TELZIR is a registered trademark, used under license by GlaxoSmithKline Inc. VERTEX Pharmaceuticals Inc.

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 10 DRUG INTERACTIONS 13 DOSAGE AND ADMINISTRATION 24 OVERDOSAGE 27 ACTION AND CLINICAL PHARMACOLOGY 27 STORAGE AND STABILITY 30 SPECIAL HANDLING INSTRUCTIONS 30 DOSAGE FORMS, COMPOSITION AND PACKAGING 30

PART II: SCIENTIFIC INFORMATION 32

PHARMACEUTICAL INFORMATION 32 CLINICAL TRIALS 33 DETAILED PHARMACOLOGY 35 MICROBIOLOGY 38 TOXICOLOGY 39 REFERENCES 43

PART III: CONSUMER INFORMATION. 47

PrTELZIR(r) fosamprenavir calcium tablet, 700 mg fosamprenavir fosamprenavir calcium oral suspension, 50 mg/mL fosamprenavir

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

TELZIR(r) (fosamprenavir calcium) must not be administered concurrently with medicinal products with a narrow therapeutic window that are substrates of cytochrome P450 3A4 (CYP 3A4). Coadministration may result in competitive inhibition of metabolism of these medicinal products and create the potential for serious and/or life-threatening adverse events such as cardiac arrhythmia (for example terfenadine, astemizole, cisapride, pimozide), prolonged sedation or respiratory depression (for example triazolam, midazolam, diazepam, flurazepam) or peripheral vasospasm or ischemia (for example ergot derivatives). Ritonavir also inhibits CYP2D6 in vitro and in vivo but to a lesser extent than CYP3A4. TELZIR(r) in combination with ritonavir should not be coadministered 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 for ritonavir for further details). TELZIR(r) should not be given with rifampin. Rifampin reduces trough plasma concentrations of amprenavir by approximately 92% (see DRUG INTERACTIONS section). TELZIR(r) is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g. Stevens Johnson Syndrome) to fosamprenavir calcium, amprenavir, ritonavir, or to any of the excipients of the products. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph. TELZIR(r) is contraindicated in patients with severe hepatic impairment (Child- Pugh score ranging from 10 to 15).

WARNINGS AND PRECAUTIONS

Serious and/or life-threatening drug interactions could occur between TELZIR(r) (fosamprenavir calcium) and amiodarone, lidocaine (systemic), halofantrine, tricyclic antidepressants, quinidine or warfarin (monitor International Normalized Ratio). Concentration monitoring of these agents is recommended if these agents are used concomitantly with TELZIR(r). Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, were reported in less than 1% of subjects included in the clinical development programme. The TELZIR(r)/ritonavir combination should be permanently discontinued in case of severe rash, or in case of rash of moderate intensity with systemic or mucosal symptoms (see ADVERSE REACTIONS section).

Rifampin should not be used in combination with TELZIR(r) since it reduces the Cmin of amprenavir by 92% and AUC by 82% (see CONTRAINDICATIONS section).

Phenobarbital, phenytoin, carbamazepine and dexamethasone may decrease amprenavir concentrations.

HMG-CoA reductase inhibitors (statins) may interact with protease inhibitors and increase the risk of myopathy including rhabdomyolysis. Concomitant use of protease inhibitors with lovastatin or simvastatin is not recommended. Other HMG-CoA reductase inhibitors (statins), may also interact with protease inhibitors. Use the lowest possible dose of atorvastatin with careful monitoring or consider the use of pravastatin or fluvastatin as alternative HMG-CoA reductase inhibitors in combination with TELZIR(r). The concomitant use of TELZIR(r)/ritonavir with lopinavir/ritonavir is not recommended because of significant pharmacokinetic interactions (see DRUG INTERACTIONS, Tables 4 and 5). Coadministration of protease inhibitors with PDE5 inhibitors is expected to substantially increase PDE5 inhibitor concentrations and may result in an increase in PDE5 inhibitor- associated adverse events, including hypotension syncope, visual changes, and priapism (see DRUG INTERACTIONS section and the complete prescribing information for PDE5 inhibitors). Concomitant use of PDE5 inhibitors (e.g. tadalafil, vardenafil or sildenafil) in patients receiving TELZIR(r) is not recommended. Concomitant use of St. John's Wort (Hypericum perforatum) or St. John's Wort- containing products and TELZIR(r) is not recommended. Coadministration of St. John's Wort with protease inhibitors, including TELZIR(r), is expected to substantially decrease protease inhibitor concentrations and may result in suboptimal levels of amprenavir and lead to loss of virologic response and possible resistance to amprenavir or the class of protease inhibitors. 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 CYP3A4 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 TELZIR(r) and ritonavir are coadministered with bepridil. Coadministration of amprenavir with rifabutin results in a 200% increase in rifabutin plasma concentrations (AUC). When ritonavir is coadministered with TELZIR(r), a larger increase in rifabutin concentrations is expected. A reduction of rifabutin dosage of at least 75% of the recommended dose is recommended when administered with TELZIR(r) and ritonavir and patients should be clinically monitored (see DRUG INTERACTIONS section). The TELZIR(r) oral suspension contains propyl and methyl parahydroxybenzoate. These products may cause an allergic reaction in some individuals. This reaction may be delayed. Use of TELZIR(r) with ritonavir at higher than approved dosages has resulted in elevated transaminase levels in some subjects and is not recommended for use.

Sulphonamide Allergies

TELZIR(r) should be used with caution in patients with a known sulphonamide allergy. Fosamprenavir calcium contains a sulphonamide moiety. The potential for cross- sensitivity between drugs in the sulphonamide class and TELZIR(r) is unknown. In the clinical studies where patients received TELZIR(r) as the sole protease inhibitor or in combination with low-dose ritonavir, the incidence of rash was similar in patients with a history of sulphonamide allergy as compared to those who did not have a sulphonamide allergy.

Contraceptives

There may be an increased risk of clinically significant hepatic transaminase elevations and hormonal levels may be altered with co-administration of fosamprenavir, ritonavir and oral contraceptives. Therefore, concomitant use of fosamprenavir, ritonavir and oral contraceptives is not recommended and alternate methods of non-hormonal contraception are recommended for women of childbearing potential (see DRUG INTERACTIONS). No data are available on the co-administration of fosamprenavir and ritonavir with estrogens and/or progestogens when used as hormonal replacement therapies. The efficacy and safety of these therapies with fosamprenavir and ritonavir has not been established.

Data from long-term carcinogenicity studies with amprenavir has revealed histopathological evidence for hepatocellular adenomas in males at the high dose of 500 mg/kg/day in mice or 750 mg/kg/day in rats, and altered hepatocellular foci were seen in male mice only at doses of 275 and 500 mg/kg/day. The clinical relevance of these findings is unknown (see TOXICOLOGY, Carcinogenicity section).

New-onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationship between protease inhibitor therapy and these events has not been established.

Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement ("buffalo hump"), peripheral wasting, breast enlargement, and "cushingoid appearance," have been observed in patients receiving antiretroviral therapies. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Lipid Elevations

Treatment with TELZIR(r) plus ritonavir has resulted in increases in the concentration of triglycerides (see ADVERSE REACTIONS). Triglycerides and cholesterol testing should be performed prior to initiating therapy with TELZIR(r) and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate (see DRUG INTERACTIONS).

Patients with Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthroses, in hemophiliac 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. Hemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Amprenavir and ritonavir are principally metabolized by the liver. TELZIR(r) with ritonavir at higher than recommended doses may result in transaminase elevations and should not be used. TELZIR(r) with ritonavir should not be used in patients with severe hepatic impairment (see CONTRAINDICATIONS). TELZIR(r) with ritonavir should be used with caution and at reduced doses in adults with mild or moderate impairment because amprenavir concentrations may be increased (see CLINICAL TRIALS and 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 or worsening of transaminase elevations. Appropriate laboratory testing should be conducted prior to initiating therapy and at periodic intervals during treatment.

Immune Reconstitution:

During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP and TB), which may necessitate further evaluation and treatment.

The safety and efficacy of TELZIR(r) have not been studied in patients with renal impairment. 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 hemodialysis or peritoneal dialysis will significantly remove them.

Resistance/Cross-Resistance

Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored, it is unknown what effect therapy with TELZIR(r) will have on the activity of subsequently administered protease inhibitors. TELZIR(r) has been studied in patients who have experienced treatment failure with protease inhibitors (see DETAILED PHARMACOLOGY: Description of Clinical Studies section).

Severe and life-threatening skin reactions, including Stevens-Johnson Syndrome, have occurred in patients treated with amprenavir (see ADVERSE REACTIONS).

Pregnant Women

There are no adequate and well-controlled studies in pregnant women. Animal reproduction studies are not always predictive of human response; therefore, administration of TELZIR(r) in pregnancy should be considered only if the benefit to the mother outweighs the possible risk to the fetus. Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to TELZIR(r), an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling GlaxoSmithKline's Drug Surveillance Department (1-800-387-7374).

Nursing Women

Although it is not known if amprenavir is excreted in human milk, amprenavir is secreted into the milk of lactating rats. Because of both the potential for HIV transmission and possible adverse effects of amprenavir, mothers should be instructed not to breastfeed if they are receiving TELZIR(r).

Pediatrics

No pharmacokinetics, safety or efficacy data are available for pediatric patients < 2 years old.

