PRODUCT INFORMATION TELZIR(r) TABLETS AND ORAL SUSPENSION

NAME OF THE MEDICINE:

Fosamprenavir calcium The chemical name of fosamprenavir is (3S)-tetrahydrofuran-3-yl (1S,2R)-3-[[(4- aminophenyl) sulphonyl](isobutyl) amino]-1-benzyl-2-(phosphonooxy) propylcarbamate monocalcium. Fosamprenavir is a single stereoisomer with the (3S)(1S,2R) configuration. It has the following structural formula:

NH2

O

HN O O

O S

N

O

O

O P O

2+ O

Ca

It has a molecular formula of C25H34CaN3O9PS and a molecular weight of 623.7. CAS registry number 226700-81-8

DESCRIPTION:

Fosamprenavir calcium is a white to cream coloured solid, with a solubility approximately 0.31 mg/mL in water at 25C. Telzir tablets also contain the following ingredients: microcrystalline cellulose, croscarmellose sodium, Povidone K30, magnesium stearate and colloidal silicon dioxide. The film coat contains: hypromellose, Titanium dioxide (E171), glycerol triacetate, Iron oxide red (E172),

PHARMACOLOGY:

The non-clinical statements were consistent with those in the amprenavir Product Information, or were supported by limited experiments with fosamprenavir.

Pharmacodynamics

Fosamprenavir calcium is a pro-drug of amprenavir. It is the mono-calcium salt of the phosphate ester of amprenavir and is hydrolysed to inorganic phosphate and the active metabolite amprenavir as it is absorbed through the gut epithelium. Amprenavir is a non- peptide competitive inhibitor of the HIV protease. It blocks the ability of the viral protease to cleave the precursor polyproteins necessary for viral replication. Fosamprenavir has been shown to have little or no antiviral activity or enzyme inhibition properties in vitro. Any inhibition observed with fosamprenavir in these studies is considered to be due to trace amounts of amprenavir. Fosamprenavir requires metabolism in vivo to generate the active moiety, amprenavir. In the absence of in vivo metabolism, fosamprenavir has negligible activity in in vitro enzymatic and antiviral assays, and therefore such assays are performed using amprenavir. Amprenavir is a potent and selective inhibitor of HIV-1 and HIV-2 replication in vitro. In isolated experimental settings, synergy was shown in vitro in combination with nucleoside analogues including didanosine, zidovudine, abacavir and the protease inhibitor, saquinavir. It has been shown to have an additive effect in combination with indinavir, ritonavir and nelfinavir. Co-administration of ritonavir with fosamprenavir (at fosamprenavir/ritonavir doses of 700/100 mg twice daily or 1400/200 mg once daily) increased plasma amprenavir AUC by approximately 2-fold and plasma C,ss by 4- to 6-fold, compared to values obtained when fosamprenavir (at a dose of 1400 mg twice daily) is administered alone. Both fosamprenavir / ritonavir combination regimens (700 / 100 mg twice daily and 1400 / 200 mg once daily) maintain plasma amprenavir concentrations above the mean IC50 values for amprenavir against HIV for patients spanning the range from PI-naive (mean protein-binding adjusted IC50 = 0.146 g/ml) to heavily PI-experienced (mean protein-binding adjusted IC50 = 0.90

g/ml).

Resistance in vitro

Serial passage experiments have demonstrated the protease mutation I50V to be key to the development of amprenavir resistance in vitro, with the triple variant, I50V+M46I/L+I47V, resulting in a greater than 10-fold increase in IC50 to amprenavir. This triple mutation resistance profile has not been observed with other protease inhibitors either from in vitro studies or in clinical settings. In vitro variants resistant to amprenavir remained sensitive to saquinavir, indinavir and nelfinavir, but showed three to five-fold reduced susceptibility to ritonavir. The triple mutant, I50V+M46I/L+I47V, was unstable during in vitro passage in the presence of saquinavir, with loss of the I47V mutation, and the development of resistance to saquinavir resulted in resensitisation to amprenavir. Passage of the triple mutant in either indinavir, nelfinavir or ritonavir resulted in additional protease mutations being selected, leading to dual resistance. Mutation I84V, observed transiently in vitro has rarely been selected during amprenavir therapy. Additional recent data from in vitro passage experiments have also identified the selection by amprenavir of protease mutations I54M and V32I+I47V.

Resistance in vivo : protease inhibitor naive subjects

The resistance profile seen with amprenavir in clinical practice is different from that observed with other protease inhibitors. Consistent with the first in vitro experiments, the development of amprenavir resistance during therapy, is in many cases, associated with the mutation I50V. However, the three alternative mechanisms observed during in vitro passage experiments have also been observed to result in the development of resistance during the use of amprenavir in the clinic. Development of resistance to amprenavir during therapy may involve either mutations I50V or I54L/M or V32I+I47V or, rarely, I84V. Each of the four genetic patterns may be accompanied by additional secondary mutations, in particular M46I/L, and produces viruses with reduced susceptibility to amprenavir, some cross- resistance to ritonavir, but susceptibility to indinavir, nelfinavir and saquinavir is retained. The following summarises the mutations associated with the development of reduced phenotypic susceptibility to amprenavir in subjects treated with amprenavir. Protease mutations acquired on amprenavir-containing therapy which have been demonstrated to result in reduced phenotypic susceptibility to amprenavir: I50V or I54L/M or I84V or V32I with I47V In treatment naive subjects, significant differences were observed with respect to the emergence of resistance to both the PI and NRTI components of the study regimens between those subjects who received fosamprenavir / ritonavir in combination and those who received fosamprenavir without ritonavir as well as with those who received nelfinavir. Treatment emergent NRTI resistance was significantly less frequent with fosamprenavir / ritonavir treated subjects (4/32, 13 %) compared to the nelfinavir treated subjects (31/54, 57 %) (p<0.001). The incidence of treatment-emergent protease mutations (PRO mutations) associated with resistance to amprenavir was significantly lower in subjects who received fosamprenavir / ritonavir once daily (0/32, 0%) compared with fosamprenavir twice daily without ritonavir (5/29,17%) and was lower than PRO mutations associated with resistance to nelfinavir treated patients (17/54, 31%). Treatment emergence of NRTI resistance was also less frequent with fosamprenavir / ritonavir treated subjects compared with fosamprenavir alone (4/32 (13 %) vs. 16/29 (55 %)). In ART-naive patients administered fosamprenavir without low-dose ritonavir, the following amprenavir resistance-associated mutations have been found either alone or in combination:I54L/M, V32I+I47V and M46I.

Resistance in vivo: protease inhibitor-experienced subjects

Many in vitro PI-resistant variants and 322 of 433 (74 %) clinical PI-resistant variants with multiple protease inhibitor resistance mutations were susceptible to amprenavir. The principal protease mutation associated with cross-resistance to amprenavir following treatment failure with other protease inhibitors was I84V, particularly when mutations L10I/V/F were also present.

Table 1. Responders at Study Week 48 by Presence of Baseline PI Resistance- Associated Mutations *

*

Results should be interpreted with caution because the subgroups were small.

+

Most patients had >1 PI resistance-associated mutation at baseline.

