Telzir® 700 mg film-coated tablets

Each film-coated tablet contains 700 mg of fosamprenavir as fosamprenavir calcium (equivalent to approximately 600 mg of amprenavir).

For a full list of excipients, see section 6.1.

Film-coated tablet

Pink film coated, capsule shaped, biconvex tablets, marked with GXLL7 on one side.

Telzir in combination with low dose ritonavir is indicated for the treatment of Human Immunodeficiency Virus Type 1 (HIV-1) infected adults, adolescents and children of 6 years and above in combination with other antiretroviral medicinal products.

In moderately antiretroviral experienced adults, Telzir in combination with low dose ritonavir has not been shown to be as effective as lopinavir / ritonavir. No comparative studies have been undertaken in children or adolescents.

In heavily pretreated patients the use of Telzir in combination with low dose ritonavir has not been sufficiently studied.

In protease inhibitor (PI) experienced patients the choice of Telzir should be based on individual viral resistance testing and treatment history (see section 5.1).

Therapy should be initiated by a physician experienced in the management of HIV infection.

Fosamprenavir is a pro-drug of amprenavir and must not be administered concomitantly with other medicinal products containing amprenavir.

The importance of complying with the full recommended dosing regimen should be stressed to all patients.

Caution is advised if the recommended doses of Telzir with ritonavir detailed below are exceeded (see section 4.4).

Telzir tablet is administered orally.

Telzir tablet can be taken with or without food.

Telzir is also available as an oral suspension for use in patients unable to swallow tablets, and in paediatric patients less than 39 kg (please refer to the Summary of Product Characteristics for Telzir oral suspension).

Adults

The recommended dose is 700 mg fosamprenavir twice daily with 100 mg ritonavir twice daily.

Paediatric patients from 6 years of age

The adult dose of Telzir tablet 700 mg twice daily with ritonavir 100 mg twice daily may be used in children weighing at least 39 kg and able to swallow tablets.

For children weighing less than 39 kg, Telzir oral suspension is the recommended option for the most accurate dosing in children based on body weight (please refer to the Summary of Product Characteristics for Telzir oral suspension).

Children less than 6 years of age: Telzir with ritonavir is not recommended in children below 6 years due to insufficient data on pharmacokinetics, safety and antiviral response (see section 5.2).

Elderly (over 65 years of age)

The pharmacokinetics of fosamprenavir have not been studied in this patient population (see section 5.2). Therefore, no recommendations can be made in this patient population.

Renal impairment

No dose adjustment is considered necessary in patients with renal impairment (see section 5.2).

Hepatic impairment

For adults with mild hepatic impairment (Child-Pugh score: 5-6) the recommended dose is 700 mg fosamprenavir twice daily with 100 mg ritonavir once daily.

For adults with moderate hepatic impairment (Child-Pugh score: 7-9) the recommended dose is 450 mg fosamprenavir twice daily with 100 mg ritonavir once daily. As it is not possible to achieve this 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 of 300 mg fosamprenavir twice daily with 100 mg ritonavir once daily. As it is not possible to achieve this fosamprenavir dose using the tablet formulation, these patients should be treated with fosamprenavir oral suspension.

Even with these dose adjustments for adults, some patients with hepatic impairment may have higher or lower than anticipated amprenavir and/or ritonavir plasma concentrations as compared to patients with normal hepatic function, due to increased inter-patient variability (see section 5.2), therefore a close monitoring of safety and virologic response is warranted.

No dose recommendation can be made for children and adolescents with hepatic impairment as no studies have been conducted in these age groups.

Hypersensitivity to fosamprenavir, amprenavir, or ritonavir, or to any of the excipients.

Telzir must not be administered concurrently with medicinal products with narrow therapeutic windows that are substrates of cytochrome P450 3A4 (CYP3A4), e.g. alfuzosin amiodarone, astemizole, bepridil, cisapride, dihydroergotamine, ergotamine, pimozide, quinidine, terfenadine, oral midazolam (for caution on parenterally administered midazolam, see section 4.5), oral triazolam sildenafil used for the treatment of pulmonary arterial hypertension (for use of sildenafil in patients with erectile dysfunction, see sections 4.4 and 4.5)..

Concomitant use of Telzir with simvastatin or lovastatin is contraindicated because of increased plasma concentrations of lovastatin and simvastatin which can increase the risk of myopathy, including rhabdomyolysis (see section 4.5).

Telzir with ritonavir must not be co-administered with medicinal products with narrow therapeutic windows that are highly dependent on CYP2D6 metabolism, e.g. flecainide and propafenone (see section 4.5).

Combination of rifampicin with Telzir with concomitant low-dose ritonavir is contraindicated (see section 4.5).

Herbal preparations containing St John's wort (Hypericum perforatum) must not be used while taking Telzir due to the risk of decreased plasma concentrations and reduced clinical effects of amprenavir (see section 4.5).

Patients should be advised that treatment with Telzir, or any other current antiretroviral therapy, does not cure HIV and that they 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.

Fosamprenavir contains a sulphonamide moiety. The potential for cross-sensitivity between medicinal products in the sulphonamide class and fosamprenavir is unknown. In the pivotal studies of Telzir, in patients receiving fosamprenavir with ritonavir there was no evidence of an increased risk of rashes in patients with a history of sulphonamide allergy versus those who did not have a sulphonamide allergy. Yet, Telzir 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.

Liver disease

Telzir with ritonavir should be used with caution and at reduced doses in adults with mild, moderate, or severe hepatic impairment (see section 4.2).

Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Medicinal products – interactions

The use of Telzir concomitantly with halofantrine or lidocaine (systemic) is not recommended (see section 4.5).

PDE5 inhibitors used for the treatment of erectile dysfunction: The use of Telzir concomitantly with PDE5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) is not recommended (see section 4.5).

Co-administration of Telzir with low dose ritonavir and these medicinal products is expected to substantially increase their concentrations and may result in PDE5 inhibitor-associated adverse events such as hypotension, visual changes and priapism (see section 4.5). Note that co-administration of Telzir with low dose ritonavir with sildenafil used for the treatment of pulmonary arterial hypertension is contraindicated (see section 4.3).

A reduction in the rifabutin dosage by at least 75 % is recommended when administered with Telzir with ritonavir. Further dose reduction may be necessary (see section 4.5).

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 (see section 4.5).

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.

Anticonvulsants (carbamazepine, phenobarbital) should be used with caution. Telzir may be less effective due to decreased amprenavir plasma concentrations in patients taking these medicinal products concomitantly (see section 4.5).

Therapeutic concentration monitoring is recommended for immunosuppressant medicinal products (cyclosporine, tacrolimus, rapamycin) when co-administered with Telzir (see section 4.5).

Therapeutic concentration monitoring is recommended for tricyclic antidepressants (e.g. desipramine and nortriptyline) when coadministered with Telzir (see section 4.5).

When warfarin or other oral anticoagulants are coadministered with Telzir a reinforced monitoring of INR (International Normalised Ratio) is recommended (see section 4.5).

Concomitant use of Telzir with ritonavir and fluticasone 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 (see section 4.5).

Rash / cutaneous reactions

Most patients with mild or moderate rash can continue Telzir. 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 patients included in the clinical development programme. Telzir should be permanently discontinued in case of severe rash, or in case of rash of moderate intensity with systemic or mucosal symptoms (see section 4.8).

Haemophiliac patients

There have been reports of increased bleeding including spontaneous skin haematomas and haemarthroses in haemophiliac patients type A and B treated with protease inhibitors (PIs). In some patients administration of factor VIII was necessary. 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 informed of the possibility of increased bleeding.

Hyperglycaemia

New onset of diabetes mellitus, hyperglycaemia or exacerbations of existing diabetes mellitus have been reported in patients receiving antiretroviral therapy, including protease inhibitors. In some of these, the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many of the patients had confounding medical conditions, some of which required therapy with medicinal products that have been associated with the development of diabetes mellitus or hyperglycaemia. Blood glucose testing should be performed prior to initiating therapy with Telzir and at periodic intervals during therapy.

Lipodystrophy

Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution.

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 Telzir and at periodic intervals during therapy (see section 4.8).

Lipid disorders should be managed as clinically appropriate

Immune Reactivation Syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens 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 CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterium infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Osteonecrosis:

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Interaction studies have only been performed in adults.

Unless otherwise stated, studies detailed below have been performed with the recommended dosage of fosamprenavir/ritonavir (i.e. 700/100 mg twice daily), and the interaction was assessed under steady-state conditions where drugs were administered for 10 to 21 days.

