Treatment of influenza

Oselow 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 Oselow 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.

-        Oselow 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).

Oselow 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).

Oselow hard capsules 75 mg doses can be administered as a single capsule of 75 mg.

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.

* 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

of influenza.

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

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 phosphate USP once daily for up to 6 weeks (or up to 12 weeks in immunocompromised patients, see sections 4.4, 4.8 and 5.1).

Paediatric population Children 1 to 12 years of age

Oselow 75 mg capsule can be used to make a solution for appropriate dosing 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:

*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 of influenza.

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

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:

* 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.

** 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 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):

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

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.

*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.

*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, 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

Treatment: For treatment of influenza, the recommended duration for immunocompromised patients is 10 days (see sections 4.4, 4.8 and 5.1). No dose adjustment is necessary. Treatment should 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 evaluated in immunocompromised patients (see sections 4.4, 4.8 and 5.1).

Method of administration Oral use.

Oseltamivir phosphate 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).

Oselow is not a substitute for influenza vaccination. Use of Oselow must not affect the evaluation of individuals for annual influenza vaccination. The protection against influenza lasts only as long as Oselow is administered. Oselow 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 phosphate 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 Oselow.

Severe concomitant condition

No information is available regarding the safety and efficacy of oseltamivir phosphate 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 phosphate 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 phosphate 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 phosphate administration. Patients should be closely monitored for behavioural changes, and the benefits and risks of continuing treatment should be carefully evaluated for each patient (see section 4.8).

Pharmacokinetic properties of oseltamivir phosphate, 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 phosphate has no kinetic interaction with amoxicillin, which is eliminated via the same pathway, suggesting that oseltamivir phosphate 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 phosphate in subjects when taking co-excreted agents with a narrow therapeutic margin (e.g. chlorpropamide, methotrexate, phenylbutazone).

Additional information

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

Pregnancy

Influenza is associated with adverse pregnancy and foetal outcomes, with a risk of major congenital malformations, including congenital heart defects. A large amount of data on oseltamivir phosphate exposure of pregnant women from post-marketing reports and observational studies (more than 1000 exposed outcomes during the first trimester) indicate no malformative nor feto/neonatal toxicity by oseltamivir phosphate.

However, in one observational study, while the overall malformation risk was not increased, the results for major congenital heart defects diagnosed within 12 months of birth were not conclusive. In this study, the rate of major congenital heart defects following oseltamivir phosphate exposure during the first trimester was 1.76% (7 infants out of 397 pregnancies) compared to 1.01% in unexposed pregnancies from the general population (Odds Ratio 1.75, 95% Confidence Interval 0.51 to 5.98). The clinical significance of this finding is not clear, as the study had limited power. Additionally, this study was too small to reliably assess individual types of major malformations; moreover women exposed to oseltamivir phosphate and women unexposed could not be made fully comparable, in particular whether or not they had influenza. Animal studies do not indicate reproductive toxicity (see section 5.3).

The use of Oselow may be considered during pregnancy if necessary and after considering the available safety and benefit information (for data on benefit in pregnant women please refer to section 5.1 “treatment of influenza in pregnant women”), and the pathogenicity of the circulating influenza virus strain.

Breastfeeding

In lactating rats, oseltamivir phosphate and the active metabolite are excreted in milk. Very limited information is available on children breast-fed by mothers taking oseltamivir phosphate and on excretion of oseltamivir phosphate in breast milk. Limited data demonstrated that oseltamivir phosphate 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 phosphate may be considered, where there are clear potential benefits to breastfeeding mothers.

Fertility

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

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

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, 245 immunocompromised patients (including 7 adolescents and 39 children) received Oseltamivir for the treatment of influenza and 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 phosphate 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

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 phosphate given for the treatment of influenza. Of those, 851 children received treatment with oseltamivir phosphate. 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 [75 mg o.d.])

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 Oselow to those events is unknown. Such neuropsychiatric events have also been reported in patients with influenza who were not taking Oselow.

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 phosphate 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 phosphate 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

The treatment of influenza in immunocompromised patients were evaluated in two studies receiving standard dose or high dose regimens (double dose or triple dose) of oseltamivir (see section 5.1). The safety profile of oseltamivir observed in these studies was consistent with that observed in previous clinical 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 reaction reported in immunocompromised children was vomiting (28%).

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 phosphate 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 to the competent authority in Saudi Arabia as per details below:

•  Saudi Arabia

The National Pharmacovigilance Centre (NPC)

-       SFDA Call Centre: 19999

-       E-mail: npc.drug@sfda.gov.sa

-       Website: https://ade.sfda.gov.sa/

•  Other GCC States:

•        Please contact the relevant competent authority.

Reports of overdoses with oseltamivir have been received from clinical trials and during postmarketing 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.

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 phosphate 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 phosphate was supported for influenza A and B by experimental challenge studies in healthy volunteers.

Neuraminidase enzyme IC50 values for oseltamivir phosphate 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 phosphate 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 phosphate 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 phosphate 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 phosphate 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 phosphate. In influenza-positive older people, oseltamivir phosphate 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 phosphate 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 phosphate treated population (p = 0.5976).

Treatment of influenza in pregnant women: No controlled clinical studies have been conducted on the use of oseltamivir phosphate in pregnant women, however, there is evidence from postmarketing 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 % influenzapositive) 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 phosphate 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 phosphate reduced the incidence of acute otitis media from 26.5 % (53/200) in the placebo group to 16 % (29/183) in the oseltamivir phosphate 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 phosphate 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 phosphate treated group compared to 4.7 % on placebo (p = 0.0148) in this population.

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 phosphate 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, to evaluate safety and characterize the effects of oseltamivir phosphate on the development of resistant influenza virus (primary analysis) in influenza-infected immunocompromised patients, included 151 adult patients, 7 adolescents and 9 children evaluable for efficacy of oseltamivir phosphate (secondary analysis, not powered). The study included solid organ transplant [SOT] patients, haematopoietic stem cell transplant [HSCT] patients, HIV positive patients with a CD4+ cell count <500 cells/mm3, patients on systemic immunosuppressive therapy, and those with hematological malignancy. These patients were randomized to be treated, within 96 hours of symptoms onset for a duration of 10 days. The treatment regimens were: standard dose (75mg or weight adjusted dose for children) twice daily (73 adult patients, 4 adolescent patients and 4 children) or double dose (150 mg or weight-adjusted dose for children) twice daily (78 adult patients, 3 adolescent patients and 5 children) of oseltamivir phosphate.

The median time to resolution of symptoms (TTRS) for adults and adolescents was similar between the 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 small sample size. The proportion of adult patients with secondary infections in the standard dose group and double dose group was comparable (8.2% vs 5.1%). For adolescents and children, only one patient (an adolescent) in the standard dose group experienced a secondary infection (bacterial sinusitis).

A pharmacokinetics and pharmacodynamics study was conducted in severely immunocompromised children (≤12 years of age, n=30) receiving standard (75 mg or weight adjusted twice daily) vs. triple dose (225 mg or weight adjusted twice daily) oseltamivir phosphate for an adaptive dosing period of 5 to 20 days dependant on duration of viral shedding (mean treatment duration: 9 days). No patients in the standard dose group and 2 patients in the triple dose group reported secondary bacterial infections (bronchitis and sinusitis).

Prevention of influenza

The efficacy of oseltamivir phosphate 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 phosphate 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 phosphate 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 phosphate 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 phosphate 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 phosphate 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 laboratoryconfirmed 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 phosphate 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 phosphate 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 phosphate 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 phosphate], 87 patients with haemopoetic stem cell transplantation [43 placebo; 44 oseltamivir phosphate], 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 phosphate 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 phosphate resistance

Clinical studies: The risk of emergence of influenza viruses with reduced susceptibility or frank resistance to oseltamivir phosphate has been examined during Roche-sponsored clinical studies. Developing oseltamivir phosphate-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 phosphate-resistant virus in general shed the virus for a prolonged period compared with subjects with susceptible virus. However, treatment-emergent resistance to oseltamivir phosphate did not affect treatment response and caused no prolongation of influenza symptoms.

An overall higher incidence of oseltamivir phosphate-resistance was observed in adult and adolescent immunocompromised patients treated with standard dose or double dose of oseltamivir phosphate for a duration of 10 days [14.5% (10/69) in standard dose group and 2.7% (2/74) in double dose group], compared to data from studies with oseltamivir phosphatetreated otherwise healthy adult and adolescent patients. The majority of adult patients that developed resistance were transplant recipients (8/10 patients in the standard dose group and 2/2 patients in the double dose group). Most of the patients with oseltamivir phosphate-resistant virus were infected with influenza type A and had prolonged viral shedding.

The incidence of oseltamivir phosphate-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 the six immunocompromised children found with treatment-emergent resistance to oseltamivir phosphate, 3 patients received standard dose and 3 patients high dose (double or triple dose). The majority had acute lymphoid leukemia and were ≤ 5 years of age.

