounded (mg of oseltamivir)suspension Required volumeto be prepared 75 mg 45 mg 30 mg of vehicle50 ml 4 capsules Please use 10 capsules 49.5 ml(300 mg) alternative (300 mg)capsulestrength*

Total volume Required number of Ebilfumin capsulesof compounded (mg of oseltamivir)suspension Required volumeto be prepared 75 mg 45 mg 30 mg of vehicle60 ml Please use 8 capsules 12 capsules 59.5 mlalternative (360 mg) (360 mg)capsulestrength*75 ml 6 capsules 10 capsules 15 capsules 74 ml(450 mg) (450 mg) (450 mg)

*There is no combination of this capsule strength that can be used to achieve the target concentration; therefore,please use an alternative capsule strength.

Number of capsules and amount of vehicle needed to prepare the total volume of a pharmacycompounded 6 mg/ml suspension (for 10-days of treatment in immunocompromised patients)

Total volume Required number of Ebilfumin capsulesof compounded (mg of oseltamivir)suspension Required volumeto be prepared 75 mg 45 mg 30 mg of vehicle100 ml 8 capsules Please use 20 capsules 98.5 ml(600 mg) alternative (600 mg)capsulestrength*125 ml 10 capsules Please use 25 capsules 123.5 ml(750 mg) alternative (750 mg)capsulestrength*

* There is no combination of this capsule strength that can be used to achieve the target concentration; therefore,please use an alternative capsule strength.

Third, follow the procedure below for compounding the 6 mg/ml suspension from Ebilfumin capsules:1. In a glass beaker of suitable size place the stated amount of water containing 0.05 % w/vsodium benzoate added as a preservative.2. Open the stated amount of Ebilfumin capsules and transfer the content of each capsule directlyto the preserved water in the glass beaker.3. With a suitable stirring device, stir for 2 minutes.(Note: The drug substance, oseltamivir phosphate, readily dissolves in water. The suspension iscaused by some of the excipients of Ebilfumin capsules, which are insoluble.)4. Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle.

A funnel may be used to eliminate any spillage.5. Close the bottle using a child-resistant cap.6. Put an ancillary label on the bottle indicating “Shake Gently Before Use”.(Note: This compounded suspension should be gently shaken prior to administration tominimise the tendency for air entrapment.)7. Instruct the parent or caregiver that any remaining material following completion of therapymust be discarded. It is recommended that this information be provided by either affixing anancillary label to the bottle or adding a statement to the pharmacy label instructions.

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

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

Dosing chart for pharmacy compounded 6 mg/ml suspension prepared from Ebilfumincapsules for infants less than 1 year of age

Body Treatment Dose Dispenser

Weight Volume (for 10 days*) size(rounded to per dose Immuno- to usethe nearest Dose (6 Treatment Dose compromised Prophylaxis Dose (grading 0.10.5 kg) (mg) mg/ml) (for 5 days) patients (for 10 days) ml)3 kg 9 mg 2.0 ml (or 3.01.5 ml 1.5 ml twice daily 1.5 ml twice daily 1.5 ml once daily ml)3.5 kg 10.5 mg 2.0 ml (or1.8 ml 1.8 ml twice daily 1.8 ml twice daily 1.8 ml once daily 3.0 ml)4 kg 12 mg 2.0 ml 2.0 ml twice daily 2.0 ml twice daily 2.0 ml once daily 3.0 ml4.5 kg 13.5 mg 2.3 ml 2.3 ml twice daily 2.3 ml twice daily 2.3 ml once daily 3.0 ml5 kg 15 mg 2.5 ml 2.5 ml twice daily 2.5 ml twice daily 2.5 ml once daily 3.0 ml5.5 kg 16.5 mg 2.8 ml 2.8 ml twice daily 2.8 ml twice daily 2.8 ml once daily 3.0 ml6 kg 18 mg 3.0 ml 3.0 ml twice daily 3.0 ml once daily 3.0 ml (or3.0 ml twice daily 5.0 ml)6.5 kg 19.5 mg 3.3 ml 3.3 ml twice daily 3.3 ml twice daily 3.3 ml once daily 5.0 ml7 kg 21 mg 3.5 ml 3.5 ml twice daily 3.5ml twice daily 3.5 ml once daily 5.0 ml7.5 kg 22.5 mg 3.8 ml 3.8 ml twice daily 3.8 ml twice daily 3.8 ml once daily 5.0 ml8 kg 24 mg 4.0 ml 4.0 ml twice daily 4.0 ml twice daily 4.0 ml once daily 5.0 ml8.5 kg 25.5 mg 4.3 ml 4.3 ml twice daily 4.3 ml twice daily 4.3 ml once daily 5.0 ml9 kg 27 mg 4.5 ml 4.5 ml twice daily 4.5 ml twice daily 4.5 ml once daily 5.0 ml9.5 kg 28.5 mg 4.8 ml 4.8 ml twice daily 4.8 ml twice daily 4.8 ml once daily 5.0 ml10 kg 30 mg 5.0 ml 5.0 ml twice daily 5.0 ml twice daily 5.0 ml once daily 5.0 ml

* The recommended duration in immunocompromised infants (0-12 months old) is 10 days. See Special Populations,

Immunocompromised Patients for more information.

Dispense the pharmacy compounded suspension with a graduated oral syringe for measuring smallamounts of suspension. If possible, mark or highlight the graduation corresponding to theappropriate dose (according to the dosing tables above) on the oral syringe for each patient.

The appropriate dose must be mixed by the caregiver with an equal quantity of sweet liquid food,such as sugar water, chocolate syrup, cherry syrup, dessert toppings (like caramel or fudge sauce) tomask the bitter taste.

Home preparation

When commercially manufactured oseltamivir powder for oral suspension is not available, apharmacy compounded suspension prepared from Ebilfumin capsules must be used (see detailedinstructions above). If the commercially manufactured oseltamivir powder for oral suspension and thepharmacy compounded suspension is also not available, Ebilfumin suspension may be prepared athome.

When appropriate capsule strengths are available for the dose needed, the dose is given by openingthe capsule and mixing its contents with no more than one teaspoon of a suitable sweetened foodproduct. The bitter taste can be masked by products such as sugar water, chocolate syrup, cherrysyrup, dessert toppings (like caramel or fudge sauce). The mixture should be stirred and givenentirely 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 preparationof Ebilfumin suspension involves additional steps. Detailed instructions can be found in the packageleaflet of Ebilfumin capsules under “Making liquid Ebilfumin at home”.

Actavis Group PTC ehf.

Dalshraun 1220 Hafnarfjörður

Iceland

Ebilfumin 30 mg hard capsules

EU/1/14/915/001 (10 hard capsules blister)

EU/1/14/915/002 (10 hard capsules container)

Ebilfumin 45 mg hard capsules

EU/1/14/915/003 (10 hard capsules container)

EU/1/14/915/004 (10 hard capsules blister)

Ebilfumin 75 mg hard capsules

EU/1/14/915/005 (10 hard capsules blister)

EU/1/14/915/006 (10 hard capsules container)

Date of first authorisation: 22 May 2014

Date of latest renewal: 12 February 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu