TAMIFLU oseltamivir phosphate

Transcription

1 NAME OF THE MEDICINE TAMIFLU oseltamivi phosphate (CAS egisty numbe: ) O COOC 2 H 5 O HN NH. 2 H 3 PO 4 The chemical name (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethylpopoxy)-1-cyclohexene-1- caboxylic acid, ethyl este, phosphate (1:1). The chemical fomula is C 16 H 28 N 2 O 4 (fee base). The molecula weight is fo oseltamivi fee base and fo oseltamivi phosphate salt. DESCRIPTION Oseltamivi phosphate is a white cystalline solid, highly soluble in wate (> 500 mg/ml). TAMIFLU (oseltamivi phosphate) is available as had capsules fo oal use. Each 75 mg had capsule of TAMIFLU contains 98.5 mg oseltamivi phosphate, equivalent to 75 mg of oseltamivi. Each 45 mg had capsule of TAMIFLU contains 59.1 mg oseltamivi phosphate, equivalent to 45 mg of oseltamivi. Each 30 mg had capsule of TAMIFLU contains 39.4 mg of oseltamivi phosphate, equivalent to 30 mg of oseltamivi. The had capsules contain the following excipients: stach pegelatinised maize, talc, povidone K 30, coscamellose sodium and sodium steaylfumaate. The capsule shell contains gelatin, titanium dioxide, ion oxide ed CI77491, ion oxide yellow CI77492, ion oxide black CI77499, shellac and indigo camine CI TAMIFLU is also available as powde fo oal suspension. Each bottle, with 30 g powde fo oal suspension contains g of oseltamivi phosphate and when econstituted with wate esults in a concentation of 12 mg/ml of oseltamivi. Each bottle contains the following excipients: xanthan gum, sodium dihydogen citate, sodium benzoate, sobitol, sacchain sodium, titanium dioxide and Tutti-Futti flavouing. Tamiflu PI of 23

2 PHARMACOLOGY Phamacodynamics Mechanism of Action Oseltamivi phosphate is a po-dug of the active metabolite, oseltamivi caboxylate. The active metabolite is a selective inhibito of influenza vius neuaminidase enzymes, which ae glycopoteins found on the viion suface. Vial neuaminidase is essential fo the elease of ecently fomed vius paticles fom infected cells and the futhe spead of infectious vius in the body. A study in cultued tacheobonchial epithelial cells and pimay nasal epithelial cells has shown that oseltamivi may also suppess vius enty to cells. In Vito Susceptibility Tests Antivial susceptibility and development of esistance to oseltamivi is usually discussed in the context of cell cultue expeiments involving Madin-Daby Canine Kidney (MDCK) vius eduction assay and/o neuaminidase inhibition assay (NA IC 50 ). The concentations of oseltamivi caboxylate equied fo inhibition of influenza vius wee highly vaiable depending on the assay method used and the vius tested. Oseltamivi caboxylate showed antivial activity in the low nano-mola ange in all these cell assays. In vito neuaminidase enzyme IC 50 (NA IC 50 ) values fo oseltamivi susceptible clinical isolates of influenza A anged fom 0.1 nm to 1.3 nm and fo influenza B fom 2.6 nm to 8.7 nm. Reduced susceptibility to oseltamivi caboxylate has been ecoveed in vito by passage of vius in the pesence of inceasing concentations of oseltamivi caboxylate. In vito NA IC 50 assays showed that the degee of educed sensitivity (IC 50 ) diffes makedly fo diffeent mutations fom 2-fold fo esistant vaiant with the I222V mutation in influenza A N1 to 30,000-fold fo esistant vaiant with the R292K mutation in influenza A N2. The elationship between the in vito antivial activity in cell cultue and the inhibition of influenza vius eplication in humans has not been established. Vial Resistance Resistance to neuaminidase inhibitos in vito can occu by neuaminidase mutations o haemagglutinin mutations. Haemagglutinin mutations geneally educe haemagglutinin binding affinity to sialic acid and thus educe vial dependence on neuaminidase activity in vito, esulting in neuaminidase inhibito esistance indiectly. Neuaminidase mutations geneally educe binding affinity of neuaminidase inhibitos to the neuaminidase enzyme and thus confe esistance to neuaminidase inhibitos. To date, haemagglutinin mutations have not been descibed to confe esistance in vivo o in clinical studies, wheeas neuaminidase mutations can confe esistance in vivo and have been obseved to be selected at low fequency in clinical teatment studies. Neuaminidase mutations have been obseved to be selected in vito afte seveal passages in Madin-Daby Canine Kidney (MDCK) cells in the pesence of inceasing concentations of Tamiflu PI of 23

3 oseltamivi caboxylate fo influenza A vius isolates. Genetic analysis of esistant isolates obtained in vito and in clinical studies, showed that educed susceptibility to oseltamivi caboxylate is associated with pesence of esistance mutations N294S; E119V; R292K and in one instance each N294S and SASG del in N2 neuaminidase of influenza A vius isolates and esistance mutation H274Y in influenza A N1 (including H5N1). In influenza B neuaminidase one instance of G402S giving a 4-fold decease in sensitivity has been epoted and one instance of D198N (10-fold decease) in an immunocompomised child has been epoted. Also, influenza vius isolated fom an 8 month old infant gil (B/Peth/211/2001) caied neuaminidase with appoximately 10-fold educed sensitivity to oseltamivi. Sequencing indicated caying a D197E mutation (D198E in N2 numbeing) was associated with the educed sensitivity. Viuses with esistant neuaminidase genotypes have vaying degees of loss of fitness and tansmissibility compaed to wild-type. Infectivity, pathogenicity and tansmission studies in mice and feets indicate R292K mutation in N2 was associated with compomised gowth and tansmissibility, whee as the gowth and tansmissibility of viuses caying the E119V mutation in N2 o D198N in influenza B wee simila to wild-type vius. H274Y in N1 and N294S in N2 appea intemediate, although gowth and tansmissibility may depend on the genetic backgound in which these mutations occu. The isk of emegence of dug esistance in clinical use in the teatment of influenza has been extensively examined. In clinical studies in natually acquied infection (iespective of teatment dose) the incidence of patients found to cay oseltamivi-esistant vius fo adults and adolescents was 0.32% (4/1245) by phenotyping alone, 0.4% (5/1245) by genotyping and phenotyping (full genotyping was not pefomed on all studies) and 4.1% (19/464) o 5.4% (25/464) espectively, fo childen aged All these patients wee found to cay oseltamivi caboxylate esistant vius only tansiently. The patients cleaed the vius nomally and showed no clinical deteioation. In clinical studies conducted in post-exposue (7 days), post exposue within household goups (10 days) and seasonal (42 days) pophylaxis of influenza, thee was no evidence fo emegence of dug esistance associated with the use of TAMIFLU. Insufficient infomation is available to date to fully chaacteise the isk of emegence of esistance to neuaminidase inhibitos in clinical use. Coss-Resistance Coss-esistance between zanamivi-esistant influenza mutants and oseltamivi-esistant influenza mutants has been obseved in vito. Due to limitations in the assays available to detect dug-induced shifts in vius susceptibility, an estimate of the incidence of oseltamivi esistance and possible coss-esistance to zanamivi in clinical isolates cannot be made. Howeve, two of the thee oseltamivi-induced mutations (E119V, H274Y and R292K) in the vial neuaminidase fom clinical isolates occu at the same amino acid esidues as two of the thee mutations (E119G/A/D, R152K and R292K) obseved in zanamivi-esistant vius. Tamiflu PI of 23

4 Phamacokinetics Absoption Oseltamivi is absobed fom the gastointestinal tact afte oal administation of oseltamivi phosphate and is conveted pedominantly by hepatic esteases to the active metabolite. In multiple dose studies the peak concentation of the active metabolite occus 2 to 3 hous afte dosing. Following an oal dose of 75 mg twice daily, the peak concentation (C max ) of the active metabolite is appoximately ng/ml. At least 75% of an oal dose eaches the systemic ciculation as the active metabolite. Exposue to the po-dug is less than 5% elative to the active metabolite. Plasma concentations of the active metabolite ae unaffected by co-administation with food (see DOSAGE AND ADMINISTRATION). Distibution The active metabolite eaches all key sites of influenza infection as shown by studies in the feet, at and abbit. In these studies, anti-vial concentations of the active metabolite wee seen in the lung, bonchoalveola lavage, nasal mucosa, middle ea and tachea, following oal administation of oseltamivi phosphate. The mean volume of distibution (V ss ) of the active metabolite is appoximately 23 L in humans. The binding of the active metabolite to human plasma potein is negligible (appoximately 3%). Metabolism Oseltamivi is extensively conveted to the active metabolite by esteases located pedominantly in the live. Neithe oseltamivi no the active metabolite is a substate fo, o an inhibito of, the majo cytochome P450 isofoms. Thus inteactions mediated by competition fo these enzymes ae unlikely. Elimination Absobed oseltamivi is pimaily (> 90%) eliminated by convesion to the active metabolite. Peak plasma concentations of the active metabolite decline with a half-life of 6 hous to 10 hous in most subjects. The active metabolite is not futhe metabolised and is eliminated entiely (> 99%) by enal excetion. Renal cleaance (18.8 L/h) exceeds glomeula filtation ate (7.5 L/h) indicating that tubula secetion (via the anionic pathway) in addition to glomeula filtation occus. Less than 20% of an oal adiolabelled dose is eliminated in faeces. Special Populations Renal impaiment Administation of 100 mg of TAMIFLU twice daily, fo five days, to patients with vaious degees of enal impaiment showed that exposue to the active metabolite is invesely Tamiflu PI of 23

5 popotional to enal function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Teatment of influenza No dose adjustment is necessay fo patients with ceatinine cleaance above 30 ml/min. In patients with a ceatinine cleaance of ml/min, it is ecommended that the dose is educed to 75 mg of TAMIFLU once daily fo 5 days. TAMIFLU should not be ecommended fo patients undegoing outine haemodialysis and continuous peitoneal dialysis with end stage enal disease and fo patients with ceatinine cleaance 10 ml/min (see DOSAGE AND ADMINISTRATION - Special Patient Populations). Pophylaxis of influenza In patients with ceatinine cleaance between 10 and 30 ml/min eceiving TAMIFLU it is ecommended that the dose be educed to 75 mg of TAMIFLU evey othe day, o altenatively, one 30 mg capsule o 30 mg of suspension once daily. TAMIFLU should not be ecommended fo patients undegoing outine haemodialysis and continuous peitoneal dialysis with end stage enal disease and fo patients with ceatinine cleaance 10 ml/min (see DOSAGE AND ADMINISTRATION - Special Patient Populations). Hepatic impaiment Based on in vito and animal studies, significant inceases in exposue to oseltamivi o its metabolite ae not expected and this has been confimed in clinical studies in patients with mild o modeate hepatic impaiment. The phamacokinetics of a single oal dose of oseltamivi 75 mg have been established in modeately hepatic impaied (Child-Pugh scoe 7-9) patients. Results of the study showed that C max and AUC of active metabolite of oseltamivi in the 12 hepatic impaied patients fell within the theapeutic magin of safety and efficacy. The safety and phamacokinetics in patients with sevee hepatic impaiment have not been studied (see DOSAGE AND ADMINISTRATION). Eldely Exposue to the active metabolite at steady-state was appoximately 25% highe in eldely patients (age ange between 65 and 78) compaed to young adults given compaable doses of TAMIFLU. Half-lives obseved in eldely patients wee simila to those seen in young adults. On the basis of dug exposue and toleability, dosage adjustments ae not equied fo eldely patients fo eithe teatment o pophylaxis of influenza unless thee is co-existent enal impaiment (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Paediatics The phamacokinetics of TAMIFLU have been evaluated in phamacokinetic studies in childen aged 1 to 16 yeas old. Younge childen cleaed both the po-dug and the active metabolite faste than adults, esulting in lowe exposue fo a given mg/kg dose. Doses of 2 mg/kg gave compaable exposue to that achieved in adults eceiving a single 75 mg capsule dose (appoximately 1 mg/kg). With advancing age, the diffeence in exposue between childen and adults (pe mg/kg dose) lessened to the extent that the exposue in childen ove Tamiflu PI of 23

