TELZIR 700mg tablets medication leaflet

Telzir 700 mg film-coated tablets

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

For the 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 andabove in combination with other antiretroviral medicinal products.

In moderately antiretroviral experienced adults, Telzir in combination with low dose ritonavir has notbeen shown to be as effective as lopinavir/ritonavir. No comparative studies have been undertaken inchildren or adolescents.

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

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

Telzir must only be given with low dose ritonavir as a pharmacokinetic enhancer of amprenavir and incombination with other antiretroviral medicinal products. The Summary of Product Characteristics ofritonavir must therefore be consulted prior to initiation of therapy with Telzir.

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 othermedicinal products containing amprenavir.

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

Caution is advised if the recommended doses of Telzir with ritonavir detailed below are exceeded (seesection 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 inpaediatric patients less than 39 kg (please refer to the Summary of Product Characteristics for Telziroral suspension).

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 inchildren 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 mostaccurate 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 onpharmacokinetics, 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 section5.2). Therefore, no recommendations can be made in this patient population.

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

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

For adults with moderate hepatic impairment (Child-Pugh score: 7-9) the recommended dose is450 mg fosamprenavir twice daily with 100 mg ritonavir once daily. This adjusted dose has not beenevaluated in a clinical study and has been derived from extrapolation (see section 5.2). As it is notpossible to achieve this fosamprenavir dose using the tablet formulation, these patients should betreated with fosamprenavir oral suspension.

For adults with severe hepatic impairment (Child-Pugh score: 10-15): fosamprenavir should be usedwith caution and at a reduced dose of 300 mg fosamprenavir twice daily with 100 mg ritonavir oncedaily. As it is not possible to achieve this fosamprenavir dose using the tablet formulation, thesepatients should be treated with fosamprenavir oral suspension.

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

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

Hypersensitivity to fosamprenavir, amprenavir, or ritonavir, or to any of the excipients listed in section6.1.

Telzir must not be administered concurrently with medicinal products with narrow therapeuticwindows that are substrates of cytochrome P450 3A4 (CYP3A4), e.g. alfuzosin, amiodarone,astemizole, bepridil, cisapride, dihydroergotamine, ergotamine, pimozide, quetiapine, 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 ofsildenafil in patients with erectile dysfunction, see sections 4.4 and 4.5).

Co-administration of the antipsychotic medicinal product lurasidone and fosamprenavir/ritonavir(FPV/RTV) is contraindicated (see section 4.5).

Co-administration of paritaprevir and fosamprenavir/ritonavir (FPV/RTV) is contraindicated due tothe expected increase of paritaprevir exposure and the lack of clinical data assessing the magnitude ofthis increase (see section 4.5).

Concomitant use of Telzir with simvastatin or lovastatin is contraindicated because of increasedplasma 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 therapeuticwindows that are highly dependent on CYP2D6 metabolism, e.g. flecainide and propafenone (seesection 4.5).

Combination of rifampicin with Telzir with concomitant low-dose ritonavir is contraindicated (seesection 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, doesnot cure HIV and that they may still develop opportunistic infections and other complications of HIVinfection.

Fosamprenavir contains a sulphonamide moiety. The potential for cross-sensitivity between medicinalproducts in the sulphonamide class and fosamprenavir is unknown. In the pivotal studies of Telzir, inpatients receiving fosamprenavir with ritonavir there was no evidence of an increased risk of rashes inpatients 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 dailyhas not been clinically evaluated. The use of higher ritonavir doses might alter the safety profile of thecombination and therefore is not recommended.

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 anincreased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviraltherapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics forthese medicinal products.

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

Medicinal products - interactions

The use of Telzir concomitantly with halofantrine or lidocaine (systemic) is not recommended (seesection 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 tosubstantially increase their concentrations and may result in PDE5 inhibitor-associated adverse eventssuch 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 hypertensionis contraindicated (see section 4.3).

A reduction in the rifabutin dosage by at least 75 % is recommended when administered with Telzirwith 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 maybe altered with co-administration of fosamprenavir, ritonavir and oral contraceptives, alternative non-hormonal methods of contraception are recommended for women of childbearing potential (seesection 4.5).

No data are available on the co-administration of fosamprenavir and ritonavir with oestrogens and/orprogestogens when used as hormonal replacement therapies. The efficacy and safety of these therapieswith fosamprenavir and ritonavir has not been established.