The virologic response based upon baseline phenotype was assessed. Baseline isolates from PI-experienced patients responding to fosamprenavir/ritonavir twice daily had a median shift in susceptibility to amprenavir relative to a standard wild-type reference strain of 0.7 (range: 0.1 to 5.4, n = 62), and baseline isolates from individuals failing therapy had a median shift in susceptibility of 1.9 (range: 0.2 to 14, n = 29). Because this was a select patient population, these data do not constitute definitive clinical susceptibility break points. Additional data are needed to determine clinically relevant break points for Telzir. Isolates from 15 of the 20 patients receiving twice-daily fosamprenavir/ritonavir and experiencing virologic failure/ongoing replication were subjected to genotypic analysis. The following amprenavir resistance-associated mutations were found either alone or in combination: V32I, M46I/L, I47V, I50V, I54L/M, and I84V. Fosamprenavir is not recommended for use as monotherapy, due to the rapid emergence of resistant virus.

Pharmacokinetics

After oral administration, fosamprenavir is rapidly and almost completely hydrolysed to amprenavir and inorganic phosphate prior to systemic circulation. The conversion of fosamprenavir to amprenavir appears to primarily occur in the gut epithelium. Amprenavir metabolism is inhibited by ritonavir, via inhibition of CYP3A4, resulting in increased plasma concentrations of amprenavir. The pharmacokinetic properties of amprenavir following co-administration of fosamprenavir and ritonavir have been evaluated in healthy adult subjects and HIV-infected patients and no substantial differences were observed between these two groups. To aid palatability and assist compliance, the dosing recommendations are to administer the fosamprenavir oral suspension with food in children and adolescents. The dose recommendations for this population were based on the paediatric studies where the fosamprenavir oral suspension was administered with food, and therefore take into account the observed food effect (see Dosage and Administration).

Absorption:

After multiple dose oral administration of fosamprenavir 1400 mg once daily and ritonavir 200 mg once daily, amprenavir was rapidly absorbed with a geometric mean (95% CI) steady-state peak plasma amprenavir concentration (Cmax) of 7.24 (6.32-8.28) micrograms/ml occurring approximately 2 (0.8-5.0) hours after dosing (Tmax). The geometric mean steady-state plasma amprenavir trough concentration (Cmin) was 1.45 (1.16-1.81) micrograms/ml and AUC24,ss was 69.4 (59.7-80.8) h *micrograms/ml. After multiple dose oral administration of fosamprenavir 700 mg twice daily and ritonavir 100 mg twice daily, amprenavir was rapidly absorbed with a geometric mean (95% CI) steady-state peak plasma amprenavir concentration (Cmax) of 6.08 (5.38-6.86) g/ml occurring approximately 1.5 (0.75-5.0) hours after dosing (Tmax). The geometric mean steady-state plasma amprenavir trough concentration (Cmin) was 2.12 (1.77-2.54) micrograms/ml and AUC24,ss was 79.2 (69.0-90.6) h *micrograms/ml. Fosamprenavir tablet and oral suspension formulations, both given fasted, delivered an equivalent plasma amprenavir AUC values and the fosamprenavir oral suspension formulation delivered a 14% higher plasma amprenavir Cmax as compared to the oral tablet formulation. The absolute bioavailability of fosamprenavir in humans has not been established.

Figure 1. Mean ( SD) Steady-State Plasma Amprenavir Concentrations and Mean IC50 Values Against HIV from Protease Inhibitor-Naive Patients (in the Absence of Human Serum)

Tablet:

Administration of the fosamprenavir oral tablet formulation (1400 mg) with a high fat meal did not alter plasma amprenavir pharmacokinetics as compared to the administration of this formulation in the fasted state. Fosamprenavir tablets may be taken without regard to food intake.

Oral Suspension:

Administration of the fosamprenavir oral suspension formulation with a high fat meal reduced plasma amprenavir AUC by approximately 28% and Cmax by approximately 46% as compared to the administration of this formulation in the fasted state. For adult patients the fosamprenavir oral suspension should be taken without food and on an empty stomach. In children and adolescents the fosamprenavir oral suspension should be taken with food. The dose recommendations for this population therefore take into account the observed food effect (see Dosage and Administration).

Distribution:

The apparent volume of distribution is decreased by approximately 40% when fosamprenavir is co-administered with ritonavir, most likely due to an increase in amprenavir bioavailability. The apparent volume of distribution of amprenavir following administration of fosamprenavir is approximately 430 litres (6 L/kg assuming a 70 kg body weight), suggesting a large volume of distribution, with penetration of amprenavir freely into tissues beyond the systemic circulation. The concentration of amprenavir in cerebrospinal fluid is less than 1% of the plasma concentration. Amprenavir is approximately 90% protein bound. It is bound to the alpha1 acid glycoprotein (AAG) and albumin, but has a higher affinity for AAG.

Metabolism:

Following oral administration, fosamprenavir is rapidly and almost completely hydrolysed to amprenavir and inorganic phosphate as it is absorbed through the gut epithelium. Amprenavir is primarily metabolised by the liver with less than 1% excreted unchanged in the urine. The primary route of metabolism is via the cytochrome P450 3A4 enzyme. Amprenavir metabolism is inhibited by ritonavir, via inhibition of CYP3A4, resulting in increased plasma concentrations of amprenavir. Amprenavir is a less potent inhibitor of CYP3A4. Therefore drugs that are inducers, inhibitors or substrates of CYP3A4 must be used with caution when administered concurrently with fosamprenavir and ritonavir (see Contraindications and Interactions with other medicines).

Excretion:

Following administration of fosamprenavir, the half-life of amprenavir is 7.7 hours. The plasma amprenavir half-life is increased when fosamprenavir is co-administered with ritonavir. The primary route of elimination of amprenavir is via hepatic metabolism with less than 1% excreted unchanged in the urine. The metabolites account for approximately 14% of the administered amprenavir dose in the urine, and approximately 75% in the faeces.

Special populations:

Paediatrics:

The pharmacokinetics of amprenavir in children (2 years of age and above) and adolescents are similar to those in adults. Dosages of fosamprenavir (oral suspension or tablets) plus ritonavir (oral solution or capsules) were administered to subjects. The dosage regimen studies were on an age / weight basis. Mean steady state amprenavir pharmacokinetic parameters in this population are presented by dosing regimen and age group in the table below.

Table 2: Pharmacokinetic parameters in paediatric patients receiving fosamprenavir with ritonavir twice daily

Currently there are insufficient pharmacokinetic data in children < 2 years of age to support dosing in this age group.

Elderly:

The pharmacokinetics of fosamprenavir when given in combination with ritonavir has not been studied in patients over 65 years of age. When treating elderly patients' consideration should be given to potential hepatic, renal or cardiac dysfunction, concomitant disease or other drug therapy.

Impaired renal function

: Patients with renal impairment have not been specifically studied. Renal elimination is not a major route of elimination of amprenavir or ritonavir. The impact of renal impairment on amprenavir and ritonavir elimination should be minimal, therefore no dose adjustment of the fosamprenavir / ritonavir combination is considered necessary.

Impaired hepatic function:

Fosamprenavir is converted in man to amprenavir. The principal route of amprenavir and ritonavir elimination is hepatic metabolism. The plasma amprenavir pharmacokinetics were evaluated in a repeat-dose study in HIV-1 infected adult subjects with hepatic impairment receiving fosamprenavir with ritonavir compared to matched control subjects with normal hepatic function.