6 12 yeas of age was simila to that in adults (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). TAMIFLU should not be used in childen unde 1 yea of age (see PRECAUTIONS - Toxicology). CLINICAL TRIALS Teatment of Influenza in Adults A total of 1,355 patients wee included in two phase III multicente, placebo-contolled tials in natually acquied influenza which wee conducted in the Nothen Hemisphee influenza season of 1997 to 1998 (Studies WV15670 & WV15671). An identical tial (Study WV15730) followed in the Southen Hemisphee winte of 1998 whee 60 patients wee ecuited. The population used in the pimay analyses was the intent-to-teat infected (ITTI) population. This population included only subjects who eceived at least one dose of study teatment and had laboatoy confimed influenza. The intent-to-teat (ITT) population included all subjects who took at least one dose of study medication, egadless of whethe they poved to have influenza. The esults fo the two pivotal studies ae shown in Tables 1 and 2. Table 1: Median Time (hous) to Alleviation of All Symptoms in the ITTI and ITT Populations Study WV15671 WV15670 ITTI ITT ITTI ITT ITT Intent-to-teat ITTI Intent-to-teat infected * Diffeence between medians Placebo (95% CI) n = ( ) n = ( ) n = ( ) n = ( ) TAMIFLU 75 mg bd (95% CI) n = ( ) n = ( ) n= ( ) n = ( ) p-value* < Tamiflu PI of 23

7 Table 2: Summay of Seconday Efficacy Results (Median and 95% Confidence Inteval) fom the Studies in the Teatment of Natually Acquied Influenza Study (Potocol Numbe(s)) Teatment goup Study WV15671 Placebo (n = 129) TAMIFLU 75 mg bd (n = 124) AUC of total symptom scoe (h) Time to become afebile (h) # 64.6 ( ) # 41.5 ( ) AUC of vius tite (log 10 TCID 50.h/ ml) Duation of vius shedding (h) # 70.2 ( ) # 66.8 ( ) p-value* < Not calculated Study WV15670 Placebo (n = 161) TAMIFLU 75 mg bd (n = 158) # 73.5 ( ) # 43.6 ( ) # 71.0 ( ) 78.2 # 70.2 ( ) p-value* Not calculated n = numbe of subjects in the intent to teat infected population * Compaison of placebo with TAMIFLU # 95% confidence inteval not calculated Studies WV15670 and WV15671 Studies WV15670 and WV15671 wee multicente, double blind, andomised, paallel goup studies with the objective of assessing the safety and antivial efficacy of TAMIFLU. Subjects who enolled in these studies pesented with symptoms of influenza defined as: feve (defined as body tempeatue 38 ºC) plus one espiatoy symptom [cough, soe thoat, nasal symptoms (hinohoea/ congestion)] plus one constitutional symptom [headache, malaise (feeling unwell), myalgia (aches and pains), sweats/chills (feeling feveish), postation (fatigue)]. Subjects wee andomised to eceive eithe 75 mg TAMIFLU twice daily, 150 mg TAMIFLU twice daily o placebo twice daily fo a peiod of five days, commencing up to 36 hous, late amended to 48 hous afte the epoted onset of symptoms. Pimay efficacy paamete: Time to alleviation of all symptoms was significantly educed by up to 30 hous in both the 75 mg and 150 mg active teatment goups compaed with placebo, demonstating a moe apid ecovey fo subjects on TAMIFLU. Teatment with TAMIFLU esulted in a educed median time to alleviation all of the seven defined influenza symptoms. No incease in efficacy was demonstated in subjects who eceived TAMIFLU 150 mg twice daily compaed to 75 mg twice daily. Tamiflu PI of 23

8 Seconday efficacy paametes: Both doses of TAMIFLU significantly educed the median total symptom scoe AUC (measue of extent and seveity of illness) by up to 40% compaed to placebo. The duation of vius shedding was also educed in subjects teated with TAMIFLU. Tempeatue AUC was educed in TAMIFLU-teated subjects compaed with placebo. Fewe subjects epoted feve following dosing with TAMIFLU, despite a lowe consumption of symptom elief medication (paacetamol) by the TAMIFLU goups compaed to the placebo goup. This was in addition to a maked eduction in the time taken fo subjects on TAMIFLU to etun to an afebile state duing the teatment inteval compaed with placebo. The oveall incidence of seconday illnesses (such as bonchitis, otitis media, sinusitis and pneumonia) equiing antibiotic medication was educed by 50% in TAMIFLU teated subjects when compaed with placebo. Subjects teated with TAMIFLU ated thei health, activity and quality of sleep to be bette than patients on placebo duing the dosing peiod. Moeove, teatment with TAMIFLU was associated with a eduction in time taken to etun to nomal (pe-influenza) health status and ability to pefom daily activity. Teatment of Influenza in Adolescents, Adults and Eldely Study M76001 In a ecent study which included adolescents, adults and eldely (13 to 80 yeas) patients, time to alleviation of all symptoms was significantly educed by up to 24.2 hous in patients teated with TAMIFLU. Thee was a significant eduction of the median total symptom scoe AUC in the teatment goup compaed to placebo. Consistent with othe studies, tempeatue AUC, numbe of patients with feve and the time to afebile state wee educed in TAMIFLU teated subjects compaed with placebo. Thee was also a educed need fo patients eceiving TAMIFLU to take symptom elief medication (paacetamol). Teatment of Influenza in High Risk Populations Study WV15758/872 In a sepaate study, patients aged > 13 yeas with influenza and co-existing chonic cadiac and/o espiatoy disease eceived TAMIFLU 75 mg o placebo twice daily. No diffeence in the median time to alleviation of all symptoms was seen between patients taking TAMIFLU o placebo. Howeve, the duation of febile illness was educed by appoximately one day in the TAMIFLU teatment goup. The numbe of patients shedding vius on days 2 and 4 was also makedly educed in those teated with TAMIFLU. Thee was no diffeence in the safety pofile of TAMIFLU in the at-isk populations compaed to the geneal adult population. Pevention of Influenza in Adults and Adolescents The efficacy of TAMIFLU in peventing natually occuing influenza illness has been demonstated in thee seasonal pophylaxis studies and a post-exposue pophylaxis study in households. The pimay efficacy paamete fo all these studies was the incidence of laboatoy confimed clinical influenza. Laboatoy confimed clinical influenza was defined as oal tempeatue 99.0 ºF/37.2 ºC plus at least one espiatoy symptom (cough, soe thoat, nasal congestion) and at least one constitutional symptom (aches and pain, fatigue, headache, chills/sweats), all ecoded within 24 hous, plus eithe a positive vius isolation o a 4-fold incease in vius antibody tites fom baseline. Tamiflu PI of 23