Anticonvulsants (carbamazepine, phenobarbital) should be used with caution. Telzir may be lesseffective due to decreased amprenavir plasma concentrations in patients taking these medicinalproducts 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. desipramineand 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 metabolisedby CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk ofsystemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression (see section4.5).

Co-administration of fosamprenavir/ritonavir with other antineoplastics metabolised by CYP3A (forexample dasatinib, nilotinib, ibrutinib, vinblastine and everolimus) may increase concentrations ofthese medicinal products, potentially increasing the risk of adverse events usually associated withthese agents. Please refer to the relevant product information for these medications (see section 4.5).

Hepatitis C virus (HCV) Direct-Acting Antivirals: When hepatitis C virus direct-acting antiviral(DAA) drugs, which are metabolised by CYP3A4 or are inducers/inhibitors of CYP3A4, are co-administered with fosamprenavir/ritonavir, altered plasma concentrations of medications are expecteddue to inhibition or induction of CYP3A4 enzyme activity (see sections 4.3 and 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 andlife-threatening skin reactions, including Stevens-Johnson syndrome, were reported in less than 1% ofpatients included in the clinical development programme. Telzir should be permanently discontinuedin case of severe rash, or in case of rash of moderate intensity with systemic or mucosal symptoms(see section 4.8).

There have been reports of increased bleeding including spontaneous skin haematomas andhaemarthroses in haemophiliac patients type A and B treated with protease inhibitors (PIs). In somepatients administration of factor VIII was necessary. In more than half of the reported cases, treatmentwith protease inhibitors was continued, or reintroduced if treatment had been discontinued. A causalrelationship has been evoked, although the mechanism of action has not been elucidated.

Haemophiliac patients should therefore be informed of the possibility of increased bleeding.

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviraltherapy. Such changes may in part be linked to disease control and life style. For lipids, there is insome cases evidence for a treatment effect, while for weight gain there is no strong evidence relatingthis to any particular treatment. For monitoring of blood lipids and glucose reference is made toestablished HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

In HIV-infected patients with severe immune deficiency at the time of institution of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticpathogens 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 treatmentinstituted when necessary. Autoimmune disorders (such as Graves’ disease) have also been reportedto occur in the setting of immune reactivation; however, the reported time to onset is more variableand can occur many months after initiation of treatment.

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported particularly in patients with advanced HIV-disease and/or long-term exposure to CART.

Patients should be advised to seek medical advice if they experience joint aches and pain, jointstiffness or difficulty in movement.

This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially‘sodium-free’.

When fosamprenavir and ritonavir are co-administered, the ritonavir metabolic druginteraction profile may predominate because ritonavir is a more potent CYP3A4 inhibitor. Thefull prescribing information for ritonavir must therefore be consulted prior to initiation oftherapy with Telzir with ritonavir. Ritonavir also inhibits CYP2D6 but to a lesser extent than

CYP3A4. Ritonavir induces CYP3A4, CYP1A2, CYP2C9 and glucuronosyl transferase.

Additionally, both amprenavir, the active metabolite of fosamprenavir, and ritonavir are primarilymetabolised in the liver by CYP3A4. Therefore, any medicinal products that either share thismetabolic pathway or modify CYP3A4 activity may modify the pharmacokinetics of amprenavir andritonavir. Similarly administration of fosamprenavir with ritonavir may modify the pharmacokineticsof other active substances that share this metabolic pathway.

Interaction studies have only been performed in adults.

Unless otherwise stated, studies detailed below have been performed with the recommended dosage offosamprenavir/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.

Drugs by Therapeutic Area Interaction Recommendationconcerning co-

Geometric mean change administration(%)(Possible mechanism)

ANTIRETROVIRAL

MEDICINAL PRODUCTS

Non-nucleoside reversetranscriptase inhibitors:

Efavirenz No clinically significant No dosage adjustment600 mg once daily interaction is observed. necessary.

Nevirapine No clinically significant No dosage adjustment200 mg twice daily interaction is observed. necessary.

Etravirine Amprenavir AUC ↑ 69% Telzir may require dose

Amprenavir Cmin ↑ 77% reduction (using oral

Amprenavir Cmax ↑ 62% suspension).(Study conducted in 8patients) Etravirine AUC ↔a

Etravirine C amin↔

Etravirine C ↔amaxa Comparison based onhistoric control.

Nucleoside/Nucleotidereverse transcriptaseinhibitors:

Abacavir No clinically significant No dosage adjustment

Lamivudine interaction is expected. necessary.