For subjects with mild hepatic impairment (Child-Pugh score of 5-6), a dosage regimen of fosamprenavir 700 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily is recommended (see Dosage and Administration) based on slightly higher plasma amprenavir Cmax (17%), slightly higher plasma amprenavir AUC(0-) (22 %), and similar C values compared to subjects with normal hepatic function receiving the standard fosamprenavir / ritonavir 700 mg/100 mg twice daily regimen. For subjects with moderate hepatic impairment (Child-Pugh score of 7-9), a dosage regimen of fosamprenavir 450 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily is recommended (see Dosage and Administration) Although the fosamprenavir 450 mg twice daily + ritonavir 100 mg once daily dosage regimen is predicted to deliver approximately 35 % lower plasma total amprenavir C values, plasma unbound amprenavir C values will be approximately 67 % higher than achieved in subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg / 100 mg twice daily regimen. For subjects with moderate hepatic impairment, the fosamprenavir 700 mg once daily + ritonavir 100 mg once daily regimen delivered 24 % lower plasma amprenavir Cavg, 65 % lower C, and approximately 42 % lower unbound C compared to subjects with normal hepatic function receiving the standard fosamprenavir / ritonavir 700 mg /100 mg twice daily regimen. Therefore, a fosamprenavir tablet regimen in subjects with moderate hepatic impairment could not achieve comparable plasma amprenavir pharmacokinetics to the fosamprenavir / ritonavir 700 mg /100 mg twice daily regimen in subjects with normal hepatic function. In subjects with severe hepatic impairment (Child-Pugh score of 10-13), a reduced dose of fosamprenavir 300 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily delivered 19% lower plasma amprenavir Cmax, 23% lower AUC(0-), and 38% lower C values, but similar unbound plasma amprenavir C values than achieved in subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg / 100 mg twice daily regimen. Despite reducing the dosing frequency of ritonavir, subjects with severe hepatic impairment had 64% higher ritonavir Cmax, 40% higher ritonavir Cavg, and 38% higher ritonavir C than achieved in subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg / 100 mg twice daily regimen.

CLINICAL TRIALS

Treatment-naive patients: Study APV30002 was a randomised, open-label, two arm study to compare a regimen containing fosamprenavir 1400mg + ritonavir 200mg (N=322) once daily to nelfinavir 1250mg twice daily (N=327), when administered in combination with abacavir 300mg twice daily and 3TC 150mg twice daily in HIV-1 infected treatment naive subjects over a 48 week period. The primary efficacy parameter for study APV30002 was the proportion of subjects with plasma HIV-1 RNA levels below 400copies/mL at 48 weeks. In the ITT Population, the treatment groups were well matched with regard to demographic characteristics and baseline characteristics.

Table 3: Summary of Baseline Characteristics for APV30002 - ITT Population

The median baseline CD4 count was low in both groups. A total of 55% of subjects had a CD4+ cell count <200 cells/mm3 at baseline, and 20% of subjects had CD4+ cell counts <50 cells/mm3. Overall, the baseline characteristics demonstrate that a more advanced treatment naive population was enrolled in this study compared to the population of previous studies in treatment naive subjects. The proportion of subjects at Week 48 with plasma HIV-1 RNA <400 copies/mL and HIV-1 RNA <50 copies/mL using the ITT (RD=F) * analysis are summarised in the following table.

Table 4: Summary of Proportions of Subjects With Plasma HIV-1 RNA

<400 copies/mL and HIV RNA <50 copies/mL at Week 48

Rebound or Discontinuation = Failure The results from study APV 30002 indicates that, in antiretroviral-naive patients, fosamprenavir given once daily in combination with low dose ritonavir as part of a regimen including abacavir and lamivudine (given twice daily) showed comparable efficacy over 48 weeks compared to nelfinavir given twice daily in combination with abacavir/lamivudine. Median HIV-1 RNA decreased from a baseline value of 4.78 log10 copies/mL in the fosamprenavir/ritonavir once daily group and 4.83 log10 copies/mL in the nelfinavir twice daily group to the lower limit of detection of assay (50 copies/mL or 1.69 log10 copies/mL) at Week 20 in both groups and remained at this level through Week 48. Median changes from baseline in plasma HIV-1 RNA were comparable between treatment groups at each time point. The median change in plasma HIV-1 RNA from baseline to Week 48 was -3.08 log10 copies/mL in the fosamprenavir/ritonavir once daily group and -2.96 log10 copies/mL in the nelfinavir twice daily group. CD4+ cell counts increased in both treatment groups with median increases from baseline being similar in magnitude at Week 48 (fosamprenavir/ritonavir: 203 cells mm3; nelfinavir twice daily: 207 cells mm3). Treatment-experienced patients: Study APV30003 was a randomised, parallel group, three-arm, open-label, multicentre, comparative study of two dosage regimens of fosamprenavir 700mg with ritonavir 100mg twice daily (N=105) and fosamprenavir 1400mg and ritonavir 200mg once daily (N=105) versus lopinavir 400mg and ritonavir 100mg twice daily (N=107), in HIV-1-infected subjects with previous PI experience, documented virological failure on a prior PI regimen, and currently receiving antiretroviral therapy. The primary end-point was average area under the curve minus baseline plasma HIV-1 RNA. In the ITT Population, the treatment groups were largely comparable with regard to demographic and baseline characteristics, as indicated in the following table.

Table 5: Summary of Baseline Characteristics in APV30003 ITT Population

Mean plasma HIV-1 RNA AAUCMB values at Week 48 are summarised below for the ITT Population Observed analysis.

Table 6: Mean plasma HIV-1 RNA AAUCMB values at Week 48 for the ITT Population.

The following table provides plasma HIV-1 -RNA at week 48 for <400 and <50 copies/mL using the ITT Rebound or Discontinued = Failure (RD=F) analysis.

Table 7: Proportion of Subjects with Plasma HIV-1 RNA <400 and <50 copies/ml at Week 48