9 In a pooled analysis of two seasonal pophylaxis studies in healthy unvaccinated adults (aged 18 to 65 yeas), TAMIFLU 75 mg once daily taken fo 42 days duing a community outbeak educed the incidence of laboatoy confimed clinical influenza fom 4.8% (25/519) fo the placebo goup to 1.2% (6/520) fo the TAMIFLU goup. In a seasonal pophylaxis study in eldely esidents of nusing homes, TAMIFLU 75 mg once daily taken fo 42 days educed the incidence of laboatoy confimed clinical influenza fom 4.4% (12/272) fo the placebo goup to 0.4% (1/276) fo the TAMIFLU goup. About 80% of this eldely population wee vaccinated, 14% of subjects had chonic aiway obstuctive disodes and 43% had cadiac disodes. In a post-exposue pophylaxis study, household contacts (aged 13 yeas) who had no laboatoy evidence of influenza at baseline, and who wee living with an index case who was subsequently shown to have had influenza infection, wee andomised to teatment (the intentto-teat index-infected, not infected at baseline [ITTIINAB] population). In this population, TAMIFLU 75 mg administeed once daily within 2 days of onset of symptoms in the index case and continued fo 7 days, educed the incidence of laboatoy confimed clinical influenza in the contacts fom 12% (24/200) in the placebo goup to 1% (2/205) fo the TAMIFLU goup (isk eduction 91.9%, p < 0.001). Fo the study population as a whole (the ITT population), including contacts of index cases in whom influenza infection was not confimed, the incidence of laboatoy confimed clinical influenza was educed fom 7.4% (34/462) in the placebo goup to 0.8% (4/493) fo the TAMIFLU goup (isk eduction 89%, p < 0.001). Index cases did not eceive TAMIFLU in the study. In the ITT population, 13.9% of contacts in the placebo goup and 11.4% of contacts in the TAMIFLU goup had been vaccinated. Teatment of Influenza in Paediatic Patients One double-blind placebo contolled teatment tial was conducted in childen, aged 1 to 12 yeas (mean age 5.3 yeas), who had feve ( 37.8 C) plus one espiatoy symptom (cough o coyza) when influenza vius was known to be ciculating in the community. Of 698 patients enolled in this tial, 452 (65%) wee influenza-infected (50% male; 68% Caucasian). Of the 452 influenza-infected patients, 67% wee infected with influenza A and 33% with influenza B. The pimay endpoint in this study was the time to feedom fom illness, a composite endpoint which equied 4 individual conditions to be met. These wee: alleviation of cough, alleviation of coyza, esolution of feve, and paental opinion of a etun to nomal health and activity. TAMIFLU teatment of 2 mg/kg twice daily, stated within 48 hous of onset of symptoms, significantly educed the total composite time to feedom fom illness by 1.5 days compaed to placebo. The median time to feedom fom illness in the intent-to-teat infected (ITTI) population was 5.7 days in the placebo goup and 4.2 days in patients teated with TAMIFLU. In the intent-to-teat population (ITT), the median time to feedom fom illness was 5.2 days in the placebo goup and 4.4 days in patients teated with TAMIFLU. The median time to feedom fom illness was significantly educed in the subgoup of patients infected with influenza A and teated with TAMIFLU, compaed to patients infected with influenza B and teated with TAMIFLU (not statistically significant). The popotion of patients developing acute otitis media was educed by 40% in childen eceiving TAMIFLU compaed to placebo. Subgoup analyses of this study by gende showed no diffeences in the teatment effect of TAMIFLU in males and females. Tamiflu PI of 23

10 A second study was conducted in 334 asthmatic childen aged 6 to 12 yeas of age, 53.6% of whom wee influenza-positive. The median time to feedom fom illness was educed by 8% in patients teated with TAMIFLU compaed to placebo (not statistically significant). By day 6 (the last day of teatment) FEV 1 had inceased by 10.8% in the TAMIFLU-teated goup compaed to 4.7% in the placebo goup (p = ) although thee was no diffeence in the use of asthma medication between goups. Pevention of Influenza in Paediatic Patients Study WV16193 The efficacy of oseltamivi in peventing natually occuing influenza illness has been demonstated in a post-exposue pevention study in households that included adults, adolescents, and childen aged 1 to 12 yeas, both as index cases and as family contacts. The pimay efficacy paamete fo this study was the incidence of laboatoy-confimed clinical influenza in the households. Oseltamivi pophylaxis lasted fo 10 days (pophylactic efficacy in adults and adolescents 13 yeas has peviously been demonstated with a 7 day dosing egimen [see above]) In the total population, thee was a eduction in the incidence of laboatoy-confimed clinical influenza in households fom 20% (27/136) in the goup not eceiving pevention to 7% (10/135) in the goup eceiving pevention (62.7% eduction, [95% CI ]; p = ). In households of influenza-infected index cases, thee was a eduction in the incidence of influenza fom 26% (23/89) in the goup not eceiving pevention to 11% (9/84) in the goup eceiving pevention (58.5% eduction, [95% CI ]; p = ). Accoding to subgoup analysis in childen at 1-12 yeas of age, the incidence of laboatoyconfimed clinical influenza among childen was significantly educed fom 19% (21/111) in the goup not eceiving pevention to 7 % (7/104) in the goup eceiving (64.4% eduction, [95% CI ]; p = 0.01; ITT). Among childen who wee not aleady shedding vius at baseline, the incidence of laboatoy-confimed clinical influenza was educed fom 21% (15/70) in the goup not eceiving pevention to 4% (2/47) in the goup eceiving pevention (80.1% eduction, [95% CI ]; p = ; ITTIINAB) (see Table 3). Tamiflu PI of 23

11 Table 3: Incidence of Influenza Infection among Paediatic Contacts Population Numbe of Contacts 1-12 yeas Influenza-infected Contacts P T Total Index Case Infected % Potective efficacy of oseltamivi p-value Oveall ITT (7%) 21 (19%) ITTII (11%) 18 (24%) ITTIINAB (4%) 15 (24%) P = pophylaxis T = teatment ITTII = intent-to-teat index-infected ITTIINAB = intent-to-teat index-infected, not infected at baseline. INDICATIONS TAMIFLU is indicated fo the teatment of infections due to influenza A and B viuses in adults and childen aged 1 yea and olde. Teatment should commence as soon as possible, but no late than 48 hous afte the onset of the initial symptoms of infection. TAMIFLU is indicated fo the pevention of influenza in adults and childen aged 1 yea and olde. Vaccination is the pefeed method of outine pophylaxis against infection with influenza vius. CONTRAINDICATIONS TAMIFLU is containdicated in patients with known hypesensitivity to any of the components of the poduct. PRECAUTIONS TAMIFLU is a specific teatment fo infections due to influenza A o B viuses. Use should be limited to patients who have chaacteistic symptoms of influenza when influenza A o B vius infections have been documented locally. Data on the teatment of influenza B ae limited. Thee is no cuent evidence fo the safety o efficacy of oseltamivi in pesons with complications of an acute influenza episode such as vial o bacteial pneumonia. Such patients may equie extensive suppotive and adjunctive cae. Antivial theapy has not been shown to educe the need fo such cae and monitoing. Efficacy of oseltamivi in the teatment of subjects with chonic cadiac diseases/o espiatoy diseases has not been established. Safety and efficacy of epeated teatment o pophylaxis couses have not been studied. Tamiflu PI of 23