Zidovudine

Study performed withamprenavir.

No FPV/RTV druginteraction studies.

Didanosine chewable tablet No clinically significant No dose separation or dosageinteraction is expected. adjustment necessary (see

No drug interaction studies. Antacids).

Didanosine gastro-resistant No clinically significant No dosage adjustmentcapsule interaction is expected. necessary.

No drug interaction studies.

Tenofovir disoproxil No clinically significant No dosage adjustment245 mg once daily interaction observed. necessary.

Protease Inhibitors:

According to current treatment guidelines, dual therapy with protease inhibitors is generallynot recommended.

Lopinavir/ritonavir Lopinavir: Cmax↑ 30% Concomitant use is not400 mg/100 mg Lopinavir: AUC ↑ 37% recommended.twice daily Lopinavir: Cmin ↑ 52%

Amprenavir: Cmax ↓ 58%

Amprenavir: AUC ↓ 63%

Amprenavir: Cmin ↓ 65%

Lopinavir: Cmax ↔*

Lopinavir: AUC ↔*

Lopinavir: Cmin ↔*

* compared to lopinavir /ritonavir 400 mg/100 mgtwice daily

Amprenavir: Cmax ↓ 13%*

Lopinavir/ritonavir Amprenavir: AUC ↓ 26%*533 mg/133 mg twice daily Amprenavir: Cmin ↓ 42 %*

* compared to fosamprenavir/ ritonavir 700 mg/100 mg(Telzir 1400 mg twice daily) twice daily(Mixed CYP3A4induction/inhibition, Pgpinduction)

Indinavir No dose recommendations

Saquinavir can be given.

No drug interaction studies.

Atazanavir Atazanavir: Cmax ↓ 24%* No dosage adjustment

Atazanavir: AUC↓ 22%* necessary.300 mg once daily Atazanavir: Cmin↔*

*compared to atazanavir/ritonavir 300 mg/ 100 mgonce daily

Amprenavir: Cmax ↔

Amprenavir: AUC ↔

Amprenavir: Cmin ↔

Integrase inhibitors

Raltegravir Fasting state Concomitant use is notrecommended. Significant400 mg twice daily Amprenavir : reductions in exposure and

Cmax ↓ 14% (-36%; +15%) Cmin observed for both

AUC ↓ 16% (-36%; +8%) amprenavir and raltegravir

Cmin ↓ 19% (-42%; +13%) (especially in fed conditions)may result in virological

Raltegravir: failure in patients.

Cmax ↓ 51% (-75%; -3%)

AUC ↓ 55% (-76%; -16%)

Cmin ↓ 36 % (-57%; -3%)

Fed state

Amprenavir:

Cmax ↓ 25% (-41%; -4%)

AUC ↓ 25% (-42%; -3%)

Cmin ↓ 33% (-50%; -10%)

Raltegravir:

Cmax ↓ 56% (-70%; -34%)

AUC ↓ 54% (-66%; -37%)

Cmin ↓ 54 % (-74%; -18%)

Dolutegravir Dolutegravir No dosage adjustment offosamprenavir or50 mg once daily Cmax ↓ 24% dolutegravir is recommended

AUC ↓ 35% based on observed exposure-

Cτ ↓ 49% response relationships ofclinical data. Caution is

Amprenavir: Cmax ↔ warranted and close

Amprenavir: AUC ↔ monitoring is recommended

Amprenavir: Cmin ↔ when this combination isgiven in integrase inhibitor-resistant patients.

CCR5-receptor antagonists

Maraviroc Maraviroc: AUC12 ↑ 2.49 Concomitant use is not

Maraviroc: Cmax ↑ 1.52 recommended. Significant300 mg twice daily Maraviroc: C12 ↑ 4.74 reductions in amprenavir Cminobserved may result in

Amprenavir: AUC12 ↓ 0.65 virological failure in patients.

Amprenavir: Cmax ↓ 0.66

Amprenavir: C12 ↓ 0.64

Ritonavir AUC12 ↓ 0.66

Ritonavir Cmax ↓ 0.61

Ritonavir C12 ↔ 0.86

Anti-hepatitis C virus medicinal products

Simeprevir Not studied. Not recommended.

Daclatasvir Results from studies withother HIV protease inhibitorsand simeprevir or daclatasvir,suggest that co-administration withfosamprenavir/ritonavir islikely to lead to increasedplasma exposures ofsimeprevir or daclatasvir dueto CYP3A4 enzymeinhibition.