Incidence of Oseltamivir Phosphate Resistance in Clinical Studies

* 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 Oselow 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 phosphate in vitro have been detected in influenza A and B viruses isolated from patients without exposure to oseltamivir phosphate. Resistant strains selected during oseltamivir phosphate 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 phosphate-resistant viruses isolated from oseltamivir phosphate-treated patients and oseltamivir phosphate-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 phosphate 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 phosphate, with only sporadic reports of resistance in connection with both therapeutic and prophylactic regimens.

General Information

Absorption

Oseltamivir phosphate 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 prodrug 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 phosphate 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 phosphate 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 (18.8l/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 phosphate have been evaluated in single-dose pharmacokinetic studies in infants, children and adolescents 1 to 16 years of age. Multiple-dose pharmacokinetics was 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 phosphate 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 phosphate. 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 phosphate 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 oseltamivir 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 nonpregnant women. The lower predicted exposure however, remains above inhibitoy 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).

Immunocompromised Patients

Population pharmacokinetic analyses indicate that treatment of adult and paediatric (<18 years old) immunocompromised patients with oseltamivir phosphate (as described in Section 4.2. Posology and method of administration) results in an increased predicted exposure (from approximately 5% up to 50%) to the active metabolite when compared to nonimmunocompromised patients with comparable creatinine clearance. Due to the wide safety margin of the active metabolite, no dose adjustments are required in patients due to their immunocompromised status. However, for immunocompromised patients with renal impairment, doses should be adjusted as outlined in section 4.2. Posology and method of administration.

Pharmacokinetic and pharmacodynamic analyses from two studies in immunocompromised patients indicated that there was no meaningful additional benefit in exposures higher than those achieved after the administration of the standard dose.

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 benefitrisk 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 phosphate 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 phosphate and the active metabolite are excreted in the milk. Limited data indicate that oseltamivir phosphate 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 phosphate 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).

Capule content

Pregelatinized starch 

Povidone K-30

Croscarmellose sodium 

Talc 

Sodium stearyl fumarate 

Capsule shell Gelatin,

Titanium Dioxide,

Iron oxide red,

Iron oxide yellow,

Black iron oxide,

Black ink for printing

Not applicable.

Store below 30℃.

Triplex blister pack (PVC/PE/PVDC, sealed with aluminium foil).

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

Extemporaneous formulation

When oseltamivir w powder for oral suspension is not available

Commercially manufactured Oselow 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 Oselow 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 Oselow capsules under “Making liquid Oselow (oseltamivir) 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. For immunocompromised patients, a 10-day course of treatment is needed.

The pharmacist may compound a 6 mg/ml suspension from Oselow 75 mg capsule 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. For immunocompromised patients, calculate the total volume needed to be compounded and dispensed to provide a 10-day course of treatment for the patient. The total volume needed is indicated in the table below for immunocompromised patients and is determined by the patient's weight. To allow for accurate 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's weight for 5-day treatmentor 10-day prophylaxis course

*Depending on the capsule strength used.

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

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 (for 5 days of treatment or 10-days of prophylaxis)

*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 pharmacy compounded 6 mg/ml suspension (for 10 days of treatment in immunocompromised patients)

* 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 Oselow 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 Oselow 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 Oselow 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 Oselow capsules for patients 1 year of age or older

*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 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. For immunocompromised patients, a 10-day course of treatment for the patient is needed.

The pharmacist may compound a 6 mg/ml suspension from Oselow 75 mg capsule 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.

For immunocompromised patients, calculate the total volume needed to be compounded and dispensed to provide a 10-day course of treatment for the patient. The total volume needed is indicated in the table below and is determined by the patient's weight. To allow for accurate 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's weight (for 5 days of treatment or 10-days of prophylaxis)

*  Depending on the capsule strength used.

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

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 (for 5 days of treatment or 10-days of prophylaxis)

*   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 pharmacy compounded 6 mg/ml suspension (for 10-days of treatment in immunocompromised patients)

*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 Oselow 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 Oselow 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 Oselow 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 Oselow capsules for infants less than 1 year of age

*  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 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 oral suspension is not available, a pharmacy compounded suspension prepared from Oselow capsules must be used (see detailed instructions above). If the commercially manufactured oseltamivir oral suspension and the pharmacy compounded suspension is also not available, oseltamivir 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 oseltamivir suspension involves additional steps. Detailed instructions can be found in the package leaflet of Oselow capsules under “Making liquid Oselow (oseltamivir) at home”.