The fosamprenavir/ritonavir twice daily regimen and the lopinavir/ritonavir twice daily regimen showed similar immunological improvements through 48 weeks of treatment, as measured by median CD4+ cell count and change from baseline. In PI-experienced HIV-infected subjects with evidence of virological failure, substantial virologic suppression was observed through 48 weeks of treatment with fosamprenavir 700mg/ritonavir 100mg twice daily or lopinavir 400mg/ritonavir 100 mg twice daily dosing in combination with two RTIs. A lower level of virological suppression was observed through 48 weeks of treatment with fosamprenavir 1400mg/ritonavir 200mg once daily dosing in combination with two RTIs. After 48 weeks treatment, the results of this study did not satisfy the criteria for non-inferiority of either fosamprenavir/ritonavir once daily or fosamprenavir/ritonavir twice daily versus lopinavir/ritonavir twice daily with respect to the primary endpoint, plasma HIV-1 RNA AAUCMB. Treatment-naive patients dosed without ritonavir: APV30001 was a randomised, open-label study where treatment naive subjects were randomised to either receive fosamprenavir 1400mg twice daily (N=166) or nelfinavir 1250mg twice daily (N=83), when administered in combination with abacavir 300mg twice daily and 3TC 150mg twice daily . Most subjects were male and American Hispanic or Black. The median plasma HIV-1 RNA levels were 4.83 log10 copies/mL, and the median baseline CD4 cell count was 212 cells/mm3 at baseline. 20% of subjects had a prior history of a CDC Class C event. A greater proportion of subjects prematurely discontinued their randomised PI from the nelfinavir twice daily group (47%) than from the fosamprenavir twice daily (31%) group. More subjects in the nelfinavir twice daily group prematurely discontinued from randomised PI due to insufficient viral load response than in the fosamprenavir twice daily group. Greater efficacy was obtained with fosamprenavir (66% of patients achieved HIV-1 RNA levels <400 copies/mL) compared with nelfinavir (51% of patients) through 48 weeks of therapy. The proportions of patients with plasma HIV-1 RNA <50 copies/mL at Week 48 were also higher in the group treated with fosamprenavir (55% for TELZIR compared with 41% for nelfinavir). Children and Adolescents: The safety, pharmacokinetic profile, and virologic response of fosamprenavir have been evaluated in paediatric patients 2 to 18 years of age. Use of fosamprenavir in this patient population is supported by evidence from well controlled studies of fosamprenavir in adults with additional data from two open label studies of fosamprenavir in paediatric patients. Very limited data is available for paediatric patients less than 2 years of age. In one study (APV29005), twice daily dosing regimen (Telzir with or without ritonavir) were evaluated in combination with other antiretroviral agents while in the second study (APV20003), once daily dosing regimen of Telzir with ritonavir were evaluated in combination with other antiretroviral agents. Doses and formulations (fosamprenavir tablets or oral suspension, ritonavir capsules or oral solution) were determined by patient weight and age. APV29005 enrolled 25 patients aged 6 to 11 (the majority of whom were treated with fosamprenavir / ritonavir 18/3 mg/kg twice daily or the adult tablet regimen), and 29 patients aged 12 to 18 (the majority of whom were treated with the adult tablet regimen). Overall, 27 (50 %) were PI-naive, 9 of whom were ART naive, and 27 (50 %) were PI-experienced. Prior NRTI exposure was extensive, with median durations of 421 and 389 weeks for the PI naive and experienced patients respectively. The median duration of prior PI exposure was 239 weeks. Overall, patients enrolled with a median 4.6 HIV-1 RNA log10 copies/ml (33 % of whom had > 100,000 copies/ml at baseline) and a median % CD4+ cell of 18 % (37 % of whom had % CD4+ of < 15% at baseline). Through 24 weeks of therapy, 70 % (19/27) of protease inhibitor naive and 56 % (15/27) of protease inhibitor experienced patients achieved and maintained a plasma HIV 1 RNA <400 copies/ml (ITT(E), TLOVR). In the ITT(E) population (Observed analysis) at Week 24 the median % CD4+ cell counts increased by 8 % in the PI-naive subjects and 4 % in the PI- experienced subjects. The once daily study APV20003 enrolled 52 patients aged 6-18. Of these, 26 (50 %) were PI-naive and 26 (50 %) were PI-experienced. At Week 24 of therapy, 62 % (16/26) of protease inhibitor naive and 42 % (11/26) of protease inhibitor experienced patients achieved a plasma HIV 1 RNA <400 copies/ml (ITT(E), TLOVR). At Week 48 of therapy, 46 % (12/26) of protease inhibitor naive and 31 % (8/26) of protease inhibitor experienced patients achieved HIV-1 RNA <400 copies/ml. There are currently insufficient data on pharmacokinetics, safety and antiviral response of fosamprenavir with ritonavir in children below 6 years of age. No direct comparative studies have been undertaken in children or adolescents.

CONTRAINDICATIONS:

Known hypersensitivity to fosamprenavir, amprenavir, and ritonavir or to any of the excipients of these medicinal products. Fosamprenavir in combination with ritonavir must not be administered concurrently with medicinal products with narrow therapeutic windows that are substrates of cytochrome P450 3A4 (CYP 3A4). Co-administration may result in competitive inhibition of the metabolism of these medicinal products and create the potential for serious and/or life threatening adverse events such as cardiac arrhythmia (for example astemizole, terfenadine, cisapride, pimozide), hypotension (for example, the alpha blocker alfuzosin), prolonged sedation or respiratory depression (for example triazolam, midazolam) or peripheral vasospasm or ischaemia (for example. ergotamine, dihydroergotamine and ergometrine) (see Interactions with other medicines). Fosamprenavir/ritonavir must not be administered concomitantly with sildenafil when used for the treatment of pulmonary arterial hypertension (for use of sidenafil in patients with erectile disfunction. (See Precautions, Interactions with other medicines). There is increased potential for sildenafil-associated serious adverse events. Ritonavir also inhibits CYP2D6 in vitro and in vivo but to a lesser extent than CYP3A4. Fosamprenavir in combination with ritonavir should not be co-administered with medicinal products that are highly dependent on CYP2D6 metabolism and for which elevated plasma concentrations are associated with serious and/or life threatening results. These medicinal products include flecainide and propafenone (please refer to the full prescribing information of ritonavir for further details) (see Interactions with other medicines). Fosamprenavir in combination with ritonavir must not be administered concurrently with rifampicin due to expected large decreases in plasma concentrations of amprenavir. (See Interactions with other medicines).

PRECAUTIONS:

General:

Tablet and oral suspension:

Patients should be advised that fosamprenavir in combination with ritonavir, or any other current antiretroviral therapy does not cure HIV, they may still develop opportunistic infections, and other complications of HIV infection. Current antiretroviral therapies, including fosamprenavir / ritonavir combinations, have not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken. Fosamprenavir contains a sulphonamide moiety. The potential for cross-sensitivity between drugs in the sulphonamide class and fosamprenavir is unknown. In the pivotal studies of fosamprenavir, there was no evidence of an increased risk of rashes in patients with a history of sulphonamide allergy that received fosamprenavir versus those who received fosamprenavir and did not have a sulphonamide allergy. Yet, the fosamprenavir/ritonavir combination should be used with caution in patients with a known sulphonamide allergy. Co-administration of Telzir 700 mg twice daily with ritonavir in doses greater than 100 mg twice daily has not been clinically evaluated. The use of higher ritonavir doses might alter the safety profile of the combination and therefore is not recommended. Use of fosamprenavir with ritonavir at higher than approved dosages has resulted in elevated transaminase levels in some subjects and are not recommended for use.

Impaired hepatic and renal function:

Amprenavir and ritonavir are both principally metabolised by the liver. Fosamprenavir with ritonavir should be used with caution and at reduced doses in adults with mild, moderate or severe hepatic impairment (see Dosage and Administration). Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk of developing transaminase elevations. Appropriate laboratory testing should be conducted prior to initiating therapy and at periodic intervals during treatment. Since the renal clearance of amprenavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment. Because amprenavir and ritonavir are highly protein bound, it is unlikely that haemodialysis or peritoneal dialysis will significantly remove them.

Hepatitis C virus (HCV) protease inhibitors

HCV protease inhibitors have structural similarities with HIV protease inhibitors, and there is evidence to suggest they share a common route of metabolism. Co-administration of fosamprenavir with ritonavir and telaprevir results in reduced steady state exposure to both amprenavir and telaprevir, with the possibility of sub-therapeutic concentrations. Co- administration of fosamprenavir with ritonavir and telaprevir is not recommended (see Interactions with other medicines). A pharmacokinetic interaction has been reported between boceprevir and some HIV protease inhibitors in combination with ritonavir, leading to decreased HIV protease inhibitor concentrations, and in some cases, decreased boceprevir concentrations. Although co- administration of fosamprenavir with ritonavir and boceprevir has not been studied, a similar interaction is likely, therefore co-administration is not recommended.

Paediatric use:

Children (0-6 years of age)

The pharmacokinetics safety and efficacy of fosamprenavir in children below 6 years of age has not yet been fully established (see Clinical Trials).

