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Ebilfumin (oseltamivir) – Summary of product characteristics - J05AH02

Updated on site: 06-Oct-2017

Medication nameEbilfumin
ATC CodeJ05AH02
Substanceoseltamivir
ManufacturerActavis Group PTC ehf

1.NAME OF THE MEDICINAL PRODUCT

Ebilfumin 30 mg hard capsules

Ebilfumin 45 mg hard capsules

Ebilfumin 75 mg hard capsules

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

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.

3.PHARMACEUTICAL FORM

Ebilfumin 30 mg hard capsules

The hard capsule consists of a rich yellow body and cap bearing the black imprint “OS 30”. Capsule size: 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”. Capsule size: 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 “OS 75”. Capsule size: 2

The capsule contains a white granulated powder.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

Treatment of influenza

Ebilfumin is indicated in adults and children including full-term neonates who present with symptoms typical of influenza, when influenza virus is circulating in the community. Efficacy has been demonstrated when treatment is initiated within two days of first onset of symptoms.

Prevention of influenza

-Post-exposure prevention in individuals 1 year of age or older following contact with a clinically diagnosed influenza case when influenza virus is circulating in the community.

-The appropriate use of Ebilfumin for prevention of influenza should be determined on a case by case basis by the circumstances and the population requiring protection. In exceptional situations (e.g. in case of a mismatch between the circulating and vaccine virus strains, and a

pandemic situation) seasonal prevention could be considered in individuals one year of age or older.

-Ebilfumin is indicated for post-exposure prevention of influenza in infants less than 1 year of age 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 of official recommendations. Decisions regarding the use of oseltamivir for treatment and prophylaxis should take into consideration what is known about the characteristics of the circulating influenza viruses, available information on influenza drug susceptibility patterns for each season and the impact of the disease in different geographical areas and patient populations (see section 5.1).

4.2Posology and method of administration

Posology

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

-one 75 mg capsule or

-one 30 mg capsule plus one 45 mg capsule.

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

Adults, and adolescents 13 years and over

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

Body Weight

Recommended dose for 5 days

> 40 kg

75 mg twice daily

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

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

Body Weight

Recommended dose for 10 days

> 40 kg

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 of influenza during a community outbreak is 75 mg oseltamivir once daily for up to 6 weeks.

Paediatric population

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 or older

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

Body Weight

Recommended dose for 5 days

10 kg to 15 kg

30 mg twice daily

> 15 kg to 23 kg

45 mg twice daily

> 23 kg to 40 kg

60 mg twice daily

> 40 kg

75 mg twice daily

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

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

Body Weight

Recommended dose for 10 days

10 kg to 15 kg

30 mg once daily

> 15 kg to 23 kg

45 mg once daily

> 23 kg to 40 kg

60 mg once daily

> 40 kg

75 mg once daily

Prevention during an influenza epidemic in the community: Prevention during an influenza epidemic has 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 months provides plasma concentrations of the pro-drug and active metabolite that are anticipated to be clinically efficacious with a safety profile comparable to that seen in older children and adults (see section 5.2). The following dosing regimen is recommended for treatment of infants 0 - 12 months of age:

Body weight*

Recommended dose for 5 days

 

 

3 kg

9 mg twice daily

 

 

4 kg

12 mg twice daily

5 kg

15 mg twice daily

 

 

6 kg

18 mg twice daily

7 kg

21 mg twice daily

 

 

8 kg

24 mg twice daily

9 kg

27 mg twice daily

 

 

10 kg

30 mg twice daily

* This table is not intended to contain all possible weights for this population. For all patients under the age of 1 year, 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 of influenza.

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 whom different 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 age during a pandemic influenza outbreak is half of the daily treatment dose. This is based upon clinical data in infants and children 1 year of age or older and adults showing that a prophylaxis dose

equivalent to half the daily treatment dose is clinically efficacious for the prevention of influenza. The following 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

0 - 12 months

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 whom different dosing may be 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 0-12 months of age.

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

Special populations

Hepatic impairment

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

Renal impairment

Treatment of influenza: Dose adjustment is recommended for adults and adolescents (13 to 17 years of age) 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 of oseltamivir carboxylate is expected to be higher when automated peritoneal dialysis (APD) mode is used. Treatment mode can be switched from APD to CAPD if considered necessary by a nephrologist.

Prevention of influenza: Dose adjustment is recommended for adults and adolescents (13 to 17 years of 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 of oseltamivir carboxylate is expected to be higher when automated peritoneal dialysis (APD) mode is used. Treatment mode can be switched from APD to CAPD if considered necessary by a nephrologist.

There is insufficient clinical data available in infants and children (12 years of age and younger) with renal impairment to be able to make any dosing recommendation.

Elderly

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

Immunocompromised patients

Longer duration of seasonal prophylaxis up to 12 weeks has been evaluated in immunocompromised patients (see sections 4.4, 4.8 and 5.1).

Method of administration

Oral use.

Patients who are unable to swallow capsules may receive appropriate extemporaneous formulation, see section 6.6 for preparation.

4.3Contraindications

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

4.4Special warnings and precautions for use

Oseltamivir is effective only against illness caused by influenza viruses. There is no evidence for efficacy of oseltamivir in any illness caused by agents other than influenza viruses (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. The protection against influenza lasts only as long as oseltamivir is administered. Oseltamivir should be used for the treatment and prevention of influenza only when reliable epidemiological data indicate that influenza virus is circulating in the community. Susceptibility of circulating influenza virus strains to oseltamivir has been shown to be highly variable (see section 5.1). Therefore, prescribers should take into account the most recent information available on oseltamivir susceptibility patterns of the currently circulating viruses when deciding whether to use oseltamivir.

Severe concomitant condition

No information is available regarding the safety and efficacy of oseltamivir in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalisation.

Immunocompromised patients

The efficacy of oseltamivir in either treatment or prophylaxis of influenza in immunocompromised patients 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 respiratory disease has not been established. No difference in the incidence of complications was observed between the treatment and placebo groups in this population (see section 5.1).

Paediatric population

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

Severe renal impairment

Dose adjustment is recommended for both treatment and prevention in adolescents (13 to 17 years of age) and adults with severe renal impairment. There is insufficient clinical data available in infants and children (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 with influenza, especially in children and adolescents. These events are also experienced by patients with

influenza without oseltamivir administration. Patients should be closely monitored for behavioural changes, and the benefits and risks of continuing treatment should be carefully evaluated for each patient (see section 4.8).

4.5Interaction with other medicinal products and other forms of interaction

Pharmacokinetic properties of oseltamivir, such as low protein binding and metabolism independent of the CYP450 and glucuronidase systems (see section 5.2), suggest that clinically significant drug interactions via these mechanisms are unlikely.

Probenecid

No dose adjustment is required when co-administering with probenecid in patients with normal renal function. Co-administration of probenecid, a potent inhibitor of the anionic pathway of renal tubular secretion, results in an approximate 2-fold increase in exposure to the active metabolite of oseltamivir.

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 the active metabolite (glomerular filtration and anionic tubular secretion) and the excretion capacity of these pathways. However, care should be taken when prescribing oseltamivir in subjects when taking co-excreted agents with a narrow therapeutic margin (e.g. chlorpropamide, methotrexate, phenylbutazone).

Additional information

No pharmacokinetic interactions between oseltamivir or its major metabolite have been observed when co-administering oseltamivir with paracetamol, acetylsalicylic acid, cimetidine, antacids (magnesium and aluminium hydroxides and calcium carbonates), rimantadine or warfarin (in subjects stable on warfarin and without influenza).

4.6Fertility, pregnancy and lactation

Pregnancy

While no controlled clinical studies have been conducted on the use of oseltamivir in pregnant women, data on use in pregnancy has been collected from post-marketing and observational studies (please refer to section 5.1 “Treatment of influenza in pregnant women”; for data on exposure in pregnant women please refer to section 5.2). These data in conjunction with animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal or postnatal development (see section 5.3). Pregnant women may receive oseltamivir, after considering the available safety information, the pathogenicity of the circulating influenza virus strain and the underlying condition of the pregnant woman.

Breastfeeding

In lactating rats, oseltamivir and the active metabolite are excreted in milk. Very limited information is available on children breast-fed by mothers taking oseltamivir and on excretion of oseltamivir in breast milk. Limited data demonstrated that oseltamivir and the active metabolite were detected in breast milk, however the levels were low, which would result in a subtherapeutic dose to the infant. Considering this information, the pathogenicity of the circulating influenza virus strain and the underlying condition of the breastfeeding woman, administration of oseltamivir may be considered, where there are clear potential benefits to breastfeeding mothers.

Fertility

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

4.7Effects on ability to drive and use machines

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

4.8Undesirable effects

Summary of the safety profile

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

In adults/adolescents, the most commonly reported adverse reactions (ARs) were nausea and vomiting in the treatment studies, and nausea in the prevention studies. The majority of these ARs were reported on a single occasion on either the first or second treatment day and resolved spontaneously within 1-2 days. In children, the most commonly reported adverse reaction was vomiting. In the majority of patients, these ARs did not lead to discontinuation of oseltamivir.

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

Tabulated list of adverse reactions

The ARs listed in the tables below fall into the following categories: Very common (≥ 1/10), common

(≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000). ARs are added to the appropriate category in the tables according to the pooled analysis from clinical studies.

Treatment and prevention of influenza in adults and adolescents:

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

The safety profile reported in subjects who received the recommended dose of oseltamivir 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 oseltamivir for treatment and prevention of influenza 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 respiratory

 

 

 

 

tract infections,

 

 

 

 

Sinusitis

 

 

 

 

 

Blood and

 

 

 

Thrombocytopenia

lymphatic

 

 

 

 

system disorders

 

 

 

 

Immune system

 

 

Hypersensitivity

Anaphylactic

disorders

 

 

reaction

reactions,

 

 

 

 

Anaphylactoid

 

 

 

 

reactions

Psychiatric

 

 

 

Agitation,

disorders

 

 

 

Abnormal behaviour,

 

 

 

 

Anxiety,

 

 

 

 

Confusion,

 

 

 

 

Delusions, Delirium,

 

 

 

 

Hallucination,

 

 

 

 

Nightmares,

 

 

 

 

Self-injury

Nervous system

Headache

Insomnia

Altered level of

 

disorders

 

 

consciousness,

 

 

 

 

Convulsion

 

Eye disorders

 

 

 

Visual disturbance

Cardiac

 

 

Cardiac

 

disorders

 

 

arrhythmia

 

Respiratory,

 

Cough,

 

 

thoracic and

 

Sore throat,

 

 

mediastinal

 

Rhinorrhea

 

 

disorders

 

 

 

 

Gastrointestinal

Nausea

Vomiting

 

Gastrointestinal

disorders

 

Abdominal pain

 

bleedings,

 

 

(incl. upper

 

Haemorrhagic

 

 

abdominal pain),

 

colitis

 

 

Dyspepsia

 

 

Hepatobiliary

 

 

Elevated liver

Fulminant hepatitis,

disorders

 

 

enzymes

Hepatic failure,

 

 

 

 

Hepatitis

Skin and

 

 

Eczema,

Angioneurotic

subcutaneous

 

 

Dermatitis, Rash,

oedema,

tissue disorders

 

 

Urticaria

Erythema

 

 

 

 

multiforme,

 

 

 

 

Stevens-Johnson

 

 

 

 

syndrome,

 

 

 

 

Toxic epidermal

 

 

 

 

necrolysis

General

 

Pain

 

 

disorders 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 asthmatic children aged 6-12 years old) participated in clinical studies of oseltamivir given for the treatment of influenza. Of those, 851 children received treatment with oseltamivir suspension. A total of 158 children received the recommended dose of oseltamivir once daily in a post-exposure prophylaxis study 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 and prevention of influenza 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

 

 

Headache

 

 

disorders

 

 

 

 

 

Eye disorders:

 

 

Conjunctivitis

 

 

 

 

 

(including red

 

 

 

 

 

eyes, eye

 

 

 

 

 

discharge and eye

 

 

 

 

 

pain)

 

 

Ear and

 

 

Earache

Tympanic

 

labyrinth

 

 

 

membrane disorder

 

disorders:

 

 

 

 

 

Respiratory,

Cough,

 

Rhinorrhoea

 

 

thoracic and

Nasal congestion

 

 

 

 

mediastinal

 

 

 

 

 

disorders

 

 

 

 

 

Gastrointestinal

Vomiting

 

Abdominal pain

 

 

disorders

 

 

(incl. upper

 

 

 

 

 

abdominal pain),

 

 

 

 

 

Dyspepsia,

 

 

 

 

 

Nausea

 

 

Skin and

 

 

 

Dermatitis

 

subcutaneous

 

 

 

(including allergic

 

tissue disorders

 

 

 

and atopic

 

 

 

 

 

dermatitis)

 

Description of selected adverse reactions

 

 

Psychiatric disorders and nervous system disorders

Influenza can be associated with a variety of neurologic and behavioural symptoms which can include events such as hallucinations, delirium, and abnormal behaviour, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease.

In patients with influenza who were receiving oseltamivir, there have been postmarketing reports of convulsions and delirium (including symptoms such as altered level of consciousness, confusion, abnormal behaviour, delusions, hallucinations, agitation, anxiety, nightmares), in a very few cases resulting in self-injury or fatal outcomes. These events were reported primarily among paediatric and adolescent patients and often had an abrupt onset and rapid resolution. The contribution of oseltamivir to those events is unknown. Such neuropsychiatric events have also been reported in patients with influenza who were not taking oseltamivir.

Hepato-biliary disorders

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

Other special populations

Paediatric population (infants less than one year of age)

In two studies to characterise the pharmacokinetics, pharmacodynamics and safety profile of oseltamivir therapy in 135 influenza infected children less than one year of age, the safety profile was similar among age cohorts with vomiting, diarrohea and diaper rash being the most frequently reported 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 less than one year of age from prospective and retrospective observational studies (comprising together more than 2,400 infants of that age class), epidemiological databases research and postmarketing reports suggest that the safety profile in infants less than one year of age is similar to the established safety profile of children aged one year and older.

Older people and patients with chronic cardiac and/or respiratory disease

The population included in the influenza treatment studies is comprised of otherwise healthy adults/adolescents and patients “at risk” (patients at higher risk of developing complications associated with influenza, e.g. 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 healthy adults/adolescents.

Immunocompromised patients

In a 12-week prophylaxis study in 475 immunocompromised patients, including 18 children 1 to 12 years of age and older, the safety profile in the 238 patients who received oseltamivir was consistent with 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 qualitatively similar to that of otherwise healthy children.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9Overdose

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 observed with therapeutic doses of oseltamivir, described in section 4.8 Undesirable effects.

No specific antidote is known.

Paediatric population

Overdose has been reported more frequently for children than adults and adolescents. Caution should be exercised when preparing oseltamivir oral suspension and when administering oseltamivir products to children.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic 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 active metabolite is a selective inhibitor of influenza virus neuraminidase enzymes, which are glycoproteins found on the virion surface. Viral neuraminidase enzyme activity is important both for viral entry into uninfected cells and for the release of recently formed virus particles from infected cells, and for the further spread of infectious virus in the body.

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

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

Neuraminidase enzyme IC50 values for oseltamivir for clinically isolated influenza A ranged from

0.1 nM to 1.3 nM, and for influenza B was 2.6 nM. Higher IC50 values for influenza B, up to a median of 8.5 nM, have been observed in published studies.

Clinical studies

Treatment of influenza infection

The indication is based on clinical studies of naturally occurring influenza in which the predominant infection 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 pooled treatment study population, which included both influenza-positive and -negative subjects (ITT), primary efficacy was reduced proportionally to the number of influenza-negative individuals. In the overall treatment population, influenza infection was confirmed in 67 % (range 46 % to 74 %) of the recruited patients. Of the older subjects, 64 % were influenza-positive and of those with chronic cardiac and/or respiratory disease 62 % were influenza-positive. In all phase III treatment studies, patients were recruited only during the period in which influenza was circulating in the local community.

Adults and adolescents 13 years of age and older: Patients were eligible if they reported within 36 hours of onset of symptoms, had fever ≥ 37.8 °C, accompanied by at least one respiratory symptom (cough, nasal symptoms or sore throat) and at least one systemic symptom (myalgia, chills/sweats, malaise, fatigue or headache). In a pooled analysis of all influenza-positive adults and adolescents (N = 2,413) enrolled into treatment studies, oseltamivir 75 mg twice daily for 5 days reduced the median duration of influenza illness by approximately one day from 5.2 days (95 % CI 4.9 – 5.5 days) in the placebo group to 4.2 days (95 % CI 4.0 – 4.4 days; p ≤ 0.0001).

The proportion of subjects who developed specified lower respiratory tract complications (mainly bronchitis) treated with antibiotics was reduced from 12.7 % (135/1,063) in the placebo group to 8.6 % (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 older subjects (≥ 65 years) and in subjects with chronic cardiac and/or respiratory disease receiving oseltamivir 75 mg twice daily for 5 days was not reduced significantly. The total duration of fever was reduced by one day in the groups treated with oseltamivir. In 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 incidence of lower respiratory tract complications (mainly bronchitis) treated with antibiotics was 17 % (22/133) in the placebo group and 14 % (16/118) in the oseltamivir treated population (p = 0.5976).

Treatment of influenza in pregnant women: No controlled clinical studies have been conducted on the use of oseltamivir in pregnant women, however, there is evidence from post-marketing and retrospective observational studies showing benefit of the current dosing regimen in this patient population in terms of lower morbidity/mortality. Results from pharmacokinetic analyses indicate a lower exposure to the active metabolite, however dose adjustments are not recommended for pregnant women 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. Oseltamivir treatment, started within 48 hours of onset of symptoms, significantly reduced the time to freedom from illness (defined as the simultaneous return to normal health and activity and alleviation of fever, cough and coryza) by 1.5 days (95 % CI 0.6 – 2.2 days; p < 0.0001) compared to placebo. Oseltamivir reduced the incidence of acute otitis media from 26.5 % (53/200) in the placebo group to 16 % (29/183) in the oseltamivir treated children (p = 0.013).

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

treated group compared to 4.7 % on placebo (p = 0.0148) in this population.

The European Medicines Agency has deferred the obligation to submit the results of studies with oseltamivir in one or more subsets of the paediatric population in influenza. See section 4.2 for information on paediatric use.