Pregnancy

There is no clinical experience with fosamprenavir in pregnant women. In animal studies at systemic plasma exposures (AUC) to amprenavir lower than therapeutic exposure in patients treated with Telzir, some developmental toxicity was observed (see section 5.3). In view of the low exposure in reproductive toxicity studies, the potential developmental toxicity of Telzir has not been fully determined.

Telzir should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Lactation

Amprenavir-related material was found in rat milk, but it is not known whether amprenavir is excreted in human milk. Rat pups exposed pre and post-natally to amprenavir and fosamprenavir showed developmental toxicity (see section 5.3).

It is therefore recommended that mothers treated with Telzir do not breast-feed their infants. As a general rule, it is recommended that HIV-infected women must not breast-feed under any circumstances to avoid transmission of HIV.

No studies on the effects of Telzir in combination with ritonavir on the ability to drive and use machines have been performed. The adverse reaction profile of Telzir should be borne in mind when considering the patient's ability to drive or operate machinery (see section 4.8).

Summary of safety profile

The adverse reaction profile was similar across all the respective adult studies: antiretroviral naïve patients (APV30002, ESS100732), protease inhibitor experienced (twice daily dosing, APV30003) patients. This is based on safety data from a total of 864 patients exposed to fosamprenavir/ritonavir in these three studies.

The most frequently (> 5% of adult subjects treated) reported adverse reactions with fosamprenavir/ritonavir combination were gastrointestinal reactions (nausea, diarrhoea, abdominal pain and vomiting) and headache. Most adverse reactions associated with fosamprenavir/ritonavir combination therapies were mild to moderate in severity, early in onset and rarely treatment limiting. More serious adverse reactions such as serious skin rashes and hepatic transaminase elevations have also been reported (cf paragraph Description of selected adverse reactions).

Tabulated summary of adverse reactions

Adverse reactions are listed by MedDRA system organ class and absolute frequency. Frequencies are defined as: Very common ( 1/10), Common ( 1/100 to < 1/10), Uncommon ( 1/1,000 to < 1/100), Rare ( 1/10,000 to < 1/1,000) or Very rare (< 1/10,000), or Not known.

Frequency categories for the reactions below have been based on clinical trials and postmarketing data.

Most of the adverse reactions below were reported from three large clinical studies in adults, where the adverse events were of at least moderate intensity (Grade 2 or more) occurring in at least 1% of patients and reported by investigators as being attributable to the medicinal products used in the studies.

Description of selected adverse reactions

Rash / cutaneous reactions: erythematous or maculopapular cutaneous eruptions, with or without pruritus, may occur during therapy. The rash generally will resolve spontaneously without the necessity of discontinuing treatment with the fosamprenavir with ritonavir.

Severe or life-threatening cases of rash, including Stevens-Johnson syndrome are rare. Fosamprenavir with ritonavir therapy should be definitively stopped in case of severe rash or in case of rash of mild or moderate intensity associated with systemic or mucosal signs (see section 4.4).

Clinical chemistry abnormalities: clinical chemistry abnormalities (Grade 3 or 4) potentially related to treatment with fosamprenavir with ritonavir and reported in greater than or equal to 1 % of adult patients, included: increased ALT (common), AST (common), serum lipase (common) and triglycerides (common).

Lipodystrophy: combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see section 4.4).

Metabolic abnormalities: combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).

Hyperglycaemia: new onset of diabetes mellitus, hyperglycaemia or exacerbations of existing diabetes mellitus have been reported in patients receiving antiretroviral protease inhibitors (see section 4.4).

Rhabdomyolysis: an increase in CPK, myalgia, myositis, and rarely, rhabdomyolysis, have been reported with protease inhibitors, more specifically in association with nucleoside analogues.

Immune Reactivation Syndrome: in HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4).

Osteonecrosis: cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

Paediatric / other populations

Children and adolescents: The adverse reaction profile in children and adolescents is based on integrated safety data from two studies (APV29005 and APV20003) in which 126 HIV-1 infected subjects 2 to 18 years of age received fosamprenavir with ritonavir with background nucleoside reverse transcriptase inhibitor therapy (see section 5.1 for information on dosing regimens applied for each age group). 70 % of subjects received greater than 48 weeks of exposure.