Geriatrics

The pharmacokinetics of TELZIR(r) 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.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

New onset of diabetes mellitus, hyperglycemia or exacerbations of existing diabetes mellitus has been reported in patients receiving antiretroviral protease inhibitors (see WARNINGS AND PRECAUTIONS section). An increase in CPK, myalgia, myositis, and rarely, rhabdomyolysis, has been reported with protease inhibitors, more specifically in association with nucleoside analogues. There have been reports of increased spontaneous bleeding in hemophiliac patients receiving antiretroviral protease inhibitors (see WARNINGS AND PRECAUTIONS section).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Studies in Adults:

The safety of TELZIR(r) (fosamprenavir calcium) in combination with ritonavir has been studied in adults in controlled clinical trials, in combination with various other antiretroviral agents. The most frequently (> 5% of adult subjects treated) reported undesirable effects were gastrointestinal events (nausea, diarrhea, abdominal pain and vomiting), headache and rash. Most undesirable effects associated with TELZIR(r)/ritonavir combination therapies were mild to moderate in severity, early in onset and rarely treatment limiting. For many of these events, it is unclear whether they are related to the TELZIR(r)/ritonavir combination, to concomitant treatment used in the management of HIV disease or to the disease process. Adverse events are listed by MedDRA system, organ class and frequency category. Frequencies are defined as Common (>= 1% - < 10%) and Rare (.1 in 10,000 and ,1 in 1000). Frequency categories for the events below have been based on clinical trials. Most of the adverse events below come from two large clinical trials in adults. The most frequent clinical adverse events related to study drugs, of at least moderate intensity (Grade 2 or more) and occurring in at least 2% of subjects treated with the TELZIR(r)/ritonavir combinations are included.

Table 2 Clinical Trial Adverse Drug Reactions

Frequency	Body System	Adverse Drug Reaction
Common	Gastrointestinal disorders	abdominal pain, diarrhea, flatulence, nausea and vomiting
	General disorders	fatigue
	Metabolic and nutrition disorders	hypertriglyceridemia
	Nervous system disorders	Headache
	Skin and subcutaneous tissue disorders	rash
Rare	Skin and subcutaneous tissue disorders	Stevens Johnson syndrome, angioedema

The adverse event profile was similar across all the respective adult studies: antiretroviral-naive (APV30002, n = 322) and PI-experienced (once-or twice-daily dosing, APV30003 n = 105 and n = 107 respectively), with the exception of flatulence. This was only reported at a frequency of > 2% in study APV30003 (PI-experienced subjects, TELZIR(r)/ritonavir 700/100 mg twice daily). In antiretroviral-naive patients (APV30002) receiving TELZIR(r)/ritonavir in combination with abacavir and lamivudine, drug hypersensitivity was commonly reported. All cases were reported as possibly related to abacavir. In cases of reported drug hypersensitivity, abacavir was discontinued and an alternative antiretroviral drug substituted. Few patients withdrew from the study due to these events. Erythematous or maculopapular cutaneous eruptions, with or without pruritus, may occur during therapy. The rash generally will resolve spontaneously without the necessity of discontinuing of treatment with the TELZIR(r)/ritonavir combination. Severe or life threatening rash, including Stevens Johnson syndrome, has been reported in less than 1% of subjects included in the clinical studies of TELZIR(r). Treatment with TELZIR(r) should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms or mucosal signs. In some patients, fat redistribution, including a decrease in subcutaneous peripheral fat, an increase in intra-abdominal fat, breast hypertrophy and an accumulation of retrocervical fat ("buffalo hump") has been reported with antiretroviral regimen containing a protease inhibitor. Metabolic abnormalities including hypertriglyceridemia, hypercholesterolemia, resistance to insulin and hyperglycemia have also been reported with protease inhibitor-containing regimens.

Studies in Pediatric Patients:

TELZIR(r) with and without ritonavir was studied in 144 pediatric patients 2 to 18 years of age in 2 open-label studies. Safety information was obtained from 75 pediatric patients receiving TELZIR(r) twice daily with or without ritonavir. All adverse events, regardless of causality, all drug-related adverse events, and all laboratory events occurred with similar frequency in pediatrics as compared to adults, with the exception of vomiting. Vomiting, regardless of causality, occurred more frequently among pediatric patients receiving TELZIR(r) twice daily with ritonavir (30% in patients between 2 and 18 years old) and without ritonavir (56%, in patients between 2 and 5 years old) as compared to adults receiving TELZIR(r) twice daily with ritonavir (10%) and without ritonavir (16%). The median duration of drug-related vomiting episodes was 1 day (range 1 to 62 days). Vomiting required the permanent discontinuation of treatment in 1 pediatric patient and temporary discontinuation of treatment in 3 pediatric patients, all of whom were receiving TELZIR(r) twice daily with ritonavir.

Abnormal Hematologic and Clinical Chemistry findings:

Clinical laboratory abnormalities (Grade 3 or 4) potentially related to treatment with TELZIR(r) in combination with ritonavir and reported in greater than or equal to 2% of adult subjects are summarized in Table 3.

Table 3 Clinical laboratory abnormalities (Grade 3 or 4) potentially related to treatment with TELZIR(r) in combination with ritonavir and reported in greater than or equal to 2% of adult subjects.

Clinical Abnormality (increased levels)	APV30002 (naive patients)	APV30003 (experienced patients)
ALT	8%	5%
AST	6%	4%
Serum Lipase	6%	4%
Triglycerides	6%	6%

Total cholesterol elevations were observed in less than 2% of adult subjects (< 1% APV30002; 0% APV30003). Grade 3 /4 neutropenia was documented in a higher proportion of pediatric subjects in Study APV20003 (20%) than in Study APV29005 (4%). The reason for the amount of neutropenia seen in APV20003 is unclear, and confounded by several factors (concomitant medications, compromised sample integrity, and changes in the toxicity grading scale). In APV29005, the rate of neutropenia was comparable to that seen in the adult population.

Post-Market Adverse Drug Reactions

Body as a Whole:

Redistribution/accumulation of body fat (see WARNINGS AND PRECAUTIONS: Fat redistribution section).

Endocrine and Metabolism:

Skin and Subcutaneous Tissue Disorders:

Stevens Johnson Syndrome and angioedema

DRUG INTERACTIONS

When TELZIR(r) (fosamprenavir calcium) and ritonavir are coadministered, 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 TELZIR(r) and ritonavir. Interaction studies have only been performed in adults. Amprenavir, the active metabolite of TELZIR(r), is metabolized in the liver by the cytochrome P450 enzyme system. Amprenavir inhibits CYP3A4. Caution should be used when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4. TELZIR(r) should not be administered concurrently with medications with a narrow therapeutic window that are substrates of CYP3A4. Ritonavir also inhibits CYP2D6 and induces CYP3A4, CYP1A2, CYP2C9 and glucuronosyl transferase. Therefore, the combination of ritonavir with TELZIR(r) may result in increased plasma concentrations of medicinal products that are primarily metabolized by CYP2D6. There are also other agents that may result in serious and/or life-threatening drug interactions (see CONTRAINDICATIONS section).

Drug interaction studies were performed with TELZIR(r) tablets and amprenavir formulations. The effects of coadministration of amprenavir on the AUC, Cmax, and Cmin are summarized in Table 4. The effects of TELZIR(r) on the pharmacokinetics of other drugs are summarized in Table 5.

Table 4 Drug Interactions: Pharmacokinetic Parameters for Amprenavir After Administration of TELZIR(r) (fosamprenavir calcium) in the Presence of Coadministered Drug

Table 5 Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir After Administration of TELZIR(r) (fosamprenavir calcium)

* *administered as a combination oral contraceptive tablet: ethinyl estradiol 0.035 mg/norethisterone 0.5 mg.

ND=interaction cannot be determined as Cmin was below the lower limit of quantification.

dose normalized to 100 mg methadone. The unbound concentration of the active moiety, R-methadone, was unchanged.

Although interactions with TELZIR(r) to the following drugs have not been studied, since fosamprenavir calcium is metabolized to the active moiety, amprenavir, the information is included for reference in Table 6.

Table 6 Drug Interactions: Pharmacokinetic Parameters after Administration of Amprenavir

| = Increase; | = Decrease; - = no significant change; NA = Not applicable; sd = Single-dose study

ND = Interaction cannot be determined as Cmin was below lower limit of quantitation

DOSAGE AND ADMINISTRATION

A physician experienced in the management of HIV infection should initiate therapy. Higher than approved dose combinations of TELZIR(r) (fosamprenavir calcium) with ritonavir is not recommended for use (see WARNINGS AND PRECAUTIONS) due to risk of transaminase elevations.

Once-daily administration of TELZIR(r)/ritonavir combination is not recommended in protease inhibitor-experienced patients or any pediatric patients.

Adults (>= 18 years of age):

Low doses of ritonavir may be used to enhance the pharmacokinetic profile of amprenavir. Higher than approved dose combinations of fosamprenavir with ritonavir is not recommended for use. The recommended oral dose of fosamprenavir, in combination with ritonavir is outlined below.

Therapy Naive Patients:

Once Daily: 1400 mg TELZIR(r) and 200 mg ritonavir Twice Daily: 700 mg TELZIR(r) and 100 mg ritonavir

Protease Inhibitor-Experienced Patients:

Twice Daily: 700 mg TELZIR(r) and 100 mg ritonavir TELZIR(r) tablets can be taken with or without food.

Therapy Naive Patients:

Once Daily: 1400 mg TELZIR(r) and 200 mg ritonavir Twice Daily: 700 mg TELZIR(r) and 100 mg ritonavir

Protease Inhibitor-Experienced Patients:

Twice Daily: 700 mg TELZIR(r) and 100 mg ritonavir TELZIR(r) oral suspension should be taken by adults without food and on an empty stomach. Shake the bottle vigorously before use.