The indication in infants below the age of 1 is based upon extrapolation of efficacy data from older 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 by influenza B, proportions ranging from 1 to 33 % in individual studies. The median duration of illness in influenza B infected subjects did not differ significantly between the treatment groups in individual studies. Data from 504 influenza B infected subjects were pooled across all studies for analysis. Oseltamivir reduced the time to alleviation of all symptoms by 0.7 days (95 % CI 0.1 – 1.6 days; p = 0.022) and the duration of fever (≥ 37.8 °C), cough and coryza by one day (95 % CI 0.4 – 1.7 days; p < 0.001) compared to placebo.

Prevention of influenza

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

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

of true influenza cases was 10 (95 % CI 9 – 12) and was 16 (95 % CI 15 – 19) in the whole population (ITT) regardless of infection status in the index case.

The efficacy of oseltamivir in preventing naturally occurring influenza illness has been demonstrated in a post-exposure prevention study in households that included adults, adolescents, and children aged 1 to 12 years, both as index cases and as family contacts. The primary efficacy parameter for this study was the incidence of laboratory-confirmed clinical influenza in the households. Oseltamivir prophylaxis lasted for 10 days. In the total population, there was a reduction in the incidence of laboratory-confirmed clinical influenza in households from 20 % (27 / 136) in the group not receiving prevention to 7 % (10 / 135) in the group receiving prevention (62.7 % reduction [95 % CI 26.0 – 81.2; p = 0.0042]). In households of influenza-infected index cases, there was a reduction in the incidence of influenza from 26 % (23 / 89) in the group not receiving prevention to 11 % (9 / 84) in the group receiving prevention (58.5 % reduction [95 % CI 15.6 – 79.6; p = 0.0114]). According to subgroup analysis in children at 1 to 12 years of age, the incidence of laboratory-confirmed clinical influenza among children was significantly reduced from 19 % (21 / 111) in the group not receiving prevention to 7 % (7 / 104) in the group receiving prevention (64.4 % reduction [95 % CI 15.8 – 85.0; p = 0.0188]). Among children who were not already shedding virus at baseline, the incidence of laboratory-confirmed clinical influenza was reduced from 21 % (15 / 70) in the group not receiving prevention to 4 % (2 / 47) in the group receiving prevention (80.1 % reduction [95 % CI 22.0 – 94.9; p = 0.0206]). The NNT for the total paediatric population was 9 (95 % CI 7 – 24) and 8 (95 % CI 6, upper limit not estimable) in the whole population (ITT) and in paediatric contacts of infected index cases (ITTII), respectively.

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 children 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 studies conducted in unvaccinated otherwise healthy adults, oseltamivir 75 mg once daily given for 6 weeks significantly reduced the incidence of clinical influenza illness from 25 /519 (4.8 %) in the placebo group to 6/520 (1.2 %) in the oseltamivir group (76 % reduction [95 % CI 1.6 – 5.7; p = 0.0006]) during a community outbreak of influenza. The NNT in this study was 28 (95 % CI 24 – 50). A study in older people in nursing homes, where 80 % of participants received vaccine in the season of the study, oseltamivir 75 mg once daily given for 6 weeks significantly reduced the incidence of clinical influenza illness from 12/272 (4.4 %) in the placebo group to 1/276 (0.4 %) in the oseltamivir group (92 % reduction [95 % CI 1.5 – 6.6; p = 0.0015]). The NNT in this study was 25 (95 % CI 23 – 62).

Prophylaxis of influenza in immunocompromised patients: A double-blind, placebo-controlled, randomised study was conducted for seasonal prophylaxis of influenza in 475 immunocompromised patients (388 patients with solid organ transplantation [195 placebo; 193 oseltamivir], 87 patients with haemopoetic stem cell transplantation [43 placebo; 44 oseltamivir], no patient with other immunosuppressant conditions), including 18 children 1 to 12 years of age. The primary endpoint in this study was the incidence of laboratory-confirmed clinical influenza as determined by viral culture and/or a four-fold rise in HAI antibodies. The incidence of laboratory-confirmed clinical influenza was 2.9 % (7/238) in the placebo group and 2.1 % (5/237) in the oseltamivir group (95 % CI -2.3 % –

4.1 %; p = 0.772).

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

Oseltamivir resistance

Clinical studies: The risk of emergence of influenza viruses with reduced susceptibility or frank resistance to oseltamivir has been examined during Roche-sponsored clinical studies. Developing oseltamivir-resistant virus during treatment was more frequent in children than adults, ranging from less than 1% in adults to 18% in infants aged below 1 year. Children who were found to carry oseltamivir-resistant virus in general shed the virus for a prolonged period compared with subjects

with susceptible virus. However treatment-emergent resistance to oseltamivir did not affect treatment response and caused no prolongation of influenza symptoms.