Overall the safety profile in these 126 children and adolescents was similar to that observed in the adult population. Drug-related adverse reactions were more common in APV20003 (55%) where subjects received once daily fosamprenavir / ritonavir when compared to APV29005 (39%) where subjects received twice daily fosamprenavir / ritonavir.

Haemophiliac patients: there have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease inhibitors (see section 4.4).

There is no known antidote for Telzir. It is not known whether amprenavir can be removed by peritoneal dialysis or haemodialysis. If overdose occurs, the patient should be monitored for evidence of toxicity (see section 4.8) and standard supportive treatment applied as necessary.

Pharmacotherapeutic group: Antivirals for systemic use, protease inhibitor, ATC Code: J05AE07

Mechanism of action

The in vitro antiviral activity observed with fosamprenavir is due to the presence of trace amounts of amprenavir. Amprenavir is a competitive inhibitor of the HIV-1 protease. Amprenavir binds to the active site of HIV-1 protease and thereby prevents the processing of viral gag and gag-pol polyprotein precursors, resulting in the formation of immature non-infectious viral particles.

Administration of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily results in plasma amprenavir concentrations (data from study APV30003 in antiretroviral experienced patients) which results in protein adjusted median ratios of C_min/IC₅₀ and C_min/IC₉₅ of 21.7 (range 1.19-240) and 3.21 (range 0.26-30.0), respectively.

Antiviral activity in vitro

The in vitro antiviral activity of amprenavir was evaluated against HIV-1 IIIB in both acutely and chronically infected lymphoblastic cell lines (MT-4, CEM-CCRF, H9) and in peripheral blood lymphocytes. The 50% inhibitory concentration (IC₅₀) of amprenavir ranged from 0.012 to 0.08 μM in acutely infected cells and was 0.41 μM in chronically infected cells (1 μM = 0.50 μg/ml). The relationship between in vitro anti-HIV-1 activity of amprenavir and the inhibition of HIV-1 replication in humans has not been defined.

Resistance

In vivo

a) ART-naïve or PI-naïve patients

Various regimens have been assessed in the amprenavir/fosamprenavir development programs with and without co-administration of ritonavir. Analysis of the virological failure samples across these regimens defined four main resistance pathways: V32I+I47V, I50V, I54L/M and I84V. Additional mutations observed which may contribute to resistance were: L10V/F/R, I13V, K20R/T, L33F/V, M36I, M46I/L, I47V/L Q58E, I62V, L63P, V77I, I85V, and I93L.

When ART naïve patients were treated with the currently approved doses of fosamprenavir/ritonavir, as for other ritonavir boosted PI regimens, the mutations described were infrequently observed. Sixteen of 434 ART-naïve patients who received fosamprenavir 700mg/ritonavir 100mg twice daily in ESS100732 experienced virological failure by Week 48 with 14 isolates genotyped. Three of 14 isolates had protease resistance mutations. One resistance mutation was observed in each of 3 isolates: K20K/R, I54I/L and I93I/L respectively

Genotypic analysis of isolates from 13 of 14 paediatric patients exhibiting virological failure among the 59 PI-naïve patients enrolled, demonstrated resistance patterns similar to those observed in adults.

b) PI-experienced patients

Amprenavir

In the studies of PI-experienced patients, PRO30017 (amprenavir 600 mg / ritonavir 100 mg twice daily in sub-study A and B with 80 and 37 patients respectively), the following mutations emerged in patients with virological failure: L10F/I/V, V11I, I13V, K20R, V32I, L33F, E34Q, M36I, M46I/L, I47V, G48V, I50V, I54L/M/T/V, Q58E, D60E, I62V, A71V, V77I, V82A/I, I84V, I85V, L90M and I93L/M.

Fosamprenavir

In the studies of PI-experienced patients, APV30003 and its extension, APV30005 (fosamprenavir 700 mg / ritonavir 100 mg twice daily: n=107), the following mutations emerged in patients experiencing virological failure through 96 weeks: L10F/I, L24I, V32I, L33F, M36I, M46I/L, I47V, I50V, I54L/M/S, A71I/T/V, G73S, V82A, I84V, and L90M.