Children and Adolescent Patients (6- 18 years of age)

The fosamprenavir oral suspension is the recommended formulation for the most accurate dosing in children based on body weight (see Dosage and Administration). If vomiting occurs within 30 minutes after dosing, the dose should be repeated.

Rash/cutaneous reactions:

Most patients with mild or moderate rash can continue the fosamprenavir. Appropriate antihistamines (e.g. cetirizine dihydrochloride) may reduce pruritus and hasten the resolution of rash. Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, were reported in less than 1% of subjects included in the clinical development programme. Fosamprenavir should be permanently discontinued in case of severe rash, or in case of rash of moderate intensity with systemic or mucosal symptoms (see Adverse Effects).

Haemophilia:

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses in haemophiliac patients type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued, or reintroduced if treatment had been discontinued. A causal relationship has been evoked, although the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Hyperglycaemia:

New onset of diabetes mellitus, hyperglycaemia or exacerbation of existing diabetes mellitus have been reported in patients receiving antiretroviral therapy, including protease inhibitors. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketacidosis has occurred. A causal relationship between protease inhibitor therapy and these events has not been established.

Redistribution of body fat:

Combination antiretroviral therapy, including regimens containing a protease inhibitor, is associated with redistribution/accumulation of body fat in some patients. A causal relationship has not been established.

Lipid elevations:

Treatment with fosamprenavir has resulted in increases in the concentration of triglycerides and cholesterol. Triglyceride and cholesterol testing should be performed prior to initiating therapy with fosamprenavir and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate.

Immune Reconstitution Syndrome:

In HIV-infected patients with severe immune deficiency at the time of initiation of anti- retroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of ART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci (P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Autoimmune disorders (such as Graves' disease, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment and sometimes can be an atypical presentation.

Oral suspension:

The fosamprenavir oral suspension contains propyl and methyl parahydroxybenzoate. These products may cause an allergic reaction in some individuals. This reaction may be delayed.

Information for patients:

Patients should be advised that Telzir, or any other current antiretroviral therapy, does not cure HIV. Patients may still develop opportunistic infections, and other complications of HIV infection. Current antiretroviral therapies, including Telzir, have not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.

Carcinogenicity and mutagenicity

In long-term carcinogenicity studies, fosamprenavir was administered orally for up to 104 weeks at doses of 250, 400, or 600 mg/kg/day in mice and at doses of 300, 825, or 2250 mg/kg/day in rats. Exposures to amprenavir at these doses were 0.2 to 0.3-fold (mice) and 0.3 to 0.7-fold (rats) those in humans given 1400 mg once daily of fosamprenavir plus 200 mg ritonavir once daily. Exposures in the carcinogenicity studies were 0.1 to 0.3-fold (mice) and 0.3 to 0.6-fold (rats) those in humans given 700 mg of fosamprenavir plus 100 mg ritonavir twice daily. There was an increase in hepatocellular adenomas and hepatocellular carcinomas at all doses in male mice, and in hepatocellular adenomas and thyroid follicular cell adenomas at all doses in male rats and at 825 and 2250 mg/kg/day in female rats. The relevance of the hepatocellular findings in the rodents for humans is uncertain. Repeat dose studies with fosamprenavir in rats produced effects consistent with enzyme induction, which predisposes rats, but not humans, to thyroid neoplasms. In addition, in rats only there was an increase in interstitial cell hyperplasia at 825 and 2250 mg/kg/day, and an increase in uterine endometrial adenocarcinoma at 2250 mg/kg/day. The incidence of endometrial findings was slightly increased over concurrent controls, but within background range for female rats. The relevance of the uterine endometrial adenocarcinoma findings in rats for humans is uncertain. The carcinogenicity of fosamprenavir in combination with ritonavir has not been tested in animals. Fosamprenavir was not mutagenic or genotoxic in a battery of in vitroandin vivo assays. These assays included bacterial reverse mutation (Ames), mouse lymphoma, rat micronucleus, and chromosome aberrations in human lymphocytes.

Effects on fertility

Fertility in male and female rats was unaffected by oral fosamprenavir dose resulting in systemic exposures (plasma AUC) to amprenavir that were similar to that seen in humans treated with the maximum recommended dose of fosamprenavir in combination with ritonavir.

Use in Pregnancy:

Fosamprenavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Category B3

. Embryo-foetal development was unaffected by oral treatment of pregnant rats and rabbits with fosamprenavir during the period of organogenesis. Systemic plasma

exposure (AUC) to amprenavir in these studies was similar (rats) or lower (rabbits) than exposure in patients in clinical studies with fosamprenavir. In view of the low exposure in rabbits, the potential developmental toxicity of fosamprenavir has not been fully determined.

Use in lactation:

Due to the possibility of transfer of the HIV virus in maternal milk, breast-feeding of infants by infected mothers is contra-indicated. It is not known whether amprenavir is excreted in human milk, but it is found in the milk of lactating rats.

Effects on the Ability to Drive and Operate Machinery:

No studies on the effects of fosamprenavir in combination with ritonavir on the ability to drive and use machines have been performed.

INTERACTIONS WITH OTHER MEDICINES (See Contraindications and Precautions):

Both amprenavir the active metabolite of fosamprenavir and ritonavir are inhibitors of the cytochrome P450 3A4 enzyme (CYP3A4). Consequently, fosamprenavir in combination with ritonavir may increase plasma levels of medicines that have a narrow therapeutic window and are substrates of CYP3A4 and should not be administered concurrently. Other medicinal products that are inducers, inhibitors or substrates of CYP3A4 may also result in serious and/or life threatening drug interactions. Caution is therefore advised whenever fosamprenavir in combination with ritonavir is co-administered with such products (see Contraindications). Co-administration of fosamprenavir and ritonavir with halofantrine is not recommended as halofantrine concentrations may be increased, potentially increasing the risk of serious adverse effects such as cardiac arrhythmia. The HMG-CoA reductase inhibitors lovastatin and simvastatin are highly dependent on CYP3A4 for metabolism, thus concomitant use of fosamprenavir and ritonavir with simvastatin or lovastatin is not recommended due to an increased risk of myopathy, including rhabdomyolysis. Caution must also be exercised if fosamprenavir and ritonavir are used concurrently with atorvastatin, which is metabolised to a lesser extent by CYP3A4. In this situation, a reduced dose of atorvastatin should be considered (see Interactions with other medicines). If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin are recommended. Concomitant use of fosamprenavir with ritonavir and fluticasone propionate or other glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression. Although the isozyme(s) responsible for bepridil metabolism has (have) not been elucidated, the metabolic pathways primarily responsible for bepridil metabolism are mediated by the CYP450 enzyme system. Because amprenavir and ritonavir are inhibitors of the CYP 3A4 isozyme, the CYP450 isozyme most commonly responsible for drug metabolism, and because increased plasma bepridil exposure may increase the risk of life-threatening arrhythmia, caution is warranted when amprenavir and bepridil are co-administered. Serious and/or life-threatening drug interactions could occur between amprenavir and amiodarone, lidocaine (systemic), tricyclic antidepressants, quinidine and warfarin. Concentration monitoring (warfarin - monitor International Normalised Ratio) of these agents is recommended as this should minimise the risk of potential safety problems with concomitant use. Concomitant use of PDE5 inhibitors (eg sildenafil) for the treatment of erectile dysfunction in patients receiving the fosamprenavir/ritonavir combination is not recommended. Concomitant use of fosamprenavir and ritonavir with PDE5 inhibitors is expected to substantially increase PDE5 inhibitor concentrations and may result in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes and priapism. Co-administration of amprenavir with rifabutin results in a 200% increase in rifabutin plasma concentrations (AUC). When ritonavir is co-administered a larger increase in rifabutin concentrations is expected. A reduction of rifabutin dosage of at least 75% the recommended dose is recommended when administered with fosamprenavir and ritonavir and patients clinically monitored. Concomitant use of the fosamprenavir/ritonavir combination and products containing Hypericum perforatum (also known as St John's Wort) is not recommended. A pharmacokinetic study with indinavir indicates that Hypericum perforatum may reduce amprenavir and/or ritonavir serum concentrations when administered concomitantly. Because there may be an increased risk of hepatic transaminase elevations and hormonal levels may be altered with co-administration of fosamprenavir, ritonavir and oral contraceptives alternative non-hormonal methods of contraception are recommended for women of childbearing potential. No data are available on the co-administration of fosamprenavir and ritonavir with oestrogens and/or progestogens when used as hormonal replacement therapies. The efficacy and safety of these therapies with fosamprenavir and ritonavir has not been established. Fosamprenavir/ritonavir must not be administered concomitantly with sildenafil when used for the treatment of pulmonary arterial hypertension. There is increased potential for sildenafil-associated serious adverse events (see Contraindications). Ritonavir, as well as being a potent inhibitor of CYP3A4, is also an inhibitor of CYP2D6 and an inducer of CYP1A2, CYP2C9 and glucuronosyl transferase. Fosamprenavir in combination with ritonavir should not be co-administered with medicinal products that are highly dependent on CYP2D6 metabolism and for which elevated plasma concentrations are associated with serious and/or life threatening results. These medicinal products include flecainide and propafenone (see Contraindications). The full prescribing information of Norvir (ritonavir) should be referred to prior to undertaking the dosing regimen of fosamprenavir and ritonavir.