Patient Population

Patients with Resistance Mutations (%)

Phenotyping*

Geno- and Phenotyping*

Adults and adolescents

0.62% (14/2253)

0.67% (15/2253)

 

 

 

Children (1-12 years)

3.89% (66/1698)

4.24% (72/1698)

Infants (<1year)

18.31% (13/71)

18.31% (13/71)

* Full genotyping was not performed in all studies.

There has been no evidence for emergence of drug resistance associated with the use of oseltamivir in clinical studies conducted to date in post-exposure (7 days), post-exposure within household groups (10 days) and seasonal (42 days) prevention of influenza in immunocompetent patients. There was no resistance observed during a 12-week prophylaxis study in immunocompromised patients.

Clinical and surveillance data: Natural mutations associated with reduced susceptibility to oseltamivir in vitro have been detected in influenza A and B viruses isolated from patients without exposure to oseltamivir. Resistant strains selected during oseltamivir treatment have been isolated from both immunocompetent and immunocompromised patients. Immunocompromised patients and young children are at a higher risk of developing oseltamivir-resistant virus during treatment.

Oseltamivir-resistant viruses isolated from oseltamivir-treated patients and oseltamivir-resistant laboratory strains of influenza viruses have been found to contain mutations in N1 and N2 neuraminidases. Resistance mutations tend to be viral sub-type specific. Since 2007 naturally occurring resistance 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 and geographically. In 2008, H275Y was found in > 99 % of circulating H1N1 influenza isolates in Europe. The 2009 H1N1 influenza (“swine flu”) was almost uniformly susceptible to oseltamivir, with only sporadic reports of resistance in connection with both therapeutic and prophylactic regimens.

5.2Pharmacokinetic properties

General Information

Absorption

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

Distribution

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

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

Biotransformation

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

Elimination

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

Other special populations

Paediatric population

Infants less than 1 year of age: The pharmacokinetics, pharmacodynamics and safety of oseltamivir have been evaluated in two uncontrolled open-label studies including influenza infected children less than 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 the youngest 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 a safety profile comparable to that seen in older children and adults using the approved dose (see sections 4.1 and 4.2). 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 12 years 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 or higher than for once daily dosing of 75 mg in adults. Exposure does not exceed that for treatment of infants < 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 evaluated in 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 clinical efficacy study. Younger children cleared both the pro-drug and its active metabolite faster than adults, resulting in a lower exposure for a given mg/kg dose. Doses of 2 mg/kg give oseltamivir carboxylate exposures comparable to those achieved in adults receiving a single 75 mg dose (approximately 1 mg/kg). The pharmacokinetics of oseltamivir in children and adolescents 12 years of age or older are similar to those in adults.

Elderly

Exposure to the active metabolite at steady state was 25 to 35 % higher in older people (age 65 to 78 years) compared to adults less than 65 years of age given comparable doses of oseltamivir. Half-lives observed in older people were similar to those seen in young adults. On the basis of drug exposure and tolerability, dosage adjustments are not required for older people unless there is evidence of moderate or severe renal impairment (creatinine clearance below 60 ml /min) (see section 4.2).

Renal impairment

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

Hepatic impairment

In vitro studies have concluded that exposure to oseltamivir is not expected to be increased significantly nor is exposure to the active metabolite expected to be significantly decreased in patients with hepatic impairment (see section 4.2).

Pregnant Women

A pooled population pharmacokinetic analysis indicates that the Ebilfumin dosage regimen described in Section 4.2 Posology and method of administration results in lower exposure (30% on average across all trimesters) to the active metabolite in pregnant women compared to

non-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 is evidence from observational studies showing benefit of the current dosing regimen in this patient population. Therefore, dose adjustments are not recommended for pregnant women in the treatment or prophylaxis of influenza (see section 4.6 Fertility, pregnancy and lactation).

5.3Preclinical safety data

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

Teratology studies have been conducted in rats and rabbits at doses of up to 1,500 mg/kg/day and 500 mg/kg/day, respectively. No effects on foetal development were observed. A rat fertility study up to a dose of 1,500 mg/kg/day demonstrated no adverse reactions on either sex. In pre- and post-natal rat studies, prolonged parturition was noted at 1,500 mg/kg/day: the safety margin between human exposure and the highest no-effect dose (500 mg/kg/day) in rats is 480-fold for oseltamivir and 44-fold for the active metabolite, respectively. Foetal exposure in the rats and rabbits was approximately 15 to 20 % of that of the mother.

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

A potential for skin sensitisation to oseltamivir was observed in a "maximisation" test in guinea pigs. Approximately 50 % of the animals treated with the unformulated active substance showed erythema after challenging the induced animals. Reversible irritancy of rabbits' eyes was detected.

Whereas very high oral single doses of oseltamivir phosphate salt, up to the highest dose tested (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. At 500 mg/kg, no adverse reactions were seen, including upon chronic treatment (500 mg/kg/day administered from 7 to 21 days post partum).