In the paediatric studies APV20003 and APV29005, 67 PI-experienced patients were treated with fosamprenavir / ritonavir and of 22 virological failure isolates genotyped, nine patients were found with treatment-emergent protease mutations. The mutational profiles were similar to those described for PI-experienced adults treated with fosamprenavir / ritonavir.

Antiviral activity according to genotypic/phenotypic resistance

Genotypic resistance testing.

Genotypic interpretation systems may be used to estimate the activity of amprenavir / ritonavir or fosamprenavir / ritonavir in subjects with PI-resistant isolates. The current (July 2006) ANRS AC-11 algorithm for fosamprenavir / ritonavir defines resistance as the presence of the mutations V32I+I47A/V, or I50V, or at least four mutations among: L10F/I/V, L33F, M36I, I54A/L/M/S/T/V, I62V, V82A/C/F/G, I84V and L90M and is associated with increased phenotypic resistance to fosamprenavir with ritonavir as well as reduced likelihood of virological response (resistance). Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.

Phenotypic resistance testing.

Clinically validated phenotypic interpretation systems may be used in association with the genotypic data to estimate the activity of amprenavir / ritonavir or fosamprenavir / ritonavir in patients with PI-resistant isolates. Resistance testing diagnostic companies have developed clinical phenotypic cut-offs for FPV/RTV that can be used to interpret resistance test results.

Clinical experience

Clinical experience with fosamprenavir boosted with ritonavir is mainly based on two open label studies one in antiretroviral naïve patients (study ESS100732), and one study in antiretroviral experienced patients (study APV30003). Both of these studies compared fosamprenavir/ritonavir with lopinavir / ritonavir.

Antiretroviral Naïve Adult Patients

In a randomised open-label study (ESS100732 - KLEAN) in antiretroviral naïve patients, fosamprenavir (700 mg) co-administered with low dose ritonavir (100 mg) in a twice daily regimen including abacavir / lamivudine (600 mg / 300 mg) fixed dose combination tablet once daily showed comparable efficacy over 48 weeks to lopinavir / ritonavir (400 mg / 100 mg) given twice daily in combination with abacavir / lamivudine (600 mg / 300 mg once daily).

Non-inferiority was demonstrated between fosamprenavir co-administered with ritonavir and lopinavir / ritonavir based on the proportions of patients achieving plasma HIV-1 RNA levels < 400 copies/ml at 48 weeks (primary endpoint). In the Time to loss of virological response (TLOVR) analysis for the ITT(E) population, the proportion of patients achieving <400 copies/ml was 73 % (315 / 434) in the fosamprenavir with ritonavir group compared to 71 % (317 / 444) of patients receiving lopinavir / ritonavir, with a 95 % confidence interval of the difference of [-4,84%; 7;05%].

Efficacy outcomes by subgroups are described in the table below.

Table 1 Efficacy Outcome at Week 48 in ESS100732 (ART-Naïve Patients)

Following completion of the 48 week treatment period, subjects at European and Canadian sites were eligible to participate in a study extension to Week 144 maintaining their treatment regimen as per the original randomisation. Only 22% of the original population of the KLEAN study was enrolled in the study extension.

Efficacy outcomes are described in the table below.

Table 2 Efficacy Outcome at Weeks 96 and 144 in ESS100732 Extension (ART-Naïve Patients)

Antiretroviral Experienced Adult Patients

In a randomised open-label study (APV30003) in protease inhibitor experienced patients with virological failure (less than or equal to two PIs) the fosamprenavir with ritonavir combination (700 / 100 mg twice daily or 1400 / 200 mg once daily) did not demonstrate non-inferiority to lopinavir / ritonavir with regard to viral suppression as measured by the average area under the curve minus baseline (AAUCMB) for plasma HIV-1 RNA over 48 weeks (the primary end point). Results were in favour of the lopinavir / ritonavir arm as detailed below.

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). However, only 65 % of patients were receiving a PI based regimen at study entry.

The population enrolled mainly consisted of moderately antiretroviral experienced patients. The median durations of prior exposure to NRTIs were 257 weeks for patients receiving fosamprenavir with ritonavir twice daily (79 % had 3 prior NRTIs) and 210 weeks for patients receiving lopinavir/ritonavir (64 % had 3 prior NRTIs). The median durations of prior exposure to protease inhibitors were 149 weeks for patients receiving fosamprenavir with ritonavir twice daily (49 % received 2 prior PIs) and 130 weeks for patients receiving lopinavir/ritonavir (40 % received 2 prior PIs).