Tablet and oral suspension:

When fosamprenavir and ritonavir are co-administered, the ritonavir metabolic drug interaction profile may predominate because ritonavir is a more potent CYP3A4 inhibitor. The full prescribing information for ritonavir must therefore be consulted prior to initiation of therapy with fosamprenavir and ritonavir.

Interaction studies have only been performed in adults.

Interactions involving CYP2D6

Ritonavir is an inhibitor of CYP2D6. Therefore fosamprenavir in combination with ritonavir may result in increased plasma concentrations of medicinal products that are primarily metabolised by CYP2D6 (see Contraindications and Precautions).

Additional associations, precaution for use

Drug interaction studies were performed with Telzir and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration on AUC, Cmax, and Cmin values are summarised in Table 7 (effect of other drugs on amprenavir) and Table 9 (effect of Telzir on other drugs). In addition, since Telzir delivers comparable amprenavir plasma concentrations as Agenerase, drug interaction data derived from studies with Agenerase are provided in Tables 8 and 10. For information regarding clinical recommendations, see PRECAUTIONS: Medical products - potential Interactions.

Table 8: Drug Interactions: Pharmacokinetic Parameters for Amprenavir in the Presence of the Coadministered Drug After Administration of Telzir

*

MAALOX TC is a Trademark of Rhone-Poulenc Rorer.

Table 9: Drug Interactions: Pharmacokinetic Parameters for Amprenavir After Administration of Agenerase in the Presence of the Coadministered Drug

* Median percent change, confidence interval not reported. a. Concomitant baseline medication is also shown in this column where appropriate. = Increase; = Decrease; = No change ( or <10%); NA = Cmin not calculated for single-dose study.

Table 10: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir After Administration of Telzir

Table 11: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir After Administration of Agenerase

* Median percent change, confidence interval not reported. a. Concomitant baseline medication is also shown in this column where appropriate. = Increase; = Decrease; = No change ( or <10%); NA = Cmin not calculated for single-dose study; ND = interaction cannot be determined as Cmin was below the lower limit of quantification.

Table 12: Drugs That Should Not Be Coadministered With Telzir

Table 13: Established and other Potentially Significant Drug Interactions: Alteration in dose or regimen may be recommended based on drug interaction studies or predicted Interaction (Information in the table applies to TELZIR with or without ritonavir, unless otherwise indicated.)

Antiretroviral agents:

Non-nucleoside reverse transcriptase inhibitors:

Nevirapine: the AUC and Cmin of amprenavir were decreased by 11 % and 19 % respectively, with Cmax unchanged when fosamprenavir (700 mg twice daily) plus ritonavir (100 mg twice daily) was given concomitantly with nevirapine (200 mg twice daily). The AUC, Cmax and Cmin of nevirapine were increased by 14 %, 13 % and 22 % respectively. Therefore, if nevirapine is given in combination with fosamprenavir (700 mg twice daily) plus ritonavir (100 mg twice daily), no dose adjustment is necessary. The fosamprenavir with ritonavir once daily regimen has not been studied. Delavirdine: no dose recommendations can be given for the co-administration of the fosamprenavir / ritonavir combination and delavirdine.

Nucleoside / Nucleotide reverse transcriptase inhibitors:

No dose adjustment is considered necessary when the following antiretroviral agents are co- administered with fosamprenavir: zidovudine, didanosine, stavudine, lamivudine, abacavir and tenofovir.

Protease Inhibitors:

No dose recommendation can be given for the use of fosamprenavir and ritonavir in combination with other protease inhibitors. Available interaction data are presented in tables 7 - 10. Atazanavir: Co-administration of fosamprenavir (700mg twice daily) plus ritonavir (100mg twice daily) with atazanavir (300mg once daily) for 10 days had no effect on steady state plasma amprenavir pharmacokinetics. Atazanavir plasma AUC(0-) decreased by 22%, Cmax by 24% and C remained unchanged relative to values obtained from atazanavir (300 mg once daily) plus ritonavir (100 mg once daily).

Integrase inhibitors:

Raltegravir: There is potential for a pharmacokinetic interaction with co-administration of fosamprenavir/ritonavir 700/100mg twice daily and raltegravir 400mg twice daily. This may lead to reductions in the Cmin of both medicinal products. The clinical significance of these reductions is unknown.

CCR5-receptor antagonists:

Maraviroc: A decrease in amprenavir C12h of 36% was observed when fosamprenavir 700 mg and ritonavir 100 mg twice daily were co-administered with maraviroc 300 mg twice daily and a decrease in amprenavir C24h of 15% when fosamprenavir 1400 mg and ritonavir 100 mg once daily were co-administered with maraviroc 300 mg once daily (see Table 8). Clinical studies showed comparable efficacy between fosamprenavir/ritonavir with maraviroc 150 mg twice daily and other boosted PIs with maraviroc 150 mg twice daily. Maraviroc exposures are increased by approximately 2-fold when administered with fosamprenavir/ritonavir (see Table 10). If fosamprenavir/ritonavir is co-administered with maraviroc, the recommended dose of maraviroc is 150 mg twice daily. No dosage adjustment is required for fosamprenavir with ritonavir.

Anti-hepatitis C medicinal products

Telaprevir: Concomitant administration of fosamprenavir with ritonavir and telaprevir results in reduced steady state exposure to both amprenavir and telaprevir. The mechanism of interaction is unknown. Concomitant administration of fosamprenavir with ritonavir and telaprevir is not recommended.