12 TAMIFLU powde fo oal suspension contains sobitol. One dose of 45 mg TAMIFLU oal suspension administeed twice daily delives 2.6 g of sobitol. Fo subjects with heeditay fuctose intoleance, this is above the ecommended daily maximum limit of sobitol. Diving and Opeating Machiney Thee have been no epoted effects of TAMIFLU on diving pefomance o the ability to opeate machiney. Advese effects on such activities ae not pedicted fom the phamacology of TAMIFLU. Paediatic Use The safety and efficacy of TAMIFLU in paediatic patients have not been established in childen aged less than 1 yea of age. TAMIFLU should not be used in childen unde 1 yea of age (see PRECAUTIONS - Toxicology) Toxicology In unweaned ats a single oal dose of oseltamivi phosphate 500 mg/kg (fee base equivalent) to 7-day old pups esulted in deaths associated with high exposue to the podug. Howeve, at 1520 mg/kg in 14-day old unweaned pups, thee wee no deaths o othe significant effects. No advese effects occued at 300 mg/kg administeed to 7-day old ats. This dose level esulted in maximum plasma concentations of 42.4 μg/ml fo the podug and 9.4 μg/ml fo the active metabolite, and maximum bain concentations of 10.7 μg/g fo the podug and 0.54 μg/g fo the active metabolite. Based on the coelation between motality and plasma exposue acoss the dose-ange, the podug, but not the active metabolite, appeas to undelie the toxicity in 7-day old juvenile ats. Use in Eldely Patients Limited numbes of subjects aged 65 and ove have been included in the clinical tials. Howeve, on the basis of dug exposue and toleability, dose adjustments ae not equied fo eldely patients unless thee is co-existent enal impaiment (see PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Use in Renal Impaiment Dose adjustment is ecommended fo patients with ceatinine cleaance of ml/min fo the teatment and pevention of influenza. TAMIFLU should not be ecommended fo patients undegoing outine haemodialysis and continuous peitoneal dialysis with end stage enal disease and fo patients with ceatinine cleaance < 10 ml/min. Theefoe, caution should be taken when administeing TAMIFLU to those patients (see PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Tamiflu PI of 23

13 Cacinogenicity A two-yea cacinogenicity study with oseltamivi phosphate in ats was negative at oal doses up to 500 mg/kg/day, esulting in espective elative systemic exposues (based on AUC 0-24h, maximum clinical dose of 75 mg twice daily) to oseltamivi phosphate and its active metabolite of 352 times and 52 times, espectively. A two-yea cacinogenicity study with oseltamivi phosphate in mice was negative at oal doses up to 400 mg/kg/day, esulting in espective elative systematic exposues (based on AUC 0-24h, maximum clinical dose of 75 mg twice daily) to oseltamivi phosphate and its active metabolite of 130 times and 15 times, espectively. A 26-week demal cacinogenicity study of oseltamivi caboxylate in FVB/Tg.AC tansgenic mice was negative when tested at doses up to 780 mg/kg/day. Mutagenicity Oseltamivi phosphate was found to be non-genotoxic in the Ames test and the human lymphocyte chomosome assay, with o without metabolic activation, and negative in the mouse miconucleus test. It was found to be positive in a Syian Hamste Embyo (SHE) cell tansfomation test. The active metabolite of oseltamivi phosphate was non-mutagenic in the Ames test and the L5178Y mouse lymphoma assay and negative in the SHE cell tansfomation test. Effects on Fetility No effect on male o female fetility was obseved in ats exposed to oseltamivi phosphate. The highest dose has appoximately 180 times the human systemic exposue (AUC) to the active metabolite. Use in Pegnancy Categoy B1 Thee ae insufficient human data upon which to base an evaluation of isk of TAMIFLU to the pegnant woman o developing foetus. Studies fo effects on embyo-foetal development wee conducted in ats (at doses up to 1500 mg/kg/day) and abbits (at doses up to 500 mg/kg/day) by the oal oute. Relative exposues in these studies wee 180 times human exposue (AUC 0-24h of the active metabolite) in the at and 50 times human exposue in the abbit. Foetal exposue in both species was appoximately 15% to 20% of that of the mothe. In the at study, minimal matenal toxicity was epoted in the 1500 mg/kg/day goup. In the abbit study, slight and maked matenal toxicities wee obseved, espectively, in the 150 and 500 mg/kg/day goups. The duation of patuition was inceased in ats at oal doses of 1500 mg/kg/day of oseltamivi phosphate, 180 times human exposue (AUC 0-24h ), but it was not affected at 500 mg/kg/day (appoximately 40 times human exposue). Oseltamivi phosphate was not teatogenic in these studies. Because animal epoductive studies may not be pedictive of human esponse, and thee ae no adequate and well-contolled studies in pegnant women, TAMIFLU should be used duing pegnancy only if the potential benefit justifies the potential isk to the foetus. Tamiflu PI of 23

14 Use in Lactation In lactating ats, oseltamivi and the active metabolite ae exceted in the milk. Offsping development was not affected at matenal doses of 1500 mg/kg/day in ats. It is not known whethe oseltamivi o the active metabolite ae exceted in human milk. TAMIFLU should theefoe be used only if the potential benefit fo the lactating mothe justifies the potential isk fo the nusing infant. Dug Inteactions Infomation deived fom phamacology and phamacokinetic studies of oseltamivi phosphate suggest that clinically significant dug inteactions ae unlikely. Oseltamivi phosphate is apidly conveted to the active metabolite by esteases, located pedominantly in the live. Dug inteactions involving competition fo esteases have not been extensively epoted in the liteatue. These esteases have been shown not to be satuable at concentations of oseltamivi 100 times those which occu duing teatment. Theefoe, dug inteactions caused by competition fo these enzymes ae highly unlikely. In vito studies demonstated that neithe oseltamivi phosphate no the active metabolite is a good substate fo P450 mixed-function oxidases o fo glucuonyl tansfeases. Thus, dug inteactions involving P450 isozymes ae unlikely. Oseltamivi is a weak substate in vito fo the P-glycopotein tanspot system; howeve, no advese event fo oseltamivi o the concomitant administated dug which could be due to an inteaction at the P-glycopotein level has been detected. Cimetidine has no effect on plasma levels of oseltamivi o its active metabolite. Clinically impotant dug inteactions involving competition fo enal tubula secetion ae unlikely, due to the known safety magin fo most of these dugs, the elimination chaacteistics of the active metabolite (glomeula filtation and anionic tubula secetion) and the excetion capacity of these pathways. No phamacokinetic inteactions between oseltamivi o its majo metabolite have been obseved when co-administeing oseltamivi with paacetamol, acetyl-salicylic acid (aspiin), cimetidine o with antacids (magnesium and aluminium hydoxides and calcium cabonates). Thee is no mechanistic basis fo an inteaction with oal contaceptives. Dug inteaction studies have not been undetaken with oseltamivi and a numbe of dugs and dug classes, including eythomycin and macolide antibiotics, theophylline deivatives and antihistamines. Co-administation with amoxicillin does not alte plasma levels of eithe compound, indicating that competition fo the anionic pathway is weak. Tamiflu PI of 23