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Ebilfumin 30 mg hard capsules

Capsule core

Pregelatinised starch (derived from maize starch)

Talc

Povidone (K-29/32)

Croscarmellose sodium

Sodium stearyl fumarate

Capsule shell

Gelatin

Yellow iron oxide (E172)

Titanium dioxide (E171)

Printing ink

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

Capsule shell

Gelatin

Titanium dioxide (E171)

Printing ink

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

Capsule shell

Cap:

Gelatin

Yellow iron oxide (E172)

Titanium dioxide (E171)

Body:

Gelatin

Titanium dioxide (E171)

Printing ink

Shellac Glaze-45% (20% esterified)

Black iron oxide (E172)

Propylene glycol (E1520)

Ammonium hydroxide 28% (E527)

6.2Incompatibilities

Not applicable.

6.3Shelf life

5 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.

6.4Special precautions for storage

Store below 25 C.

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

6.5Nature and contents of container

PVC/PE/PVdC/Al blisters or HDPE containers with LDPE lid (and a desiccant). Pack-size 10 capsules.

6.6Special precautions for disposal and other handling

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

Extemporaneous formulation

When oseltamivir powder for oral suspension is not available

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

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

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

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 intact capsules

This procedure describes the preparation of a 6 mg/ml suspension that will provide one patient with enough medicine for a 5-day course of treatment or a 10-day course of prophylaxis.

The pharmacist may compound a 6 mg/ml suspension from Ebilfumin 30 mg, 45 mg or 75 mg capsules 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 of treatment or a 10-day course of prophylaxis for the patient. The total volume required is determined by the weight of the patient according to the recommendation in the table below. To allow for accurate

volume withdrawal of up to 10 doses (2 withdrawals per daily treatment dose for 5 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’s weight

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

10 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.

Second, determine the number of capsules and the amount of vehicle (water containing 0.05 % w/v sodium benzoate added as a preservative) that is needed to prepare the total volume (calculated from 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 a pharmacy compounded 6 mg/ml suspension

Total volume

Required number of Ebilfumin capsules

 

of compounded

 

(mg of oseltamivir)

 

 

suspension

 

 

 

Required volume

to be prepared

75 mg

45 mg

30 mg

of vehicle

60 ml

Please use

8 capsules

12 capsules

59.5 ml

 

alternative

(360 mg)

(360 mg)

 

 

capsule

 

 

 

 

strength*

 

 

 

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 ml

 

alternative

(540 mg)

(540 mg)

 

 

capsule

 

 

 

 

strength*

 

 

 

100 ml

8 capsules

Please use

20 capsules

98.5 ml

 

(600 mg)

alternative

(600 mg)

 

 

 

capsule

 

 

 

 

strength*

 

 

125 ml

10 capsules

Please use

 

123.5 ml

 

(750 mg)

alternative

25 capsules

 

 

 

capsule

(750 mg)

 

 

 

strength*

 

 

137.5 ml

11 capsules

Please use

Please use

136 ml

 

(825 mg)

alternative

alternative

 

 

 

capsule

capsule

 

 

 

strength*

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.

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/v sodium benzoate added as a preservative.

2.Open the stated amount of Ebilfumin capsules and transfer the content of each capsule directly to 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 is caused 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 to minimise the tendency for air entrapment.)

7.Instruct the parent or caregiver that any remaining material following completion of therapy must be discarded. It is recommended that this information be provided by either affixing an ancillary 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 local pharmacy regulations. Refer to the table below for the proper dosing instructions.

Dosing chart for pharmacy-compounded 6 mg/ml suspension prepared from Ebilfumin capsules for infants and children 1 year of age or older

Body weight

Dose

Volume per dose

Treatment dose

Prophylaxis dose

(kg)

(mg)

6 mg/ml

(for 5 days)

(for 10 days)

10 kg to 15 kg

30 mg

5 ml

5 ml twice daily

5 ml once daily

> 15 kg to 23 kg

45 mg

7.5 ml

7.5 ml twice daily

7.5 ml once daily

> 23 kg to 40 kg

60 mg

10 ml

10 ml twice daily

10 ml once daily

> 40 kg

75 mg

12.5 ml

12.5 ml twice daily

12.5 ml once daily

Dispense the pharmacy compounded suspension with a graduated oral syringe for measuring small amounts of suspension. If possible, mark or highlight the graduation corresponding to the appropriate dose (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, such as sugar water, chocolate syrup, cherry syrup, dessert toppings (like caramel or fudge sauce) to mask the bitter taste.

Infants less than 1 year of age

This procedure describes the preparation of a 6 mg/ml suspension that will provide one patient with enough medication for a 5-day course of treatment or a 10-day course of prophylaxis.