Pediatric Patients (>= 6 years old):

The recommended dosage of TELZIR(r) in patients >= 6 years of age should be calculated based on body weight (kg) and should not exceed the recommended adult dose. The data in pediatrics are insufficient to recommend: (1) once daily dosing or (2) any dosing in patients < 6 years old. TELZIR(r) oral suspension is the recommended option for the most accurate dosing based on body weight. Pediatric patients should take oral suspension with food to aid palatability and assist adherence. The dose recommendations for this population are based on studies where the TELZIR(r) oral suspension was administered with ritonavir and with food, and therefore take into account the observed food effect (see DETAILED PHARMACOLOGY). Should vomiting occur within 30 minutes after dosing, the oral suspension should be re-dosed.

Therapy Naive and Protease Inhibitor Experienced:

18 mg/kg plus ritonavir 3 mg/kg administered twice daily not to exceed the adult dose of 700 mg plus ritonavir 100 mg.

Therapy Naive and Protease Inhibitor Experienced:

The adult tablet regimens of TELZIR(r)/ ritonavir may be used in patients who weigh at least 39 kg (ritonavir tablets may be used in patients who weight at least 33kg) and can swallow the tablets whole (see DOSAGE AND ADMINISTRATION: Adults > 18 years of age).

Pediatrics (< 2 years of age)

The safety and efficacy of TELZIR(r) in combination with ritonavir have not yet been established in this patient population.

Geriatrics (>= 65 years of age):

The safety and efficacy of TELZIR(r) in combination with ritonavir have not yet been established in this patient population.

Patients with Hepatic Impairment

TELZIR(r) in combination with ritonavir is contraindicated in adults with severe hepatic impairment (Child-Pugh score 10-15) (see CONTRAINDICATIONS). TELZIR(r) and ritonavir should be used with caution and at reduced doses in adults with mild or moderate impairment (see WARNINGS AND PRECAUTIONS and CLINICAL TRIALS). There are no data on the use of TELZIR(r) with ritonavir in pediatric patients with any degree of hepatic impairment; no dose recommendation can be made in this patient population. Adults with Mild Hepatic Impairment (Child-Pugh score 5-6) TELZIR(r) 700 mg twice daily plus ritonavir 100 mg once daily Adults with Moderate Hepatic Impairment (Child-Pugh score 7-9) TELZIR(r) 450 mg twice daily plus ritonavir 100 mg once daily Although it is not possible to achieve this dose using the tablet formulation, it can be obtained with the TELZIR(r) oral suspension.

Patients with Renal Impairment

No initial dose adjustment is considered necessary in patients with renal impairment.

OVERDOSAGE

There is no known antidote for TELZIR(r) (fosamprenavir calcium). It is not known whether amprenavir can be removed by peritoneal dialysis or hemodialysis. If overdosage occurs, the patient should be monitored for evidence of toxicity and standard supportive treatment applied as necessary. Although no data are available, administration of activated charcoal may be used to aid in removal of unabsorbed drug. For management of a suspected drug overdose, please contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Fosamprenavir calcium is a pro-drug of amprenavir, a non-peptidic competitive inhibitor of HIV-1 protease. It blocks the ability of viral protease to process gag and gag-pol polyproteins necessary for viral replication. Fosamprenavir calcium is rapidly hydrolyzed to amprenavir by enzymes in the gut epithelium as it is absorbed.

Absorption and Bioavailability

After multiple-dose oral administration of fosamprenavir calcium 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- .28) ug/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) ug/mL and AUC24,ss was 69.4 (59.7-80.8) h.ug/mL. After multiple-dose oral administration of fosamprenavir calcium 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- ug/mL occurring approximately 1.5 (0.75-5.0) hours after dosing (tmax). The mean steady-state plasma amprenavir trough concentration (Cmin) was 2.12 (1.77-2.54) ug/mL and AUC24,ss was 79.2 (69.0-90.6) h.ug/mL. The absolute oral bioavailability of amprenavir in humans has not been established. Fosamprenavir calcium tablet and oral suspension formulations, both given fasted, delivered equivalent plasma amprenavir AUC[?] values and the TELZIR(r) oral suspension formulation delivered a 14% higher plasma amprenavir Cmax as compared to the oral tablet formulation.

Effects of Food on Oral Absorption

The relative bioavailability of fosamprenavir calcium tablets was assessed in the fasted and fed states in healthy volunteers (standardized high-fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate). Administration of a single 1400 mg dose of TELZIR(r) in the fed state compared to the fasted state was associated with no changes in Cmax, Tmax or AUC0-[? ]. TELZIR(r) tablets may be taken with or without food.

The administration of fosamprenavir calcium 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. The TELZIR(r) oral suspension should be taken without food and on an empty stomach at the same dose as the tablets in the adult population; however, with food in the children and adolescent population (see DOSAGE AND ADMINISTRATION section).

Pediatrics (>= 6 years old)

The pharmacokinetics parameters of amprenavir were evaluated in 47 pediatric patients (6 to 18 years old) following administration of TELZIR(r) (oral suspension or tablets), with ritonavir and with food (see Table 9 below).

Table 9 Geometric Mean (95% CI) Steady-State Plasma Amprenavir Pharmacokinetic Parameters in Pediatric Patients ( >=6 years old) Receiving TELZIR(r) Plus Ritonavir Twice Daily

Geriatrics

The pharmacokinetics of fosamprenavir calcium have not been studied in patients over 65 years of age.

Gender

The pharmacokinetics of fosamprenavir calcium does not differ between males and females.

Hepatic Insufficiency

The pharmacokinetics of amprenavir were studied following the administration of TELZIR(r) and ritonavir for 14 days to HIV-1-infected adults with hepatic impairment (mild and moderate) and to matched controls with normal hepatic function. Following 2 weeks of dosing with TELZIR(r) plus ritonavir, the AUC of amprenavir was increased by approximately 22% in patients with mild hepatic impairment and by approximately 70% in patients with moderate hepatic impairment compared with HIV-1-infected patients with normal hepatic function. Protein binding of amprenavir was decreased in both mild and moderate hepatic impairment, with the unbound fraction at 2 hours (approximate Cmax) increasing by 18% to 57% and the unbound fraction at the end of the dosing interval (Cmin) increasing 50% to 102%. The pharmacokinetic parameters for amprenavir are summarized in Table 10 below.

Table 10 Pharmacokinetics of Amprenavir following the administration of TELZIR(r) and ritonavir for 14 days to HIV-1-infected adults with hepatic impairment (mild and moderate) vs. adults with normal hepatic function

There are no data on the use of TELZIR(r) with ritonavir in patients with severe hepatic impairment.

Renal Insufficiency

The safety and efficacy of TELZIR(r) have not been studied in patients with renal impairment. The renal elimination of unchanged amprenavir represents < 1% of the administered dose. Renal elimination of ritonavir is also negligible; therefore, the impact of renal impairment on amprenavir elimination should be minimal.

STORAGE AND STABILITY

Tablets

TELZIR(r) (fosamprenavir calcium) tablets should be stored between 15degC and 30degC.

Suspension

TELZIR(r) suspension should be stored between 2degC and 30degC. Do not freeze. The suspension should be discarded 28 days after first opening.

SPECIAL HANDLING INSTRUCTIONS

DOSAGE FORMS, COMPOSITION AND PACKAGING

TELZIR(r) (fosamprenavir calcium) tablets, 700 mg, are pink in colour and are capsule- shaped, with the letters "GX LL7" printed on one side of the tablet. TELZIR(r) tablets are available in bottles of 60 tablets per bottle with child-resistant closures. TELZIR(r) suspension is available in a bottle of 225 mL of 50 mg/mL fosamprenavir calcium oral suspension. The oral suspension is white to off-white in color with grape bubblegum and peppermint flavoring. A 10 mL dosing syringe is provided in the pack.

Tablets

TELZIR(r) tablets are available for oral administration in a strength of 700 mg of fosamprenavir as fosamprenavir calcium (equivalent to approximately 600 mg of amprenavir). Each 700 mg tablet contains the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and povidone K30. The tablet film-coating contains the inactive ingredients hypromellose, iron oxide red, titanium dioxide, and triacetin.

Suspension

TELZIR(r) oral suspension contains 50 mg/mL fosamprenavir as calcium salt (equivalent to approximately 43 mg/mL amprenavir). The oral suspension contains hypromellose, sucralose, propylene glycol, methyl parahydroxybenzoate, propyl parahydroxybenzoate, polysorbate 80, calcium chloride dihydrate, artificial grape bubblegum flavour, natural peppermint flavour, purified water.

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: fosamprenavir calcium Chemical name: (3S)-tetrahydrofuran-3-yl (1S,2R)-3-[[(4-aminophenyl) sulphony](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt Molecular formula and molecular mass: C25H34CaN3O9PS 623.7 Structural formula: Physicochemical properties: Description: Fosamprenavir calcium is a white to cream- coloured solid with a solubility of approximately 0.31 mg/mL in water at 25degC. Fosamprenavir calcium does not melt but decomposes at a temperature of 160degC. pH The pH of an aqueous solution of amprenavir at 0.31 mg/mL was determined to be 8.1 at 25degC.

CLINICAL TRIALS

Antiretroviral-Naive Adult patients

In antiretroviral-naive patients in APV30002, TELZIR(r) (fosamprenavir calcium) (1400 mg) given once daily in combination with low-dose ritonavir (200 mg) as part of a triple regimen including abacavir (300 mg twice daily) and lamivudine (150 mg twice daily) showed similar efficacy over 48 weeks compared to nelfinavir (1250 mg) given twice daily in combination with abacavir/lamivudine (300 and 150 mg twice daily respectively). In the ITT (Missing or Discontinuation =Failure (MD =F)) analysis, 68% of subjects receiving TELZIR(r)/ritonavir had plasma HIV-1 RNA below 400 copies/mL at week 48 compared to 65% (95% CI [-4 to 10% ]) in the nelfinavir arm. In the per protocol analysis the proportion of subjects was respectively 95% and 91% (95% CI [0 to 9%]). The majority of subjects who had reductions in viral load to < 400 copies/mL also had reductions to < 50 copies/mL (ITT (MD=F): 56% in the TELZIR(r)/ritonavir group vs. 52% in the nelfinavir group (95% CI [-5 to 11%]).