15 Effects on Laboatoy Tests TAMIFLU has not been found to cause any clinically elevant changes in a ange of biochemisty and haematology tests. Phamaceutical Pecautions Diect contact of oseltamivi phosphate with the skin and eyes should be avoided as it is a potential skin sensitise and eye iitant. ADVERSE EVENTS Expeience fom Clinical Tials Adult Teatment Studies In adult phase III teatment studies, the advese event pofile was found to be simila acoss all fou teatment studies (i.e. Studies WV15670, WV15671, WV15730 and WV15707) with compaable fequency and type(s) of advese event(s) being ecoded. Being essentially of simila design these studies wee subsequently pooled to bette estimate the fequency of advese events epoted duing 5 days of teatment with TAMIFLU (75 mg twice daily). A summay of advese events in adults (including eldely patients) with an incidence of > 1% (iespective of causality) and occuing moe fequently in subjects taking TAMIFLU is pesented in Table 4. Table 4: Summay of Advese Events in the Teatment of Natually Acquied Influenza With Dose of 75 mg TAMIFLU Twice Daily (Excluding Nausea Associated With Vomiting) (Studies WV15670, WV15671, WV15730 and WV15707) Placebo n = mg TAMIFLU bd n = 496 Vomiting 15 (3.2%) 59 (11.9%) Nausea (without 25 (5.3%) 52 (10.5%) vomiting)* Insomnia 3 (0.6%) 7 (1.4%) Headache 11 (2.3%) 13 (2.6%) Abdominal Pain 11 (2.3%) 12 (2.4%) * Table excludes epots of nausea associated with vomiting i.e. nausea epoted within 1 day of epot of vomiting Nausea and vomiting wee tansient events and geneally occued with the fist dose. Othe clinical advese events of any intensity, which occued with an incidence of > 1% in patients eceiving 75 mg TAMIFLU twice daily in adult phase III teatment clinical studies, wee diahoea and dizziness. These events wee consideed at least emotely elated to Tamiflu PI of 23

16 teatment with TAMIFLU. The excess epoting of headache and abdominal pain in the 75 mg twice daily TAMIFLU goup compaed with placebo was numeically maginal. Adult Pevention Studies A total of 3434 subjects (adolescents, healthy adults and eldely) paticipated in phase III pevention studies with 1480 eceiving the ecommended dose of 75 mg once daily fo up to 6 weeks. Advese events wee qualitatively vey simila to those seen in the teatment studies, despite a longe duation of dosing. Thee wee no clinically elevant diffeences in the safety pofile of the 942 eldely subjects, who eceived TAMIFLU o placebo, compaed with the younge population. The most fequently epoted advese events in all pophylaxis studies of natually acquied influenza ae summaised in Table 5. The advese events ae listed in descending ode of fequency and ae events occuing moe fequently in the TAMIFLU goup compaed with the placebo goup. Table 5: Summay of Most Fequent Advese Events in All Pophylaxis Studies in Natually Acquied Influenza (Studies WV15799, WV15673, WV15697, WV15708 and WV15825) Placebo n = mg TAMIFLU od n = 1480 Nausea 62 (4.3%) 118 (8.0%) Headache 251 (17.5%) 298 (20.1%) Vomiting 15 (1.0%) 31 (2.1%) Diahoea 38 (2.6%) 48 (3.2%) Pain 43 (3.0%) 53 (3.6%) Fatigue 107 (7.5%) 117 (7.9%) Rhinohoea 16 (1.1%) 23 (1.6%) Abdominal pain 23 (1.6%) 30 (2.0%) Insomnia 14 (1.0%) 18 (1.2%) Dizziness (excluding 21 (1.5%) 24 (1.6%) vetigo) Uppe espiatoy tact 115 (8.0%) 120 (8.1%) infection Dyspepsia 23 (1.6%) 25 (1.7%) The advese events epoted in pophylaxis studies wee consistent with the established safety pofile fo TAMIFLU in the teatment of influenza. Advese events expeienced moe fequently by subjects taking TAMIFLU than placebo included nausea (8.0% vs. 4.3%), vomiting (2.1% vs. 1.0%), diahoea (3.2% vs. 2.6%) and abdominal pain (2.0% vs. 1.6%). Headache was the most fequently epoted advese event with an incidence of 17.5% in the placebo goup and 20.1% in the goup eceiving TAMIFLU. Tamiflu PI of 23