The pharmacist may compound a 6 mg/ml suspension from Ebilfumin 30 mg, 45 mg or 75 mg capsules 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 total volume required is determined by the weight of the patient according to the recommendation in the table below. To allow for accurate volume withdrawal of up to 10 doses (2 withdrawals per daily treatment dose for 5 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’s weight

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.

Second, determine the number of capsules and the amount of vehicle (water containing 0.05 % w/v sodium benzoate added as a preservative) that is needed to prepare the total volume (calculated from 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 a pharmacy compounded 6 mg/ml suspension

Total volume

Required number of Ebilfumin capsules

 

of compounded

 

(mg of oseltamivir)

 

 

suspension

 

 

 

Required volume

to be prepared

75 mg

45 mg

30 mg

of vehicle

50 ml

4 capsules

Please use

10 capsules

49.5 ml

 

(300 mg)

alternative

(300 mg)

 

 

 

capsule

 

 

 

 

strength*

 

 

60 ml

Please use

8 capsules

12 capsules

59.5 ml

 

alternative

(360 mg)

(360 mg)

 

 

capsule

 

 

 

 

strength*

 

 

 

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.

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/v sodium benzoate added as a preservative.

2.Open the stated amount of Ebilfumin capsules and transfer the content of each capsule directly to 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 is caused 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 to minimise the tendency for air entrapment.)

7.Instruct the parent or caregiver that any remaining material following completion of therapy must be discarded. It is recommended that this information be provided by either affixing an ancillary 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 local pharmacy regulations. Refer to the table below for the proper dosing instructions.

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

Body

 

 

 

 

 

Weight

 

 

 

 

 

(rounded to

 

Volume

 

 

Dispenser size

the nearest

Dose

per dose

Treatment Dose

Prophylaxis Dose

to use

0.5 kg)

(mg)

(6 mg/ml)

(for 5 days)

(for 10 days)

(grading 0.1 ml)

3 kg

9 mg

1.5 ml

1.5 ml twice daily

1.5 ml once daily

2.0 ml (or 3.0 ml)

3.5 kg

10.5 mg

1.8 ml

1.8 ml twice daily

1.8 ml once daily

2.0 ml (or 3.0 ml)

4 kg

12 mg

2.0 ml

2.0 ml twice daily

2.0 ml once daily

3.0 ml

4.5 kg

13.5 mg

2.3 ml

2.3 ml twice daily

2.3 ml once daily

3.0 ml

5 kg

15 mg

2.5 ml

2.5 ml twice daily

2.5 ml once daily

3.0 ml

5.5 kg

16.5 mg

2.8 ml

2.8 ml twice daily

2.8 ml once daily

3.0 ml

6 kg

18 mg

3.0 ml

3.0 ml twice daily

3.0 ml once daily

3.0 ml (or 5.0 ml)

6.5 kg

19.5 mg

3.3 ml

3.3 ml twice daily

3.3 ml once daily

5.0 ml

7 kg

21 mg

3.5 ml

3.5 ml twice daily

3.5 ml once daily

5.0 ml

7.5 kg

22.5 mg

3.8 ml

3.8 ml twice daily

3.8 ml once daily

5.0 ml

8 kg

24 mg

4.0 ml

4.0 ml twice daily

4.0 ml once daily

5.0 ml

8.5 kg

25.5 mg

4.3 ml

4.3 ml twice daily

4.3 ml once daily

5.0 ml

9 kg

27 mg

4.5 ml

4.5 ml twice daily

4.5 ml once daily

5.0 ml

9.5 kg

28.5 mg

4.8 ml

4.8 ml twice daily

4.8 ml once daily

5.0 ml

10 kg

30 mg

5.0 ml

5.0 ml twice daily

5.0 ml once daily

5.0 ml

Dispense the pharmacy compounded suspension with a graduated oral syringe for measuring small amounts of suspension. If possible, mark or highlight the graduation corresponding to the appropriate 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) to mask the bitter taste.

Home preparation

When commercially manufactured oseltamivir powder for oral suspension is not available, a pharmacy compounded suspension prepared from Ebilfumin capsules must be used (see detailed instructions above). If the commercially manufactured oseltamivir powder for oral suspension and the pharmacy compounded suspension is also not available, Ebilfumin suspension may be prepared at home.

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

When only 75 mg capsules are available, and doses of 30 mg or 45 mg are needed, the preparation of Ebilfumin suspension involves additional steps. Detailed instructions can be found in the package leaflet of Ebilfumin capsules under “Making liquid Ebilfumin at home”.

7.MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf. Reykjavíkurvegi 76-78 220 Hafnarfjörður Iceland

8.MARKETING AUTHORISATION NUMBER(S)

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)

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 22 May 2014

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

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