The median plasma HIV-1 RNA had decreased by 3.1 log10 copies/ml at week 48 in both TELZIR(r)/ritonavir and nelfinavir arms. The median baseline CD4 cell count was low (170 cells/mm3) in both groups. CD4+ cell counts increased in both the TELZIR(r)/ritonavir and nelfinavir groups, with median increases above baseline being similar in magnitude at Week 48 (+203 and +207 cells/mm3, respectively). The number of subjects that prematurely discontinued due to virological failure was greater in the nelfinavir arm (15%) of the study as compared to the TELZIR(r)/ritonavir- treated group (4%). In patients experiencing therapy failure from the latter group there was no evidence of the selection by the TELZIR(r)/ritonavir combination of any primary or secondary protease resistance mutations, including those associated with development of resistance to amprenavir or ritonavir. This was in contrast to a high incidence (56%) of the development of primary or secondary protease mutations in the nelfinavir arm. The frequency of acquisition of mutations associated with resistance to the concomitantly administered NRTI (abacavir, lamivudine) in the TELZIR(r)/ritonavir-treated subjects was low (4/32 (13%)). For the nelfinavir-treated subjects, the incidence of acquisition of mutation was significantly more frequent (31/54 (57%)), p < 0.001. The absence of resistance development and any cross-resistance to other PIs indicates that the failure of a regimen containing TELZIR(r)/ritonavir should not impact susceptibility or response to a subsequent PI-containing regimen.

Protease Inhibitor-Experienced Adult Patients

APV30003 is a randomized open-label study comparing two different regimens of the TELZIR(r)/ritonavir combination with lopinavir/ritonavir in protease inhibitor-experienced patients with virological failure (less than or equal to two PI's). TELZIR(r) given in combination with low-dose ritonavir both once daily (1400 mg/200 mg) or twice daily (700 mg/100 mg) in combination with two active reverse transcriptase inhibitors (NRTIs) showed similar efficacy over 24 weeks compared to the fixed-dose combination of lopinavir/ritonavir (400 mg/100 mg twice daily). All patients in this study had failed treatment with a previous protease inhibitor regimen (defined as plasma HIV-1 RNA that never went below 1,000 copies/ml after at least 12 consecutive weeks of therapy, or initial suppression of HIV-1 RNA which subsequently rebounded to > 1,000 copies/mL). Each treatment group demonstrated viral suppression as measured by the average area under the curve minus baseline (AAUCMB) for plasma HIV-1 RNA viral load over 24 weeks. Mean AAUCMB values (log10 copies/mL) for each group were: -1.48 for once-daily TELZIR(r)/ritonavir, -1.50 for twice-daily TELZIR(r)/ritonavir, and -1.66 for lopinavir/ritonavir. The 2 regimens of TELZIR(r)/ritonavir were comparable to the lopinavir/ritonavir regimen based on AAUCMB. The TELZIR(r)/ritonavir regimens (once and twice daily) and the lopinavir/ritonavir twice-daily regimen showed similar immunological improvements through 24 weeks of treatment as measured by median change from baseline in CD4+ cell count (TELZIR(r)/ritonavir once daily: 72 cells/mm3; TELZIR(r)/ritonavir twice daily: 62 cells/mm3; lopinavir/ritonavir twice daily: 63 cells/mm3).

Pediatrics

There is no data available in pediatric patients under 2 years old. Two open label studies were conducted in pediatric patients 2 to 18 years of age. One study (APV29005) evaluated twice daily dosing regimens of TELZIR(r)with ritonavir while the other (APV20003) evaluated once daily dosing of f TELZIR(r) with ritonavir; both studies in combination with other antiretroviral agents. Doses and formulations (TELZIR(r) tablets or oral suspension, ritonavir capsules or oral solution) were determined by patient weight and age. There was insufficient data to support once daily dosing in any pediatric patient population. Twenty seven protease inhibitor naive and 30 protease inhibitor experienced pediatric patients received either the TELZIR(r) Oral Suspension or Tablets with ritonavir twice daily. At Week 24, 70% of protease inhibitor naive (19/27) and 57% of protease inhibitor experienced (17/30) patients achieved HIV 1 RNA <400 copies/mL; median increases from baseline in CD4+ cell counts were 131 cells/mm3 and 149 cells/mm3 in protease inhibitor naive and experienced patients, respectively.

DETAILED PHARMACOLOGY

Absorption

After multiple-dose oral administration of fosamprenavir calcium 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 mean steady-state plasma amprenavir trough concentration (Cmin) was 1.45 (1.16- 1.81) ug/ml and AUC24,ss was 69.4 (59.7-80.8) h.ug/mL. After multiple-dose oral administration of fosamprenavir calcium 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- g/mL occurring approximately 1.5 (0.75-5.0) hours after dosing (Tmax). The mean steady-state plasma amprenavir trough concentration (Cmin) was 2.12 (1.77-2.54) ug/mL and AUC24,ss was 79.2 (69.0-90.6) h.ug/mL. Fosamprenavir calcium tablet and oral suspension formulations, both given fasted, delivered an equivalent plasma amprenavir AUC values and the fosamprenavir calcium oral suspension formulation delivered a 14% higher plasma amprenavir Cmax as compared to the oral tablet formulation. The absolute bioavailability of fosamprenavir calcium in humans has not been established.

Administration of the fosamprenavir calcium 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.

Administration of fosamprenavir calcium oral suspension formulation with a high-fat meal reduced plasma amprenavir AUC by approximately 25% and Cmax by approximately 40% as compared to the administration of this formulation in the fasted state. The fosamprenavir calcium oral suspension should be taken without food at the same dose as the tablets (see DOSAGE AND ADMINISTRATION section). To aid palatability and assist compliance, the dosing recommendations are to administer the fosamprenavir calcium oral suspension with food in children and adolescents. The dose recommendations for this population were based on the pediatric studies where the TELZIR(r) oral suspension was administered with food, and therefore take into account the observed food effect (see DOSAGE and ADMINISTRATION section).

Table 12 Geometric Mean (95% CI) Steady-State Plasma Amprenavir Pharmacokinetic Parameters

Distribution

The apparent volume of distribution (Vz/F) of amprenavir following administration of TELZIR(r) 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. This value is decreased by approximately 40% when TELZIR(r) is coadministered with ritonavir, most likely due to an increase in amprenavir bioavailability. Amprenavir is approximately 90% protein bound. It is bound to the alpha-1 acid glycoprotein (AAG) and albumin, but has a higher affinity for AAG.

Metabolism

Fosamprenavir calcium is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate as it is absorbed through the gut epithelium, following oral administration. Amprenavir is primarily metabolized 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. Therefore drugs that are inducers, inhibitors or substrates of CYP3A4 must be used with caution when administered concurrently with TELZIR(r) and ritonavir (see CONTRAINDICATIONS and DRUG INTERACTIONS sections).

Elimination

Following administration of TELZIR(r) the half-life of amprenavir is 7.7 hours. The plasma amprenavir half-life is increased when TELZIR(r) is coadministered 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 feces.

Special populations

Pediatrics (>= 6 years old) The pharmacokinetics parameters of amprenavir were evaluated in 47 pediatric patients (6 to 18 years old) following administration of TELZIR(r) (oral suspension or tablets) with ritonavir and with food.

Table 13 Pharmacokinetic parameters in pediatric and adolescent patients receiving fosamprenavirwith ritonavir twice daily

Effects of Food on Oral Absorption

After oral administration, fosamprenavir calcium is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. The conversion of fosamprenavir calcium to amprenavir appears to primarily occur in the gut epithelium. The pharmacokinetic properties of amprenavir following co administration of TELZIR(r) and ritonavir have been evaluated in healthy adult subjects and HIV-infected patients and no substantial differences were observed between these two groups. Coadministration of ritonavir with TELZIR(r) enhances plasma amprenavir pharmacokinetics primarily through inhibition of amprenavir metabolism, thus achieving plasma amprenavir concentrations above the IC50 values for amprenavir against HIV from patients with various levels of HIV protease inhibitor experience, including PI-naive and multiple-PI-experienced patients. TELZIR(r) tablet and oral suspension formulations, both given fasted, delivered equivalent plasma amprenavir AUC[?] values and the TELZIR(r) oral suspension formulation delivered a 14% higher plasma amprenavir Cmax as compared to the oral tablet formulation.

MICROBIOLOGY

TELZIR(r) (fosamprenavir calcium) requires metabolism in vivo to generate the active moiety, amprenavir. In the absence of in vivo metabolism, fosamprenavir calcium has negligible activity in in vitro enzymatic and antiviral assays, and therefore such assays are performed using amprenavir. Amprenavir is a competitive inhibitor of the HIV protease. It blocks the ability of the viral protease to cleave the precursor polyproteins necessary for viral replication. Coadministration of ritonavir with TELZIR(r) increases plasma amprenavir AUC by approximately 2times and plasma Ct,ss by 4 to 6times, compared to values obtained when TELZIR(r) is administered alone. Administration of TELZIR(r)/ritonavir combination regimens (700/100 mg twice daily and 1400/200 mg once daily) result in 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 ug/mL) to heavily PI-experienced (mean protein-binding adjusted IC50 = 0.90 ug/mL).