Antibiotics / Antifungals:

Clarithromycin - ritonavir increases plasma concentrations of clarithromycin. A reduction in the clarithromycin dose should be considered when co-administered with fosamprenavir and ritonavir in patients with renal impairment. Erythromycin: no pharmacokinetic study has been performed with fosamprenavir in combination with erythromycin, however, plasma levels of both medicinal products may be increased when co-administered. Ketoconazole/Itraconazole: amprenavir and ritonavir both increase plasma concentrations of ketoconazole and are expected to increase itraconazole concentrations. High doses of ketoconazole and itraconazole (> 200 mg/day) should not be used concomitantly with fosamprenavir and ritonavir without assessing the risk/benefit ratio and increased monitoring for adverse events due to ketoconazole and itraconazole. Rifabutin: co-administration of amprenavir with rifabutin results in a 200% increase in rifabutin plasma concentrations (AUC) and an increase of rifabutin related adverse events. When ritonavir is co-administered a larger increase in rifabutin concentrations may occur. A reduction of rifabutin dosage of at least 75% the recommended dose is recommended when administered with fosamprenavir and ritonavir. Further dose reduction may be necessary (see Precautions). Rifampicin: co administration with Telzir may lead to loss of virologic response and possible resistance to Telzir or to the class of protease inhibitors.

Other medicinal products

Antacids: No dose adjustment for any of the respective medicinal products is considered necessary when administered concomitantly. Histamine H2 receptor antagonist: No dose adjustment for any of the respective medicinal products is considered necessary when administered concomitantly. Proton pump inhibitors: Co-administration of esomeprazole (20mg Once daily) with fosamprenavir (700mg twice daily) in combination with ritonavir (100mg twice daily) for 14 days did not alter plasma amprenavir AUC, Cmax, or Cmin and did not alter plasma esomeprazole AUC or Cmax esomeprazole tmax was delayed 1 hour. No dose adjustment for any of the respective medicinal products is considered necessary when administered concomitantly. For some substances that can cause serious or life-threatening adverse experiences, such as amiodarone, quinidine, lidocaine (by systemic route), tricyclic antidepressants, and warfarin (monitor INR), plasma concentration monitoring is available. For these medicinal products, concentration monitoring should reduce the potential for safety problems with concomitant use with fosamprenavir and ritonavir. The medications listed below are examples of substrates, inhibitors, or inducers of CYP3A4 that could interact with fosamprenavir in combination with ritonavir when used concomitantly. This list is not exhaustive. The clinical significance of these potential interactions is unknown and has not been studied. Patients should therefore be monitored for toxicities associated with such medicines when they are used in combination with fosamprenavir and ritonavir. Anticonvulsant drugs: Phenytoin: The AUC and Cmin of amprenavir were increased by 20 % and 19 % respectively, with Cmax unchanged when fosamprenavir (700 mg twice daily) plus ritonavir (100 mg twice daily) was given concomitantly with phenytoin (300 mg once daily). The AUC, Cmax and Cmin of phenytoin were decreased by 22 %, 20 % and 29 % respectively. Therefore, if fosamprenavir plus ritonavir is given in combination with phenytoin, no change to the fosamprenavir plus ritonavir dosage regimen is required. However, it is recommended that phenytoin plasma concentrations be monitored and phenytoin dose increased as appropriate. The fosamprenavir with ritonavir once daily regimen has not been studied. Other anticonvulsants: Concomitant administration of other anticonvulsant agents known as enzymatic inducers (e.g. phenobarbitone, and carbamazepine) has not been studied but may lead to a decrease in the plasma concentrations of amprenavir. Benzodiazepines: alprazolam, clorazepate, diazepam and flurazepam - serum concentrations may be increased, which could increase their activity (see Contraindications). Calcium channel blockers: amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, and verapamil - serum concentrations of these medicines may be increased, which could increase their activity and toxicity. Dexamethasone: may induce CYP3A4 and decrease plasma concentrations of amprenavir. PDE5 inhibitors: based on data for ritonavir and other protease inhibitors, plasma concentrations of PDE5 inhibitors (eg. sildenafil) are expected to substantially increase when co-administered with fosamprenavir and ritonavir and may result in an increase in PDE5 inhibitor associated adverse events. Concomitant use of PDE5 inhibitors for the treatment of erectile dysfunction or pulmonary arterial hypertension is not recommended. Concomitant use of fosamprenavir/ritonavir is contraindicated in patients being treated with sildenafil for pulmonary arterial hypertension(see Contraindications)) Fosamprenavir/ritonavir must not be administered concomitanly with sidenafil when used for the treatment of pulmonary arterial hypertension. There is increased potential for sildenafil- associated serious adverse events (see Contraindications) Fluticasone propionate (interaction with ritonavir): Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this interaction is also expected with other corticosteroids metabolised via the P450 3A pathway (see Precautions). Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. Halofantrine: plasma concentrations of halofantrine may increase when co-administered with fosamprenavir and ritonavir and may result in an increase in halofantrine associated adverse events such as cardiac arrhythmia. Concomitant use is not recommended (see Precautions). HMG-CoA reductase inhibitors: HMG-CoA reductase inhibitors which are highly dependent on CYP3A4 for metabolism, such as atovastatin, lovastatin and simvastatin, are expected to have markedly increased plasma concentrations when co-administered with fosamprenavir and ritonavir. Since increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis, the combination of these medicinal products with fosamprenavir and ritonavir is not recommended. When used with fosamprenavir and ritonavir, doses of atovastatin no greater than 20 mg/day should be administered, with careful monitoring for atovastatin toxicity. The metabolism of pravastatin and fluvastatin is not dependent on CYP3A4, and interactions are not expected with protease inhibitors. If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended (see Precautions). Immunosuppressants: plasma concentrations of cyclosporin, rapamycin and tacrolimus may be increased when co-administered with fosamprenavir and ritonavir. Therefore, frequent therapeutic concentration monitoring is recommended until levels have stabilised. Methadone: Co-administration of fosamprenavir 700 mg and ritonavir 100 mg twice daily with methadone once daily (<= 200 mg) for 14 days decreased the active (R-) methadone enantiomer AUC(0-) and Cmax by 18 % and 21 %. Unbound fraction of R-methadone was increased at 2 hours (12.4 % vs. 8.5 %) and 6 hours (11.5 % vs. 9.3 %), but plasma unbound R-methadone (active) concentrations at 2 hours and 6 hours were not significantly altered. Based on historical comparison, methadone did not appear to alter plasma amprenavir pharmacokinetic parameters. Similar effects on methadone concentrations were observed when amprenavir (without ritonavir) and methadone were coadministered. On the basis of these data no dose adjustment is necessary when fosamprenavir/ritonavir is co- administered with methadone. Paroxetine: plasma concentrations of paroxetine may be significantly decreased when co- administered with fosamprenavir and ritonavir. Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Steroids: co-administration of fosamprenavir 700 mg twice daily + ritonavir 100 mg twice daily with Brevinor (ethyinly estradiol (EE) 0.035 mg/norethisterone (NE) 0.5 mg) once daily decreased plasma EE AUC(0-t) and Cmax by 37% and 28%, respectively, and decreased plasma NE AUC(0-t), Cmax, and Ct by 34%, 38%, and 26%, respectively. Steady state plasma amprenavir pharmacokinetic (PK) parameters were not significantly affected by co- administration with Brevinor; however, ritonavir AUC(0-t) and Cmax were 45% and 63% higher, respectively, compared to historical data in female subjects dosed with fosamprenavir / ritonavir alone. In addition to the decreased hormonal contraceptive exposures, co-administration of fosamprenavir with ritonavir and Brevinor resulted in clinically significant hepatic transaminase elevations in some healthy subjects. Therefore alternative non-hormonal methods of contraception are recommended for women of childbearing potential (see Precautions). St John's wort: serum levels of amprenavir can be reduced by concomitant use of the herbal preparation St John's wort (Hypericum perforatum) (see Precautions).