17 Paediatic Teatment Studies A total of 1032 paediatic patients aged 1-12 yeas (including 698 othewise healthy childen aged 1-12 yeas and 334 asthmatic paediatic patients aged 6-12 yeas) paticipated in phase III studies investigating the use of TAMIFLU in the teatment of influenza. A total of 515 paediatic patients eceived teatment with TAMIFLU suspension. Advese events occuing in > 1% of paediatic patients eceiving TAMIFLU teatment ae listed in Table 6. The most fequently epoted advese event was vomiting. Othe events epoted moe fequently by paediatic patients teated with TAMIFLU included abdominal pain, epistaxis, ea disode and conjunctivitis. These events geneally occued once and esolved despite continued dosing. They did not cause discontinuation of dug in the majoity of cases. Table 6: Advese Event Most Fequent Advese Events Occuing in Childen Aged 1 to 12 Yeas in Studies in Natually Acquied Influenza Advese Events Occuing On Teatment in > 1% of Paediatic Patients Enolled in Phase III Tials of TAMIFLU Teatment of Natually Acquied Influenza Teatment a Teatment b Pophylaxis b Placebo Oseltamivi 2 mg/kg bd n = 515 Oseltamivi Unit dose c n = 158 Oseltamivi Unit dose c n = 99 n = 517 Vomiting 48 (9.3%) 77 (15.0%) 31 (19.6%) 10 (10.1%) Diahoea 55 (10.6%) 49 (9.5%) 5 (3.2%) 1 (1.0%) Otitis media 58 (11.2%) 45 (8.7%) 2 (1.3%) 2 (2.0%) Abdominal pain 20 (3.9%) 24 (4.7%) 3 (1.9%) 3 (3.0%) Asthma (including 19 (3.7%) 18 (3.5%) - 1 (1.0%) aggavated) Nausea 22 (4.3%) 17 (3.3%) 10 (6.3%) 4 (4.0%) Epistaxis 13 (2.5%) 16 (3.1%) 2 (1.3%) 1 (1.0%) Pneumonia 17 (3.3%) 10 (1.9%) - - Ea disode 6 (1.2%) 9 (1.7%) - - Sinusitis 13 (2.5%) 9 (1.7%) - - Bonchitis 11 (2.1%) 8 (1.6%) 3 (1.9%) - Conjunctivitis 2 (0.4%) 5 (1.0%) - - Dematitis 10 (1.9%) 5 (1.0%) 1 (0.6%) - Lymphadenopathy 8 (1.5%) 5 (1.0%) 1 (0.6%) - Tympanic membane disode 6 (1.2%) 5 (1.0%) - - a Pooled data fom phase III tials of TAMIFLU teatment of natually acquied influenza. b Uncontolled study compaing teatment (twice-daily dosing fo 5 days) with pophylaxis (once-daily dosing fo 10 days). c Unit dose = age-based dosing Advese events included ae: all events epoted in the teatment studies with fequency 1% in the oseltamivi 75 mg twice daily goup. Tamiflu PI of 23

18 Paediatic Pophylaxis Study Paediatic patients aged 1-12 yeas paticipated in a post-exposue pophylaxis study in households, both as index cases (n = 134) and as contacts (n = 222). Gastointestinal events, paticulaly vomiting, wee the most fequently epoted. TAMIFLU was well toleated in this study; the advese events noted being consistent with those peviously obseved (see Table 6). Post-Maketing Expeience Skin and subcutaneous tissue disode: ae cases of hypesensitivity eactions such as allegic skin eactions including dematitis, ash, eczema and uticaia, and vey ae cases of eythema multifome and Stevens-Johnson-Syndome have been epoted. Rae epots of toxic epidemal necolysis. Allegy, anaphylactic/ anaphylactoid eactions and face oedema have also been epoted aely. Live and biliay system disode: vey ae epots of hepatitis and elevated live enzymes have been epoted in patients with influenza-like illness eceiving oseltamivi. Psychiatic disodes/nevous system disodes: Convulsion and deliium (including symptoms such as alteed level of consciousness, confusion, abnomal behaviou, delusions, hallucinations, agitation, anxiety and nightmaes) have been epoted duing TAMIFLU administation in patients with influenza, pedominately in childen and adolescents. These events often had an abupt onset and apid esolution. In ae cases, these events esulted in accidental injuy, and some esulted in a fatal outcome. The contibution of TAMIFLU to those events is unknown. Such neuopsychiatic events have also been epoted in patients with influenza who wee not taking TAMIFLU. Patients with influenza should be closely monitoed fo signs of abnomal behaviou thoughout the teatment peiod. Gasto-intestinal disodes: in ae cases gasto-intestinal bleeding was obseved afte the use of TAMIFLU. In paticula, haemohagic colitis was epoted and subsided when the couse of influenza abated o teatment with TAMIFLU was inteupted. DOSAGE AND ADMINISTRATION TAMIFLU may be taken with o without food (see PHARMACOLOGY). Howeve, taking with food may enhance toleability in some patients. Teatment of Influenza Teatment should begin within the fist o second day of onset of symptoms of influenza. Adults and Adolescents The ecommended oal dose of TAMIFLU capsules in adults and adolescents 13 yeas of age and olde is 75 mg twice daily, fo 5 days. Adults and adolescents 13 yeas of age and olde Tamiflu PI of 23

19 who ae unable to swallow capsules may eceive the appopiate dose of TAMIFLU suspension. Paediatic Patients The ecommended oal dose of TAMIFLU fo paediatic patients 1 yea and olde who cannot swallow a 75 mg capsule is: Body weight in kg Recommended dose fo 5 days 15 kg 30 mg twice daily > kg 45 mg twice daily > kg 60 mg twice daily > 40 kg 75 mg twice daily Fo the oal suspension an oal dosing dispense with 30 mg, 45 mg, and 60 mg gaduations is povided; the 75 mg dose can be measued using a combination of 30 mg and 45 mg. It is ecommended that patients use this dispense. Paediatic patients weighing > 40 kg who ae able to swallow capsules, may also eceive teatment with a 75 mg capsule twice daily o one 30 mg capsule plus one 45 mg capsule twice a day as an altenative to the ecommended dose of TAMIFLU suspension. Pophylaxis of Influenza Adults and Adolescents The ecommended oal dose of TAMIFLU fo pevention of influenza following close contact with an infected individual is 75 mg once daily fo 10 days. Theapy should begin within two days of exposue. The ecommended dose fo pevention duing a community outbeak of influenza is 75 mg once daily. Safety and efficacy have been demonstated fo up to six weeks. The duation of potection lasts fo as long as dosing is continued. Paediatic Patients Childen weighing > 40 kg, who ae able to swallow capsules, may also eceive pophylaxis with a 75 mg capsule once daily o one 30 mg capsule plus one 45 mg capsule once a day, fo 10 days as an altenative to the ecommended dose of TAMIFLU suspension (see below). The ecommended pophylactic oal dose of TAMIFLU fo childen 1 yea of age is: Body weight in kg Recommended dose fo 10 days 15 kg 30 mg once daily > 15 to 23 kg 45 mg once daily > 23 to 40 kg 60 mg once daily > 40 kg 75 mg once daily Fo the oal suspension, a dosing syinge maked with 30 mg, 45 mg and 60 mg dosing levels is povided. It is ecommended that TAMIFLU powde fo oal suspension be constituted by a phamacist pio to dispensing to the patient. Tamiflu PI of 23