HIV-1 isolates with a decreased susceptibility to amprenavir have been selected in vitro and obtained from patients treated with fosamprenavir calcium. Genotypic analyses of isolates from amprenavir-treated patients showed mutations in the HIV-1 protease gene resulting in amino acid mutations in the p7/p1 and p1/p6 gag and gag-pol polyprotein precursor cleavage sites. Some of these amprenavir resistance-associated mutations have also been detected in HIV-1 isolates from antiretroviral-naive patients treated with TELZIR(r). Of these 488 antiretroviral-naive patients treated with TELZIR(r) or TELZIR(r)/ritonavir, 61 patients (29 receiving TELZIR(r) and 32 receiving TELZIR(r)/ritonavir) with virological failure (plasma HIV-1 RNA > 1,000 copies/mL on 2 occasions on or after Week 12) were genotyped. Five of the 29 antiretroviral-naive patients (17%) receiving TELZIR(r) without ritonavir in Study APV30001 had evidence of genotypic resistance to amprenavir: I54L/M (n =2), I54L + L33F (n =1), V32I + I47V (n=1), and M46I + I47V (n=1). No amprenavir-associated mutations were detected in antiretroviral-naive patients treated with TELZIR(r)/ritonavir in Study APV 30002.

Varying degrees of HIV-1 cross-resistance among protease inhibitors have been observed. An association between virologic response at 48 weeks (HIV-1 RNA level < 400 copies/mL) and PI-resistant mutations detected in baseline HIV-1 isolates from PI- experienced patients receiving TELZIR(r)/ritonavir twice daily (n= 88), or lopinavir/ritonavir twice daily (n= 85) in Study APV 30003 is shown in Table 14. The majority of subjects have previously received either one (47%) or 2 PIs (36%), most commonly nelfinavir (57%) and indinavir (53%). Out of 102 subjects with baseline phenotypes receiving twice-daily TELZIR(r)/ritonavir, 54% (55) had resistance to at least one PI with 98% (54) of those having resistance to nelfinavir. Out of 97 subjects with baseline phenotypes in the lopinavir/ritonavir arm, 60% (58) had resistance to at least one PI with 97% (56) of those having resistance to nelfinavir.

Table 14 Responders at Study Week 48 by Presence of Baseline PI Resistance- Associated Mutations *

The virologic response based upon baseline phenotype was assessed. Baseline isolates from PI-experienced patients responding to TELZIR(r)/ritonavir twice daily had a median shift in susceptibility to amprenavir relative to a standard wild-type reference starin 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(r). Isolates from 15 of the 20 patients receiving twice-daily TELZIR(r)/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 184V.

TOXICOLOGY

Fosamprenavir (as the calcium salt) has a very low order of acute oral toxicity in mice and rats. The oral maximum non-lethal doses were greater than 71times the proposed therapeutic dose of 1400 mg (equivalent to 28 mg/kg/day based on a 50 kg human). Fosamprenavir (as the disodium salt) also has a low order of intravenous toxicity. Microscopic findings following acute intravenous administration were similar in both species and consisted of myocardial changes (fibre degeneration and/or necrosis) and liver changes (hepatocellular hypertrophy, reduced glycogen vacuolation and periportal hepatocellular vacuolation). The myocardial changes were not observed during acute- or repeat-dose toxicity studies with amprenavir, or during oral acute- and repeat-dose studies with TELZIR(r). Since fosamprenavir calcium is indicated for oral dosing at relatively lower dosages, it is considered unlikely that these findings would be of significance for the clinical use of fosamprenavir (as the calcium salt).

Fosamprenavir calcium has been administered to rats at dose levels of up to 2240 mg/kg/day for 6 months and to dogs at dose levels of up to 337 mg/kg/day for 9 months. Gastrointestinal effects were seen in both rats (salivation only) and dogs (salivation, vomiting and fecal alterations), throughout all of the repeat-dose studies with fosamprenavir calcium. In dogs, these effects led to dehydration, electrolyte loss and deterioration to moribund condition in a number of animals. Liver was the primary target organ for fosamprenavir calcium toxicity in laboratory animals. This organ toxicity consisted of increases in serum alanine aminotransferase, aspartate aminotransferase, glutamate dehydrogenase, g-glutamyltransferase or alkaline phosphatase activity, increased liver weights and microscopic findings, including hepatocyte necrosis. Some of the liver findings may be the result of induction of drug metabolizing enzymes, which in turn contributed to changes in the thyroid gland that were noted in the 4-week rat study. The No Observable Adverse Effect Level (NOAEL) was generally determined to be equivalent to or lower than the low dose level in the longest duration repeat-dose studies in rats and dogs due to clinical signs (salivation and fecal alterations), clinical pathology changes and microscopic organ changes. Most of these changes were reversible after cessation of dosing. Systemic exposure to fosamprenavir calcium (prodrug) and amprenavir (active form) at the high dose level at the end of the 6-month rat study is equivalent to 61 times and 1.0 times, respectively, the exposure seen in humans at the proposed therapeutic fosamprenavir calcium dose (1400 mg/day with 200 mg/day ritonavir, AUC in humans 0.024 and 83.2 g.h/mL, respectively). In dogs, exposure to fosamprenavir calcium and amprenavir at the high dose level at the end of the 9-month study is equivalent to 46 times and 2.5 times the exposure seen in humans.

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 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 835 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. Fosamprenavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays. These assays included bacterial reverse mutation (Ames), mouse lymphoma, rat micronucleus, and chromosome aberrations in human lymphocytes. The significance of the observed effects for humans is uncertain. Amprenavir was not mutagenic or genotoxic in a battery of in vivo and in vitro genetic toxicity assays, including bacterial reverse mutation (Ames Test), mouse lymphoma, rat micronucleus, and chromosome aberration in human peripheral lymphocytes (see TOXICOLOGY, Mutagenicity section).

Neither fosampreanvir nor amprenavir increased the gene mutation frequency in prokaryotic (using Ames and the Yahagi-modified Ames tests at concentrations up to 5000 ug/plate) or eukaryotic cells (using the mouse lymphoma L5178Y tk+/- assay at concentrations up to 5000 or 546 ug/mL, respectively) in vitro. There was no evidence that fosamprenavir calcium had any clastogenic activity in an in vivo assay (oral rat micronucleus test at doses up to 2990 ug/kg).

In a rat fertility study, there was a reduction in gravid uterine weights following administration of 2240 mg/kg/day fosamprenavir calcium to F0 female rats, likely related to the lower number of ovarian corpora lutea and uterine implantation sites at this dose. There was no effect on pre- and post-implantation loss or mating success, and the incidence of pregnancy was not affected. Relative testes weights were increased at all dose levels but this finding was not accompanied by microscopic changes in the testes or epididymides. Testes weights were unaffected during repeat-dose studies with rats at similar dosages. In a rat-embryo fetal-development study with fosamprenavir calcium, maternal toxicity (reduced body weight gain and food consumption) was observed at 300 to 2240 mg/kg/day. There was no evidence of adverse effects on embryo fetal development at any dose level. In a rabbit-embryo fetal-development study, dose-related maternal toxicity (body weight loss, reduced food consumption, mortality and an increased incidence of abortion at 672.8 mg/kg/day) was observed. There was no evidence of adverse effects on embryo fetal development at any dose level. In a pre- and post-natal development study in rats, reduced body weight in F1 pups was seen at all dose levels. An increase in mortality was observed in F1 male and female pups at 2240 mg/kg/day group between Lactation Days 1 to 21. The reduced F1 body weights were considered at least partly responsible for developmental delays seen at all dose levels, and also were considered contributory to effects on reproductive function in the F1 generation (prolonged precoital interval and gestation period, and a slight reduction in implantation sites) at 2240 mg/kg/day. There were no effects on F2 body weight or survival. Systemic exposure to amprenavir in the rat-fertility and rat- and rabbit-embryo fetal- development studies with fosamprenavir calcium was low and thus no or very low safety margins over clinical exposure were demonstrated. The doses of fosamprenavir calcium used in these studies were limited by maternal toxicity. The lack of clear safety margins for amprenavir precludes extrapolation to the human situation.

In young rats, treatment-related mortality was seen at fosamprenavir calcium dose levels > 553 mg/kg/day. A dose level of 300 mg/kg/day resulted in increased AST and ALT levels and increased liver weights. In males, reversible hyaline droplet accumulation in the cortical tubule epithelial cells was noted in male rats at > 100 mg/kg/day. The finding was considered likely due to male rat specific metabolism of a2u-globulin and is of limited toxicological relevance to humans. Fosamprenavir calcium was non-toxic in an acute dermal toxicity study in the rat, and was non-irritant to rabbit skin. Fosamprenavir calcium was a slight irritant to the rabbit eye, but showed no potential for antigenicity in the rat or guinea pig, and was not a dermal sensitizer in the guinea pig. Coadministration of amprenavir with abacavir (a nucleoside reverse transcriptase inhibitor) to rats caused some clinical pathology changes that were most marked at the highest combination dosage, but these were reversible. Ovarian interstitial cell hypertrophy/hyperplasia occurred only in animals dosed with the combination, but this was reversible and follicular maturation was unaffected. Effects on the liver and adrenal cortex were more severe in the combination groups, but showed evidence of reversal once treatment stopped. Other findings were generally consistent with those observed after administration of either drug alone. Coadministration had no apparent effect on systemic exposure to either compound.

REFERENCES

Adkins JC, Faulds D, Moyle G, Hughes WT. Amprenavir. Drugs 1998; 55(6); 837-844.