The mean AAUCMBs (log₁₀ c/ml) in the ITT (E) population (Observed analysis) at 48 weeks (primary end-point) and other efficacy outcomes by subgroup are described in the tables below:

Table 3 Efficacy at Week 48 Outcomes in APV30003 ITT(E) Population (ART-experienced Patients)

Key: ¹GSS to OBT: Genotypic Sensitivity Score to Optimised Background. GSS was derived using ANRS 2007 guidelines. ²RD=F: Rebound or discontinuation equal failure analysis which is equivalent to TLOVR. FPV/RTV BID – Fosamprenavir with ritonavir twice daily, LPV/RTV BID – Lopinavir / ritonavir twice daily

Table 4. AAUCMB at Week 48 by genotypic sensitivity score in OBT and baseline resistance to FPV/RTV

As shown in the above table, there were only 16 patients harbouring baseline virus with resistance to FPV/RTV according to the ANRS score. Data from this small number further analysed by GSS subgroups need to be interpreted with caution.

There are insufficient data to recommend the use of fosamprenavir with ritonavir in heavily pre-treated patients.

Children and adolescent patients above the age of six

Fosamprenavir tablets and oral suspension with ritonavir in combination with NRTIs have been evaluated in protease inhibitor naïve and experienced children and adolescent patients. The benefit in this age group has mainly been derived from the ongoing study, APV29005, an open label 48 week study evaluating the pharmacokinetic profiles, safety, and antiviral activity of fosamprenavir with ritonavir administered twice daily to HIV 1 protease inhibitor experienced and naive patients 2 to 18 years of age. Results through 24 weeks of treatment are provided below.

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-naïve, 9 of whom were ART naïve, and 27 (50 %) were PI-experienced. Prior NRTI exposure was extensive, with median durations of 421 and 389 weeks for the PI naïve 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-naïve subjects and 4 % in the PI-experienced subjects.

These data were further substantiated by the supportive study APV20003; however, a different dosage regimen than that of study APV29005 was used.

After oral administration, fosamprenavir is rapidly and almost completely hydrolysed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. The conversion of fosamprenavir to amprenavir appears to primarily occur in the gut epithelium.

The pharmacokinetic properties of amprenavir following co-administration of Telzir with ritonavir have been evaluated in healthy adult subjects and HIV-infected patients and no substantial differences were observed between these two groups.

Telzir tablet and oral suspension formulations, both given fasted, delivered equivalent plasma amprenavir AUC values and the Telzir oral suspension formulation delivered a 14 % higher plasma amprenavir C_max as compared to the oral tablet formulation.

Absorption

After single dose administration of fosamprenavir, amprenavir peak plasma concentrations are observed approximately 2 hours after administration. Fosamprenavir AUC values are, in general, less than 1 % of those observed for amprenavir. The absolute bioavailability of fosamprenavir in humans has not been established.

After multiple dose oral administration of equivalent fosamprenavir and amprenavir doses, comparable amprenavir AUC values were observed; however, C_max values were approximately 30 % lower and C_min values were approximately 28 % higher with fosamprenavir.

Co-administration of ritonavir with fosamprenavir increase plasma amprenavir AUC by approximately 2-fold and plasma C_,ss by 4- to 6-fold, compared to values obtained when fosamprenavir is administered alone.

After multiple dose oral administration of fosamprenavir 700 mg with ritonavir 100 mg twice daily, amprenavir was rapidly absorbed with a geometric mean (95 % CI) steady state peak plasma amprenavir concentration (C_max) of 6.08 (5.38-6.86) μg/ml occurring approximately 1.5 (0.75-5.0) hours after dosing (t_max). The mean steady state plasma amprenavir trough concentration (C_min) was 2.12 (1.77-2.54) μg/ml and AUC_0-tau was 39.6 (34.5–45.3) h*μg/ml.

Administration of the fosamprenavir tablet formulation in the fed state (standardised high fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) did not alter plasma amprenavir pharmacokinetics (C_max, t_max or AUC_0-) compared to the administration of this formulation in the fasted state. Telzir tablets may be taken without regard to food intake.

Co-administration of amprenavir with grapefruit juice was not associated with clinically significant changes in plasma amprenavir pharmacokinetics.