DOSAGE AND ADMINISTRATION:

A physician experienced in the management of HIV infection should initiate therapy.

Tablets:

Fosamprenavir is administered orally. The tablet can be taken with or without food. Higher than approved dose combinations of fosamprenavir with ritonavir are not recommended for use (see Precautions).

Adults (greater than or equal to 18 years of age)

Antiretroviral Naive Patients:

The recommended dose is 1400 mg fosamprenavir once daily with 200 mg ritonavir once daily or 700 mg (one tablet) fosamprenavir twice daily with 100 mg ritonavir twice daily. Both regimens must be administered in combination with other antiretroviral agents.

Protease Inhibitor Experienced Patients:

The recommended dose 700 mg (one tablet) fosamprenavir twice daily with 100 mg ritonavir twice daily. This regimen must be administered in combination with other antiretroviral agents. The once daily administration of fosamprenavir plus ritonavir is not recommended in protease inhibitor experienced patients. Each Telzir 700mg tablet is equivalent to approximately 600mg of amprenavir. Fosamprenavir is also available as an oral suspension for the use of adults unable to swallow tablets.

Children and Adolescent Patients (6- 18 years of age)

The fosamprenavir oral suspension is the recommended option for the most accurate dosing in children based on body weight. The adult tablet regimens of fosamprenavir 700 mg twice daily plus 100 mg ritonavir twice daily (for protease inhibitor naive or experienced patients) may be used in children and adolescents if they weigh at least 39 kgs and can swallow the tablets whole. Ritonavir 100mg capsules may be used in children and adolescents taking the fosamprenavir oral suspension if they weigh at least 33 kgs and can swallow the capsules whole. The tablet can be taken with or without food.

Oral suspension:

Fosamprenavir is administered orally. The oral suspension should be taken without food by adults and on an empty stomach. Shake the bottle before use. Higher than approved dose combinations of fosamprenavir with ritonavir are not recommended for use (see Precautions).

Adults (greater than or equal to 18 years of age) Antiretroviral Naive Patients:

The recommended dose is 1400mg (28mL) fosamprenavir once daily with 200 mg ritonavir once daily or 700 mg (14mL) fosamprenavir twice daily with 100 mg ritonavir twice daily. Both regimens must be administered in combination with other antiretroviral agents.

Protease Inhibitor Experienced Patients:

The recommended dose is 700 mg (14mL) fosamprenavir twice daily with 100 mg ritonavir twice daily. This regimen must be administered in combination with other antiretroviral agents. Telzir oral suspension 50mg/mL is equivalent to approximately 43mg/mL of amprenavir. Caution is advised if the recommended doses of fosamprenavir with ritonavir detailed above are exceeded (See Precautions). Fosamprenavir is also available as film-coated tablets. (See above).

Children and Adolescent Patients (6 to 18 years of age)

The fosamprenavir oral suspension is the recommended formulation for the most accurate dosing in children based on body weight. The oral suspension should be taken with food by children and adolescents. Shake the bottle before use. The recommended dose for paediatric patients older than 6 years of age is as follows: Telzir oral suspension 18mg/kg plus ritonavir 3mg/kg administered twice daily not to exceed the adult dose of Telzir 700mg twice daily plus ritonavir 100mg twice daily.

Tablets and oral suspension:

Children (less than 6 years of age)

The safety and efficacy of fosamprenavir in combination with ritonavir has not yet been established in this patient population (see Clinical trials).

Elderly

The pharmacokinetics of fosamprenavir in combination with ritonavir has not been studied in patients over 65 years of age (see Pharmacokinetics).

Renal impairment

No initial dose adjustment is considered necessary in patients with renal impairment (see Pharmacology).

Hepatic impairment

Fosamprenavir is converted in man to amprenavir. The principal route of amprenavir and ritonavir elimination is hepatic metabolism. For adults with mild hepatic impairment (Child-Pugh score: 5-6): Fosamprenavir should be used with caution and at a reduced dose of 700 mg fosamprenavir twice daily with 100 mg ritonavir once daily. For adults with moderate hepatic impairment (Child-Pugh score: 7-9): Fosamprenavir should be used with caution and at a reduced dose 450 mg fosamprenavir twice daily with 100 mg ritonavir once daily. As it is not possible to achieve this latter fosamprenavir dose using the tablet formulation, these patients should be treated with fosamprenavir oral suspension. For adults with severe hepatic impairment (Child-Pugh score: 10-15): fosamprenavir should be used with caution and at a reduced dose 300 mg fosamprenavir twice daily with 100 mg ritonavir once daily. The fosamprenavir oral suspension should be used to achieve this dose reduction. Even with these dose adjustments for adults with hepatic impairment, some subjects may have higher than anticipated amprenavir and ritonavir plasma concentrations due to inter- patient variability, therefore appropriate laboratory tests for liver function should be conducted prior to initiating therapy and at periodic intervals during treatment (see Precautions). No dose recommendation can be made for children (2 years to less than 12 years of age) and adolescents (12 to 17 years of age) with hepatic impairment.

OVERDOSAGE:

There is no known antidote for fosamprenavir. Since amprenavir is highly protein bound, dialysis is unlikely to be helpful in reducing blood levels. If overdose occurs, the patient should be monitored for evidence of toxicity (see Adverse Effects) and standard supportive treatment applied as necessary. Contact Poisons Information Centre on 131126 for advice on management.

PRESENTATION AND STORAGE CONDITIONS:

Tablets:

Telzir film-coated tablets are supplied in High-Density Polyethylene (HDPE) bottles containing 60 tablets. Telzir are biconvex, capsules-shaped, pinked coloured tablets marked with GXLL7 on one face. Each tablet contains 700mg of fosamprenavir, as fosamprenavir calcium. Store below 30oC.

Oral Suspension:

Telzir oral suspension is supplied in High-Density Polyethylene (HDPE) bottles with a child resistant closure containing 225mLs of suspension. A measuring syringe is provided in the pack. Telzir oral suspension is a clear, colourless to pale yellow suspension with bubblegum/peppermint flavouring. Each 1 mL of suspension contains 50 mg of fosamprenavir as fosamprenavir calcium. Telzir oral suspension also contains the following ingredients: Hypromellose, Sucralose, propylene glycol, methyl hydroxybenzoate, propyl hydroxybenzoate, polysorbate 80, calcium chloride dihydrate, Artificial grape bubblegum flavour, natural peppermint flavour and purified water. Store below 30oC. Do not freeze. Discard 28 days after first opening.

NAME AND ADDRESS OF SPONSOR:

ViiV Healthcare Pty Ltd Level 4, 436 Johnston Street Abbotsford, Victoria, 3067 Telzir(r) is a registered trade mark of the ViiV Healthcare group of companies. Licensed from Vertex Pharmaceuticals Inc. Cambridge. MA 02139

POISON SCHEDULE OF THE MEDICINE :

S4

DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF THERAPEUTIC GOODS (THE ARTG):

26 May 2004

DATE OF MOST RECENT AMENDMENT:

14 October 2013

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