AGENERASE

Baune B, Furlan A, Taburet M, Farinotti R. Effects of Selected Antimalarial Drugs and Inhibitors of Cytochrome P-450 on Halofantrine Metabolism by Human Liver Metabolism. Drug Metabolism and Disposition 1999; Vol.27, No.5; 565-568. Cato A, Cavanaugh J, Shi H, Hsu A, Leonard J, Granneman R. The Effect of Multiple Doses of Ritonaivr on the Pharmacokinetics of Rifabutin. Clinical Pharmacol Ther. 1998; 63(4): 414-421. Charbit B, Becquemont L, Lepere B, Peytavin G, Funck-Brentano C. Pharmacokinetic and pharmacodynamic interaction between grapefruit juice and halofantrine. Clinical Pharmacology and Therapeutics, 2002, Volume 72, (5); 514-523. Decker CJ, Laitinen LM, Bridson GW, Raybuck SA, Tung RD, Chaturvedi PR. Metabolism of amprenavir in liver microsomes: Role of CYP3A4 inhibition for drug interactions. J. Pharm. Sci. 1998; 87(7): 803-807. DeSimone JA, Pomerantz RJ, Babinchak TJ. Inflammatory Reactions in HIV-1- Infected Persons after initiation of Highly Active Antiretroviral Therapy. Ann Intern Med 2000; 133(6): 447-454. Dresser GK, Spence DJ, Bailey DG. Pharmacokinetic-Pharmacodynamic consequences and Clinical Relevance of Cytochrome P450 3A4 Inhibition. Clinical Pharmacokinetics 2000; 38(1); 41-57. EuroHIV. EuroHIV. HIV/AIDS Surveillance in Europe. Mid-year report 2005. European Centre for Epidemiological Monitoring of HIV/AIDS, France; 2006. 72. Fung HB, Kirschenbaum HL, Hameed R. Amprenavir: A new human immunodeficiency virus Type 1 protease inhibitor. Clin Ther 2000; 22(5): 549- 572. Gortmaker SL, Hughes M, Cervia J, Brady M, Johnson GM, Seage GR, III, et al. Effect of combination therapy including protease inhibitors on mortality among children and adolescents infected with HIV-1. N Engl J Med 2001 Nov 22; 345(21):1522-8. Hirsch H, Kaufmann G, Sendi P, Battegay M. Immune Reconstitution in HIV- infected Patients. Clinical Infectious Disease 2004; 38(8): 1159-66. Joint United Nations Programme on HIV/AIDS (UNAIDS). 2006 Report on the Global AIDS Epidemic: Executive Summary. United Nations Programme on HIV/AIDS, Switzerland; 2006.

KALETRA

Livington DJ, Pazhanisamy S, Porter DJ, Partaledis JA, Tung RD, Painter GR, et al. Weak binding of VX-478 to human plasma proteins and implications for anti- human immunodeficiency virus therapy. J Infect Dis 1995; 172(5): 1238-1245. Mirmirani P, Maurer TA, Herndier B, McGrath M, Weistein MD, Berger TG. Sarcoidosis in a patient with AIDS: A manifestation of immune restoration syndrome. J Am Acad Dermatol 1999; 41: 285-6. Nachman SA, Stanley K, Yogev R, Pelton S, Wiznia A, Lee S, et al. Nucleoside analogs plus ritonavir in stable antiretroviral therapy-experienced HIV-infected children: a randomized controlled trial. Pediatric AIDS Clinical Trials Group 338 Study Team. JAMA 2000 Jan 26; 283(4):492-8.

NORVIR

Painter GR, Ching S, Reynolds D, St. Clair B, Elkins M, Blum R, et al. 141W94. Anti-HIV. Drugs Future 1996; 21(4): 347-350. Pazhanisamy S, Partaledis JA, Rao BG, Livingston DJ. In vitro selection and characterization of VX-478 resistant HIV-1 variants. Adv. Exp. Med. Biol. 1998; 436: 75-83. Polk RE, Brophy DF, Israel DS, Patron R, Sadler BM, Chittick GE, et al. Pharmacokinetic Interaction between Amprenavir and Rifabutin of Rifampin in Healthy Males. Antimicrob Agents Chemother. 2001; 45(2): 502-508. Ramos A, Asensio A, Perales I, Montero MC, Martin T. Prolonged paradoxical reaction of tuberculosis in an HIV-infected patient with initiation of Highly Active Antiretroviral Therapy. Eur J Clin Microbiol Inf Dis 2003; 22(6): 374-376 Saez-Llorens X, Violari A, Deetz CO, Rode RA, Gomez P, Handelsman E, et al. Forty-eight-week evaluation of lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virus-infected children. Pediatr Infect Dis J 2003 Mar; 22(3):216-24. Safdar A, Rubocki RJ, Horvath JA, Narayank K, Waldron RL. Fatal immune restoration disease in human immunodeficiency type-1 infected patients with progressive multifocal leukoencephalopathy: Impact of antiretroviral therapy- associated immune reconstitution. Clinical Infectious Diseases 2002; 35(10): 1250-7. Salama C, Policar M, Venkataraman M. Isolated pulmonary Mycobacterium avium Complex infection in patients with Human Immunodeficiency Virus infection: case reports and literature review Clinical Infectious Diseases 2003; 37(3): 374-376. Sharland M, Blanche S, Castelli G, Ramos J, Gibb DM. PENTA guidelines for the use of antiretroviral therapy, 2004. HIV Med 2004 Jul; 5 Suppl 2:61-86. Shelburne SA, Hamill RJ, Rodriguez-Barradas MC, Greenberg SB, Atmar RL, Musher DM, et al. Immune Reconstitution Inflammatory Syndrome. Medicine 2002; 81(3): 213-227 Singh R, Chang SY, Taylor LC. In vitro metabolism of a potent HIV-protease inhibitor (141W94) using rat, monkey and human liver S9. Rapid Communications in Mass Spectrometry 1996; 10(9): 1019-26. St. Clair MH, Millard J, Rooney J, Tisdale M, Parry N, Sadler BM, et al. In vitro antiviral activity of 141W94 (VX-478) in combination with other antiretroviral agents. Antiviral Res 1996; 29: 53-6.

SUSTIVA

Thaker H, Ong LC. Localised Mycobacterium avium complex infection in a patient on HAART Clin Microbiol Inf 2000; 6(10): 564-566. The French ANRS (National Agency for AIDS Research) AC11 Resistance Group, HIV-1 genotypic drug resistance interpretation algorithms, Tables of rules, 2006, Protease inhibitors, available at http://www.hivfrenchresistance.org/2006/tab2.html (3rd September, 2006). (Available upon request). The Monogram Team, PhenosenseGT(tm) HIV, PhenosenseGT(tm) HIV Report Form, available at http://www.monogramhiv.com/pdf/PSGT-Sample-Report- 2006.pdf (3rd September, 2006). (Available upon request). Tisdale M, Myers RE, Maschera B, Parry NR, Oliver NM, Blair ED, et al. Cross- resistance analysis of human immunodeficiency virus type 1 variants individually selected for resistance to five different protease inhibitors. Antimicrob Agents Chemother1995; 39(8): 1704-10. Tisdale M, Myers R, Randall S, Maguire M, Ait-Khaled M, Elston R, et al. Resistance to the HIV protease inhibitor amprenavir in vitro and in clinical studies. A review. Clin Drug Invest 2000; 20(4): 267-285. Trevenzoli M, Cattelan AM, Marino F, Marchioro U, Cadrobbi P. Sarcoidosis and HIV infection: a case report and a review of the literature. Postgrad Med J 2003; 79: 535-538.

VIRAMUNE

This leaflet is part III of a three-part "Product Monograph" published when TELZIR(r) was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about TELZIR(r). Please read this leaflet carefully before you start to take TELZIR(r). Contact your doctor or pharmacist if you have any questions about the drug.

The name of your medicine is TELZIR(r) (fosamprenavir calcium). TELZIR(r) can only be obtained with a prescription from your doctor. TELZIR(r) is an antiretroviral medication. It is used together

TELZIR(r) is to be taken in combination with ritonavir. It is therefore important that you carefully read the Consumer Information Leaflet that is provided with that medicine. If you have any further questions about ritonavir please ask your doctor or pharmacist.

The Human Immunodeficiency Virus (HIV) is a retrovirus. Infection with HIV damages the immune system and can lead to

TELZIR(r) is an antiretroviral medication. It belongs to a group of medicines called protease inhibitors. TELZIR(r) in combination with other antiretroviral agents reduces the amount of HIV in your blood. Response to treatment with TELZIR(r) varies among patients. Your doctor will be monitoring the effectiveness of your treatment. TELZIR(r) does not cure AIDS or kill the virus, but may help to prevent further damage to the immune system by slowing the production of new viruses.

Canada), diazepam, ergot medications, flurazepam, midazolam, pimozide, triazolam, flecainide, and propafenone.

Do not take rifampin with TELZIR(r) because this drug reduces the effectiveness of TELZIR(r).

TELZIR(r) tablets are available for oral administration in a strength of 700 mg of fosamprenavir as fosamprenavir

TELZIR(r) oral suspension contains 50 mg/mL fosamprenavir as calcium salt (equivalent to approximately 43 mg/mL amprenavir).

Each 700 mg tablet contains the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and

povidone K30. The tablet film-coating contains the inactive ingredients hypromellose, iron oxide red, titanium dioxide, and triacetin.

The oral suspension contains hypromellose, sucralose, propylene glycol, methyl parahydroxybenzoate, propyl parahydroxybenzoate, polysorbate 80, calcium chloride dihydrate, artificial grape bubblegum flavour, natural peppermint flavour and purified water.

TELZIR(r) suspension is available in a bottle of 225 mL of 50 mg/mL fosamprenavir calcium oral suspension.

The safe use of TELZIR(r) in pregnancy has not been determined. Your doctor will provide advice on

You are breastfeeding. The active substance in TELZIR(r) is likely to be found in human breast milk and there is no safety data available following treatment with TELZIR(r) in babies.

You have hemophilia. There have been reports of increased bleeding in patients with hemophilia taking protease inhibitors.

You are taking oral contraceptives, as TELZIR(r) may interact with contraceptives to make them less effective. Your doctor may advise that you use an alternative method to prevent pregnancy while you are taking TELZIR(r).