Distribution

The apparent volume of distribution of amprenavir following administration of Telzir is approximately 430 l (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 is co-administered with ritonavir, most likely due to an increase in amprenavir bioavailability.

In in vitro studies, the protein binding of amprenavir is approximately 90 %. It is bound to the alpha-1-acid glycoprotein (AAG) and albumin, but has a higher affinity for AAG. Concentrations of AAG have been shown to decrease during the course of antiretroviral therapy. This change will decrease the total active substance concentration in the plasma, however the amount of unbound amprenavir, which is the active moiety, is likely to be unchanged.

CSF penetration of amprenavir is negligible in humans. Amprenavir appears to penetrate into semen, though semen concentrations are lower than plasma concentrations.

Metabolism

Fosamprenavir is rapidly and almost completely hydrolysed to amprenavir and inorganic phosphate as it is absorbed through the gut epithelium, following oral administration. 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 in addition is also an inhibitor of the CYP3A4 enzyme, although to a lesser extent than ritonavir. Therefore medicinal products that are inducers, inhibitors or substrates of CYP3A4 must be used with caution when administered concurrently with Telzir with ritonavir (see sections 4.3 and 4.5).

Elimination

Following administration of Telzir, the half-life of amprenavir is 7.7 hours. When Telzir is co-administered with ritonavir, the half-life of amprenavir is increased to 15 – 23 hours.

The primary route of elimination of amprenavir is via hepatic metabolism with less than 1 % excreted unchanged in the urine and no detectable amprenavir in faeces. Metabolites account for approximately 14 % of the administered amprenavir dose in the urine, and approximately 75 % in the faeces.

Special populations

Paediatrics

In a clinical study on pharmacokinetics of fosamprenavir in paediatric patients, eight subjects 12 to 18 years of age received the standard fosamprenavir adult tablet dose of 700 mg twice daily (with ritonavir 100 mg twice daily). Compared to the historical adult population receiving fosamprenavir / ritonavir 700 / 100 mg twice daily, 12 to 18 year old subjects had 20 % lower plasma APV AUC(0-24), 23 % lower C_max, and 20 % lower C_min values. Children 6 to 11 years of age (n=9) receiving fosamprenavir / ritonavir 18 / 3 mg/kg twice daily had 26 % higher AUC(0-24) and similar C_max and C_min values when compared to the historical adult population receiving fosamprenavir / ritonavir 700 / 100 mg twice daily.

APV20002 is a 48 week, Phase II, open label study designed to evaluate the pharmacokinetics, safety, tolerability and antiviral activity of fosamprenavir with and without ritonavir in paediatric subjects 4 weeks to < 2 years of age. Compared to the historical adult population receiving fosamprenavir with ritonavir 700 mg / 100 mg twice daily, a subset of five pediatric subjects ages 6 to < 24-months receiving fosamprenavir / ritonavir 45/7 mg/kg twice daily demonstrated that despite an approximate 5-fold increase in fosamprenavir and ritonavir doses on a mg/kg basis, plasma amprenavir AUC(0-) was approximately 48 % lower, C_max 26 % lower, and C 29 % lower in the paediatric subjects. No dosing recommendations can be made for the very young (children < 2 years of age) and Telzir with ritonavir is not recommended for this patient population (see section 4.2).

Elderly

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

Renal impairment

Patients with renal impairment have not been specifically studied. Less than 1 % of the therapeutic dose of amprenavir is excreted unchanged in the urine. Renal clearance of ritonavir is also negligible, therefore the impact of renal impairment on amprenavir and ritonavir elimination should be minimal.

Hepatic impairment

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 14 day repeat-dose study in HIV-1 infected adult subjects with mild, moderate, or severe hepatic impairment receiving fosamprenavir with ritonavir compared to matched control subjects with normal hepatic function.

In subjects with mild hepatic impairment (Child-Pugh score of 5-6), the dosage regimen of fosamprenavir 700 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily provided slightly higher plasma amprenavir C_max (17 %), slightly higher plasma amprenavir AUC(0-12) (22 %), similar plasma total amprenavir C12 values and approximately 117 % higher plasma unbound amprenavir C12 values compared to subjects with normal hepatic function receiving the standard fosamprenavir / ritonavir 700 mg /100 mg twice daily regimen.