20 Patients unable to swallow capsules Adults, adolescents and childen who ae unable to swallow capsules may eceive thei equied 30 mg, 45 mg, 60 mg o 75 mg dose of TAMIFLU by following the instuctions below. 1. Hold the TAMIFLU capsule(s), coesponding to the equied dose, ove a small bowl. Caefully pull the capsule(s) open and pou the powde into the bowl, 2. Add a suitable, small amount (1 teaspoon maximum) of sweetened food poduct such as egula o suga-fee chocolate syup, honey, light bown o table suga dissolved in wate, desset toppings, sweetened condensed milk, apple sauce o yogut to mask the bitte taste of the medication. 3. Sti the mixtue well and give the entie contents to the patient. The mixtue must be swallowed immediately afte its pepaation. If thee is some mixtue left inside the bowl, inse the bowl with a small amount of wate and have the patient dink this emaining mixtue. It is not necessay to administe any undissolved white powde as this is inet mateial. If the patient equies a dose of TAMIFLU, which is diffeent to that available in capsule fom, they may eceive thei appopiate dose of TAMIFLU by following the instuctions below. 1. Hold one TAMIFLU 75 mg capsule ove a small bowl. Caefully pull the capsule open and pou the powde into the bowl. 2. Using a gaduated syinge, add 5 ml wate to the powde. Sti fo about two minutes. 3. Daw up into the syinge the coect amount of mixtue fom the bowl (see table below). The ecommended dose is body weight dependent (see tables above). Push down on the plunge of the syinge, to empty its entie contents into a second bowl. Discad any unused mixtue. Recommended dose Amount of TAMIFLU mixtue fo one dose 30 mg 2 ml 45 mg 3 ml 60 mg 4 ml 4. In the second bowl, add a suitable, small amount (1 teaspoon maximum) of sweetened food poduct such as egula o suga-fee chocolate syup, honey (only fo childen two yeas o olde), light bown o table suga dissolved in wate, desset toppings, sweetened condensed milk, apple sauce o yogut to the mixtue to mask the bitte taste of the medication. 5. Sti this mixtue well and give the entie contents of the second bowl to the patient. This mixtue must be swallowed immediately afte its pepaation. If thee is some mixtue left inside the bowl, inse the bowl with a small amount of wate and have the patient dink this emaining mixtue. Tamiflu PI of 23

21 Special Patient Populations Hepatic Impaiment No dose adjustment is equied fo patients with mild o modeate hepatic dysfunction in the teatment o pevention of influenza (see PHARMACOLOGY). The safety and phamacokinetics in patients with sevee hepatic impaiment have not been studied. Renal Impaiment Teatment of influenza No dose adjustment is necessay fo patients with ceatinine cleaance above 30 ml/min. In patients with a ceatinine cleaance of ml/min, it is ecommended that the dose is educed to 75 mg of TAMIFLU once daily, fo 5 days. TAMIFLU should not be ecommended fo patients undegoing outine haemodialysis and continuous peitoneal dialysis with end stage enal disease and fo patients with ceatinine cleaance 10 ml/min (see PHARMACOKINETICS and PRECAUTIONS). Pophylaxis of influenza No dose adjustment is necessay fo patients with ceatinine cleaance above 30 ml/min. In patients with ceatinine cleaance between ml/min eceiving TAMIFLU it is ecommended that the dose be educed to 75 mg of TAMIFLU evey othe day, o altenatively, one 30 mg capsule o 30 mg of suspension once daily. TAMIFLU should not be ecommended fo patients undegoing outine haemodialysis and continuous peitoneal dialysis with end stage enal disease and fo patients with ceatinine cleaance 10 ml/min (see PHARMACOKINETICS - Special Populations and PRECAUTIONS). Paediatics The safety and efficacy of TAMIFLU have not been established in childen aged less than 1 yea of age. TAMIFLU should not be used in childen unde 1 yea of age (see PRECAUTIONS - Toxicology) Eldely No dose adjustment is equied fo eldely patients (aged 65 yeas) in the teatment o pevention of influenza unless thee is co-existent enal impaiment (see PHARMACOLOGY and PRECAUTIONS). Fuctose Intoleance A bottle of 30 g TAMIFLU powde fo oal suspension contains g of sobitol. One dose of 45 mg TAMIFLU oal suspension administeed twice daily delives 2.6 g of sobitol. Fo subjects with heeditay fuctose intoleance this is above the ecommended daily maximum limit of sobitol. Tamiflu PI of 23

22 Pepaation of Oal Suspension It is ecommended that TAMIFLU oal suspension be econstituted by the phamacist pio to dispensing to the patient: 1. Tap the closed bottle seveal times to loosen the powde. 2. Measue 52 ml of puified wate by filling the measuing cup to the indicated level (measuing cup included in the box). 3. Add the total amount of puified wate to the bottle and shake the closed bottle well fo 15 seconds. 4. Remove the cap and push bottle adapte into neck of the bottle. 5. Close bottle with cap tightly. This will make sue that the bottle adapte fits in the bottle in the ight position. 6. Wite the date of expiy of the econstituted oal suspension on the bottle label. (The shelf life of the econstituted oal suspension is 10 days if stoed at oom tempeatue [below 25 C] o 17 days if stoed in a efigeato [between 2 C and 8 C]). Note: Shake TAMIFLU oal suspension well befoe each use. OVERDOSAGE Teatment of ovedose should consist of geneal suppotive measues. At pesent thee has been no expeience with ovedose; howeve, the anticipated manifestations of acute ovedose would be nausea, with o without accompanying emesis. Single doses of up to 1000 mg of TAMIFLU and twice daily doses of up to 500 mg of TAMIFLU fo 7 days have been well toleated. A complete pack with ten 30 mg, 45 mg o 75 mg capsules of TAMIFLU will contain a total of 300 mg, 450 mg o 750 mg of oseltamivi, espectively. Contact the Poisons Infomation Cente fo advice on management of ovedosage. PRESENTATION AND STORAGE CONDITIONS TAMIFLU 30 mg, 45 mg and 75 mg capsules ae available in bliste packages of 10 capsules. TAMIFLU 30 mg capsules ae supplied as had gelatin capsules with a light yellow/opaque cap and a light yellow/opaque body. "ROCHE" is pinted in blue ink on the yellow body and "30 mg" is pinted in blue ink on the light yellow cap. TAMIFLU 45 mg capsules ae supplied as had gelatin capsules with a gey/opaque cap and a gey/opaque body. "ROCHE" is pinted in blue ink on the gey body and "45 mg" is pinted in blue ink on the gey cap. Tamiflu PI of 23