You are taking or planning to take any other drug(s), including those available without a prescription, and herbal medicines such as St. John's Wort (Hypericum perforatum). Taking this herb may reduce the effectiveness of TELZIR(r).

TELZIR(r) oral solution contains propyl and methyl parahydroxybenzoate. These products may cause an allergic reaction in some individuals. This reaction may be delayed.

TELZIR(r) helps to control the amount of HIV found in your blood but is not a cure for HIV infection. You will need to take TELZIR(r) every day. Do not stop taking TELZIR(r) without first talking to your doctor.

HIV is usually spread by sexual contact, blood transfer or by contaminated needles. The risk of spreading HIV still exists during TELZIR(r) therapy; thus, the practice of 'safe sex' and avoidance of sharing needles is necessary.

You may continue to develop other infections and other illnesses associated with HIV disease. You should therefore keep in regular contact with your doctor while taking TELZIR(r).

Mothers with HIV should not breastfeed their infants because HIV in the breastmilk can infect the infant.

There is no information currently available that suggests taking TELZIR(r) affects the ability to drive or operate machinery.

Some drugs may change the usefulness and safety of TELZIR(r). It is important that you tell your doctor about all the medicines you are taking or planning to take, including all those that you have bought yourself. This is very important, as using more than one medicine at the same time can strengthen or weaken the effect of the medicine, causing in some cases serious medical conditions. TELZIR(r) may interact with other medicines you are being treated with. Some of the medicines that can interact with amprenavir include: amiodarone, phenobarbital, phenytoin, lidocaine (systemic),

tricyclic antidepressants, warfarin, PDE5 inhibitors (e.g. sildenafil, vardenafil, tadalafil), cholesterol-lowering drugs (statins) (e.g. lovastatin, simvastatin), anticonvulsants (e.g. carbamazepine), anti-inflammatory drugs (e.g. dexamethasone), anti-malarial drugs (e.g. halofantrine), quinidine, fluticasone, paroxetine, trazodone, methadone, itraconazole, ketoconazole and immunosuppresants (e.g. cyclosporine, rapamycin and tacrolimus).

Both regimens must be administered in combination with other antiretroviral agents.

Once-daily administration of TELZIR(r)/ritonavir combination is not recommended in protease inhibitor- experienced patients.

The twice-daily plus ritonavir dose is supported by pharmacokinetic and safety data (see CLINICAL PHARMACOLOGY and ADVERSE REACTIONS

Take TELZIR(r) tablets as your doctor has advised you. Take TELZIR(r) oral suspension as your doctor has advised you.

Low doses of ritonavir may be used to enhance the pharmacokinetic profile of amprenavir. The recommended

TELZIR(r) oral suspension should be taken by adults without food and on an empty stomach. Shake the bottle vigorously before use.

taste and better encourage compliance with dosing. If vomiting occurs within 30 minutes of dose, the oral suspension dose should be taken again.

18 mg/kg plus ritonavir 3 mg/kg administered twice daily not to exceed the adult dose of 700 mg plus ritonavir 100 mg.

The adult tablet regimens of TELZIR(r)/ ritonavir may be used in patients who weigh at least 39 kg (ritonavir tablets may be used in

The use of TELZIR(r) has not been studied in pediatric patients below the age of 2.

If you have a liver problem, your dose may be altered. Please follow the instructions of your doctor.

You should immediately contact either your doctor, your hospital emergency department or the nearest poison control centre.

If you forget to take TELZIR(r), take it as soon as you remember. Then continue as before. Do not double dose.

Always tell your doctor or pharmacist about any undesirable effects, even those not mentioned in this leaflet. If you feel ill in any other way that you do not understand, tell your doctor or pharmacist.

The following undesirable effects are thought to be related to treatment with TELZIR(r): feeling sick, diarrhea, tiredness, headache, abdominal pain, passing gas, rash, higher amounts of a type of fat in the blood and vomiting.

Changes in body fat have been seen in some patients taking antiretroviral therapy. These changes include increased amounts of fat in the upper back and neck ("buffalo hump"), breasts and around the trunk. Loss of fat from the legs, arms and face may also happen. The cause and long-term health effects of these conditions are not known at this time.

Your doctor will test your blood regularly to check for increases in liver enzymes and blood fats. These have been reported in patients taking TELZIR(r). Your blood will also be checked for increases in blood sugar levels, as occasionally protease inhibitors have been shown to cause this.

If you have a severe skin rash, check with your doctor as he may advise you to stop taking TELZIR(r).

This is not a complete list of side effects. For any unexpected effects while taking TELZIR(r), contact your doctor or pharmacist.

Store TELZIR(r) suspension between 2degC and 30degC. Do not freeze. Discard the suspension 28 days after first opening.

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

NOTE: Should you require information related to the management of side effects, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

Remember: TELZIR(r) is for you. Never give it to someone else. It may harm them even if their symptoms are the same as yours.

This leaflet does not tell you everything about TELZIR(r). If you have any questions or are not sure about anything, then ask your doctor or pharmacist. You may need to read this leaflet again. Please do not throw this leaflet away until you are no longer taking TELZIR(r). This document plus the full product monograph, prepared for health professionals can be found at: http://www.gsk.ca

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
Oral	Tablet/ 700 mg fosamprenavir Suspension/ 50 mg/mL fosamprenavir	colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, povidone K30, hypromellose, iron oxide red, titanium dioxide, and triacetin. hypromellose, sucralose, propylene glycol, methyl parahydroxybenzoate, propyl parahydroxybenzoate, polysorbate 80, calcium chloride dihydrate, artificial grape bubblegum flavour, natural peppermint flavour, purified water.

Drug Class	Drugs
Ergot Derivatives	Dihydroergotamine, ergonovine, ergotamine, methylergotamine
GI Motility agents	Cisapride
Antihistamine	astemizole, terfenadine
Antiarrhythmic	flecainide, propafenone
Neuroleptic	Pimozide
Sedatives/Hypnotics	Midazolam, triazolam, diazepam, flurazepam

Coadministered Drug(s) and Dose(s)	Dose of TELZIR (r) *	n	% Change in Amprenavir Pharmacokinetic Parameters (90% CI)
Coadministered Drug(s) and Dose(s)	Dose of TELZIR (r) *	n	C max	AUC	C min
Antacid (MAALOX TC (r) ) 30 mL single dose	1,400 mg single dose	30	\|35 (\|24 to \|42)	\|18 (\|9 to \|26)	\|14 (\|7 to \|39)
Atorvastatin 10 mg q.d. for 4 days	1,400 mg b.i.d. for 2 weeks	16	\|18 (\|34 to \|1)	\|27 (\|41 to \|12)	\|12 (\|27 to \|6)
Atorvastatin 10 mg q.d. for 4 days	700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks	16	-	-	-
Efavirenz 600 mg q.d. for 2 weeks	1,400 mg q.d. plus ritonavir 200 mg q.d. for 2 weeks	16	-	\|13 (\|30 to \|7)	\|36 (\|8 to \|56)
Efavirenz 600 mg q.d. plus Ritonavir 100 mg q.d. for 2 weeks	1,400 mg q.d. plus ritonavir 200 mg q.d. for 2 weeks	16	\|18 (\|1 to \|38)	\|11 (0 to \|24)	-
Efavirenz 600 mg q.d. for 2 weeks	700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks	16	-	-	\|17 (\|4 to \|29)
Ethinyl estradiol/norethisterone 0.035 mg/0.5 mg q.d. for 21 days	700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 21 days	23	- a	- a	- a
Lopinavir/ritonavir 533 mg/133 mg b.i.d.	1,400 mg b.i.d. for 2 weeks	18	\|13	\|26	\|42
Lopinavir/ritonavir 400 mg/100 mg b.i.d. for 2 weeks	700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks	18	\|58 (\|42 to \|70)	\|63 (\|51 to \|72)	\|65 (\|54 to \|73)
Methadone 70 to 120 mg q.d. for 2 weeks	700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks	19	- a	- a	- a
Phenytoin 300 mg q.d. for 10 days	700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 10 days	13	-	\|20 (\|8 to \|34)	\|19 (\|6 to \|33)
Ranitidine 300 mg single dose	1,400 mg single dose	30	\|51 (\|43 to \|58)	\|30 (\|22 to \|37)	- (\|19 to \|21)

Coadministered Drugs and Dose(s)	Dose of TELZIR (r) *	n	% Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI)
Coadministered Drugs and Dose(s)	Dose of TELZIR (r) *	n	C max	AUC	C min
Atorvastatin 10 mg q.d. for 4 days	1,400 mg b.i.d. for 2 weeks	16	\|304 (\|205 to \|437)	\|130 (\|100 to \|164)	\|10 (\|27 to \|12)
Atorvastatin 10 mg q.d. for 4 days	700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks	16	\|184 (\|126 to \|257)	\|153 (\|115 to \|199)	\|73 (\|45 to \|108)
Ethinyl estradiol * * 0.035 mg q.d. for 21 days	700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 21 days	25	\|28 (\|21 to \|35)	\|37 (\|30 to \|42)	ND
Lopinavir/ritonavir + 533 mg/133 mg b.i.d. for 2 weeks	1,400 mg b.i.d. for 2 weeks	18	-	-	-
Lopinavir/ritonavir + 400 mg/100 mg b.i.d. for 2 weeks	700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks	18	\|30 (\|15 to \|47)	\|37 (\|20 to \|55)	\|52 (\|28 to \|82)
Methadone 70 to 120 mg q.d. for 2 weeks	700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks	19	R-Methadone (active)
			\|21 a (\|30 to \|12)	\|18 a (\|27 to \|8)	\|11 a (\|21 to \|1)
			S-Methadone (inactive)
			\|43 a (\|49 to \|37)	\|43 a (\|50 to \|36)	\|41 a (\|49 to \|31)
Norethisterone * * 0.5 mg q.d. for 21 days	700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 21 days	25	\|38 (\|32 to \|44)	\|34 (\|30 to \|37)	\|26 (\|20 to \|32)
Phenytoin 300 mg q.d. for 10 days	700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 10 days	14	\|20 (\|12 to \|27)	\|22 (\|17 to \|27)	\|29 (\|23 to \|34)