In subjects with moderate hepatic impairment (Child-Pugh score of 7-9), a reduced dose of fosamprenavir 450 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily is predicted to deliver similar plasma amprenavir C_max and AUC(0-12), but approximately 35 % lower plasma total amprenavir C12 values and approximately 88 % higher plasma unbound amprenavir C12 values than achieved in subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg / 100 mg twice daily regimen.

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(0-12), and 38% lower C12 values, but similar unbound plasma amprenavir C12 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 AUC(0-24), and 38% higher ritonavir C12 than achieved in subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg / 100 mg twice daily regimen.

Fosamprenavir with ritonavir was generally well-tolerated in subjects with mild, moderate, or severe hepatic impairment, and these regimens had similar adverse event and clinical laboratory profiles as previous studies of HIV-1 infected subjects with normal hepatic function.

Toxicity was similar to that of amprenavir and occurred at amprenavir plasma exposure levels below human exposure after treatment with fosamprenavir in combination with ritonavir at the recommended dose.

In repeated dose toxicity studies in adult rats and dogs, fosamprenavir produced evidence of gastrointestinal disturbances (salivation, vomiting and soft to liquid faeces), and hepatic changes (increased liver weights, raised serum liver enzyme activities and microscopic changes, including hepatocyte necrosis). Toxicity was not aggravated when juvenile animals were treated as compared with adult animals, but the data did indicate a steeper dose response.

In reproductive toxicity studies with fosamprenavir in rats, male fertility was not affected, but in females gravid uterine weights, numbers of ovarian corpora lutea and uterine implantation sites were reduced. In pregnant rats and rabbits there were no major effects on embryo-foetal development. However, the number of abortions increased. In rabbits, systemic exposure at the high dose level was only 0.3 times human exposure at the maximum clinical dose and thus the developmental toxicity of fosamprenavir has not been fully determined. In rats exposed pre- and post-natally to fosamprenavir, pups showed impaired physical and functional development and reduced growth. Pup survival was decreased. In addition, decreased number of implantation sites per litter and a prolongation of gestation were seen when pups were mated after reaching maturity.

Fosamprenavir was not mutagenic or genotoxic in a standard battery of in vitro and in vivo assays. In long-term carcinogenicity studies with fosamprenavir in mice and rats, there were increases in hepatocellular adenomas and hepatocellular carcinomas in mice at exposure levels equivalent to 0.1 to 0.3-fold those in humans given 700 mg of fosamprenavir plus 100mg ritonavir twice daily, and increases in hepatocellular adenomas and thyroid follicular cell adenomas in rats at exposure levels equivalent to 0.3 to 0.6-fold those in humans given 700 mg of fosamprenavir plus 100mg ritonavir twice daily. The relevance of the hepatocellular findings in the rodents for humans is uncertain; however, there is no evidence from clinical trials or marketed use to suggest that these findings are of clinical significance. Repeat dose studies with fosamprenavir in rats produced effects consistent with hepatic enzyme induction, which predisposes rats to thyroid neoplasms. The thyroid tumorigenic potential is regarded to be species-specific. The clinical relevance of these findings is unknown. In rats only there was an increase in interstitial cell hyperplasia in males at exposure levels equivalent to 0.5-fold those in humans, and an increase in uterine endometrial adenocarcinoma in females at an exposure level equivalent to 1.1-fold those in humans. The incidence of endometrial findings was slightly increased over concurrent controls, but within background range for female rats. The relevance of the uterine endometrial adenocarcinomas for humans is uncertain; however there is no evidence from clinical trials or marketed use to suggest that these findings are of clinical significance.

Tablet core:

Microcrystalline cellulose

Croscarmellose sodium

Povidone K30

Magnesium stearate

Colloidal anhydrous silica

Tablet film-coat:

Hypromellose

Titanium dioxide (E171)

Glycerol triacetate

Iron oxide red (E172)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

HDPE bottles with a child resistant polypropylene closure containing 60 tablets.

Any unused product should be disposed of in accordance with local requirements.

ViiV Healthcare UK Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

EU/1/04/282/001

Date of first authorisation: 12 July 2004

23 May 2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu

Telzir is a registered trademark of the ViiV Healthcare group of companies.

© 2011 ViiV Healthcare group of companies. All rights reserved.