Pharmacokinetic Parameters for Amprenavir in the Presence of the Coadmininstered Drug			Coadmininstered Drug	Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir
C max	AUC	C min		C max	AUC	C min
\|47%	\|29%	\|27%	Abacavir	-	-	-
\|15%	\|18%	\|39%	Clarithromycin	\|10%	-	-
\|18%	\|33	\|25%	Indinavir	\|22%	\|38	\|27%
\|16%	\|31	NA	Ketoconazole (sd)	\|19%	\|44%	NA
-	-	NA	Lamivudine (sd)	-	-	NA
\|14%	-	\|189%	Nelfinavir	\|12%	\|15%	\|14%
-	\|15%	\|15%	Rifabutin	\|119%	\|193%	\|271%
\|70%	\|82%	\|92%	Rifampin	-	-	ND
\|37%	\|32%	\|14%	Saquinavir *	\|21%	\|19%	\|48%
-	\|13%	NA	Zidovudine (sd)	\|40%	\|31%	NA
NA (1)	NA (1)	NA (1)	R-methadone (active)	\|25%	\|13%	-
NA (1)	NA (1)	NA (1)	S-methadone (inactive)	\|48%	\|40%	\|23%
-	\|22%	\|20%	Ethinyl estradiol	-	-	\|32%
-	\|22%	\|20%	norethindrone	-	\|18%	\|45%

Concomitant Class Name: Drug Name	Effect on Concentration of Amprenavir or Concomitant Drug	Clinical Comment
Antiretroviral Agents
HIV Protease Inhibitors (see Tables 4 and 5 )
Lopinavir/ritonavir	\| Lopinavir \| Amprenavir	An increased rate of adverse events has been reported with coadministration of these medications: lopinavir and ritonavir. Appropriate doses of the combinations with respect to safety and efficacy have not been established.

Proper name	Effect	Clinical comment
St. John's Wort	May result in reduced plasma concentrations of amprenavir.	Patients on TELZIR (r) should not use products containing St. John's Wort ( Hypericum perforatum ) since it may result in reduced plasma concentrations of amprenavir (see WARNINGS AND PRECAUTIONS section).

Parameter	6 to 11 Years		12 to 18 Years
	n	Fosamprenavir 18 mg/kg plus Ritonavir 3 mg/kg b.i.d.	n	Fosamprenavir 700 mg plus Ritonavir 100 mg b.i.d.
AU C (0-24)	9	93.4	8	58.8
(mcg * hr/mL)		(67.8, 129)		(38.8, 89.0)
C max (mcg/mL)	9	6.07	8	4.33
		(4.40, 8.38)		(2.82, 6.65)
C min (mcg/mL)	17	2.69	24	1.61
		(2.15, 3.36)		(1.21, 2.15)

	Normal Hepatic Function ( FPV 700 mg BID + RTV 100 mg BID) N=10	Mild Hepatic Impairment (Child Pugh 5-6) (FPV 700 mg BID +RTV 100 mg BID) N=9		Moderate Hepatic Impairment (Child Pugh 7-9) ( FPV 300 mg BID + RTV 100mg QD) 1 N=10
	Parameter Estimate Geometric Mean [95% CI] (CVb%)	Parameter Estimate Geometric Mean [95% CI] (CVb%)	GLS Mean Ratio Mild vs Normal [90% CI]	Parameter Estimate Geometric Mean [95% CI] (CVb%)	GLS Mean Ratio Moderate vs Normal [90% CI]
AUC0- t	3.75	4.59	1.22	27.8	0.73
( u g.h/mL)	[2.52, 5.57]	[2.75, 7.67]	[0.94, 1.59]	[19.9, 38.7]	[0.56, 0.95]
Cmax	6.00	7.04	1.17	6.68	0.73
( u g/mL)	[4.97, 7.25]	[5.72, 8.66]	[0.90, 1.53]	[5.14, 8.70]	[0.56, 0.95]
Free Fraction (%)	7.53	8.92	1.24	10.1	1.33
unbound at	[6.10, 9.29]	[7.68, 10.4]	[0.99, 1.56]	[7.49, 13.5]	[1.05, 1.69]
approximate
Cmax
Cmin	2.62	2.38	0.91	1.13	0.43
( u g/mL)	[2.14, 3.21]	[1.80, 3.15]	[0.63, 1.32]	[0.74, 1.71]	[0.30, 0.62]
Free Fraction (%)	6.16	10.9	1.75	12.5	2.02
at Cmin	[4.52, 8.38]	[8.88, 13.3]	[1.38, 2.23]	[9.98, 15.5]	[1.58, 2.58]

	TELZIR (r) /ritonavir once daily % (n/N)	Nelfinavir twice daily % (n/N)	Stratified Difference	95% CI
Proportions of subjects with HIV-1 RNA < 400 copies/ml
ITT(E) MD=F	68 (220/322)	65 (213/327)	3%	-4%, 10%
Per Protocol	95 (215/226)	91 (215/237)	4%	-0%, 9%
Proportions of subjects with HIV-1 RNA < 50 copies/ml
ITT(E) MD=F	56 (179/322)	52 (171/327)	3%	-5%, 11%
Per Protocol	78 (176/226)	72 (171/237)	6%	-2%, 13%

Regimen	C max (ug/mL)	T max (hours) 1	AUC 24 (ug *hr/mL)	C min (ug /mL)
TELZIR (r) 1400 mg QD	7.24	2.1	69.4	1.45
plus ritonavir 200 mg QD	(6.32-8.28)	(0.8-5.0)	(59.7-80.8)	(1.16-1.81)
TELZIR (r) 700 mg BID	6.08	1.5	79.2	2.12
plus ritonavir 100 mg	(5.38-6.86)	(0.75-5.0)	(69.0-90.6)	(1.77-2.54)
BID	(5.38-6.86)	(0.75-5.0)	(69.0-90.6)	(1.77-2.54)

PI-mutations +	TELZIR (r) /ritonavir b.i.d. (n= 88)	Lopinavir/ritonavir b.i.d. (n= 85)
D30N	21/22 (95%)	17/19 (89%)
N88D/S	20/22 (91%)	12/12 (100%)
L90M	16/31 (52%)	17/29 (59%)
M46I/L	11/22 (50%)	12/24 (50%)
V82A/F/T/S	2/9 (22%)	6/17 (35%)
I54V	2/11 (18%)	6/11 (55%)
I84V	1/6 (17%)	2/5 (40%)

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM
Symptom / effect		Talk with your doctor or pharmacist	Stop taking drug and call your doctor or pharmacist
Common	Nausea, vomiting and hypertriglyceridemi a (high blood levels of fat called triglycerides).	9	9
Uncommon	Severe life- threatening rash. New or worsening diabetes has been reported with the use of protease inhibitors. Increase in spontaneous bleeding among hemophiliacs using protease inhibitors has been reported.	9	9
Rare	Increase in muscle wasting (rhabdomyolosis), muscle pain has been reported with protease inhibitors. Stevens-Johnson syndrome, angioedema (swelling of the blood vessels and surrounding tissue).	9	9

Submission Control Number: 119403

PART I: HEALTH PROFESSIONAL INFORMATION 3

PART II: SCIENTIFIC INFORMATION 32

PART III: CONSUMER INFORMATION. 47

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Phenobarbital, phenytoin, carbamazepine and dexamethasone may decrease amprenavir concentrations.

Sulphonamide Allergies

Contraceptives

Fat Redistribution

Lipid Elevations

Patients with Hemophilia

Immune Reconstitution:

Resistance/Cross-Resistance

Pregnant Women

Nursing Women

Pediatrics

Geriatrics

ADVERSE REACTIONS

Body as a Whole:

Endocrine and Metabolism:

Skin and Subcutaneous Tissue Disorders:

DRUG INTERACTIONS

DOSAGE AND ADMINISTRATION

Adults (>= 18 years of age):

Therapy Naive Patients:

Protease Inhibitor-Experienced Patients:

Therapy Naive Patients:

Protease Inhibitor-Experienced Patients:

Pediatric Patients (>= 6 years old):

Therapy Naive and Protease Inhibitor Experienced:

Therapy Naive and Protease Inhibitor Experienced:

Pediatrics (< 2 years of age)

Geriatrics (>= 65 years of age):

Patients with Hepatic Impairment

Patients with Renal Impairment

OVERDOSAGE

ACTION AND CLINICAL PHARMACOLOGY

Absorption and Bioavailability

Effects of Food on Oral Absorption

Pediatrics (>= 6 years old)

Geriatrics

Gender

Hepatic Insufficiency

Renal Insufficiency

STORAGE AND STABILITY

Tablets

Suspension

SPECIAL HANDLING INSTRUCTIONS

DOSAGE FORMS, COMPOSITION AND PACKAGING

Tablets

Suspension

PHARMACEUTICAL INFORMATION

Drug Substance

CLINICAL TRIALS

Antiretroviral-Naive Adult patients

Protease Inhibitor-Experienced Adult Patients

Pediatrics

DETAILED PHARMACOLOGY

Absorption

Distribution

Metabolism

Elimination

Special populations

Effects of Food on Oral Absorption

MICROBIOLOGY

TOXICOLOGY

REFERENCES

AGENERASE

KALETRA

NORVIR

SUSTIVA

VIRAMUNE