Paritaprevir Not studied. Contraindicated (see section(co-formulated with Results from studies with 4.3).ritonavir and ombitasvir other HIV protease inhibitorsand co-administered with and paritaprevir/ritonavir/dasabuvir) ombitasvir +/- dasabuvirsuggest that co-administration offosamprenavir/ritonavir withparitaprevir/ritonavir/ombitasvir+/-dasabuvir islikely to lead to increasedplasma exposures ofparitaprevir due to CYP3A4enzyme inhibition and higherritonavir dose.

ANTIARRHYTHMICS

Amiodarone Amiodarone: ↑ expected Contraindicated (see section

Bepridil Bepridil: ↑ expected 4.3). Potential for serious

Quinidine Quinidine: ↑ expected and/or life-threatening

Flecainide reactions such as cardiac

Propafenone arrhythmias.(CYP3A4 inhibition by

FPV/RTV)

Flecainide: ↑ expected

Propafenone: ↑ expected(CYP2D6 inhibition by

RTV)

ERGOT DERIVATIVES

Dihydroergotamine Dihydroergotamine: ↑ Contraindicated (see section

Ergotamine expected 4.3). Potential for serious

Ergonovine Ergonovine: ↑ expected and/or life-threatening

Methylergonovine Ergotamine: ↑ expected reactions such as acute ergot

Methylergonovine: ↑ toxicity characterized byexpected peripheral vasospasm andischemia of the extremities(CYP3A4 inhibition by and other tissues.

FPV/RTV)

GASTROINTESTINAL

MOTILITY AGENTS

Cisapride Cisapride: ↑ expected Contraindicated (see section4.3). Potential for serious(CYP3A4 inhibition by and/or life-threatening

FPV/RTV) reactions such as cardiacarrhythmias.

ANTIHISTAMINES(HISTAMINE H1

RECEPTOR

ANTAGONISTS)

Astemizole Astemizole: ↑ expected Contraindicated (see section

Terfenadine Terfenadine: ↑ expected 4.3). Potential for seriousand/or life-threatening(CYP3A4 inhibition by reactions such as cardiac

FPV/RTV) arrhythmias.

NEUROLEPTIC

Pimozide Pimozide: ↑ expected Contraindicated (see section4.3). Potential for serious(CYP3A4 inhibition by and/or life-threatening

FPV/RTV) reactions such as cardiacarrhythmias.

ANTIPSYCHOTICS

Quetiapine Due to CYP3A inhibition by Concomitant administration

Telzir, concentrations of of Telzir and quetiapine isquetiapine are expected to contra-indicated as it mayincrease. increase quetiapine-relatedtoxicity. Increased plasmaconcentrations of quetiapinemay lead to coma.

Lurasidone Lurasidone: ↑ expected Concomitant administration(CYP3A4 inhibition) of fosamprenavir /ritonavirwith lurasidone iscontraindicated due to thepotential for serious and/or

No FPV/RTV drug life-threatening reactionsinteraction studies related to lurasidone (seesection 4.3)

INFECTION

Antibacterials:

Clarithromycin Clarithromycin: moderate ↑ Use with caution.expected

Study performed withamprenavir. (CYP3A4 inhibition)

No FPV/RTV druginteraction studies.

Erythromycin Erythromycin: ↑ expected Use with caution.

No drug interaction studies. (CYP3A4 inhibition by

FPV/RTV)

Anti-mycobacterial:

Rifabutin Rifabutin: Cmax ↓ 14%* The increase of 25-O-150 mg every other day Rifabutin: AUC(0-48) ↔* desacetylrifabutin (activemetabolite) could potentially25-O-desacetylrifabutin: lead to an increase of

Cmax ↑ 6-fold* rifabutin related adverse25-O-desacetylrifabutin: events, notably uveitis.

AUC(0-48) ↑ 11-fold*

*compared to rifabutin A 75 % reduction of the300 mg once daily standard rifabutin dose (i.e.to 150 mg every other day) is

Amprenavir exposure recommended. Further doseunchanged when compared reduction may be necessaryto historical data. (see section 4.4).

(Mixed CYP3A4induction/inhibition)

Rifampicin Amprenavir: AUC ↓ 82% Contraindicated (see section600 mg once daily 4.3).

(Amprenavir without Significant ↓ APV expected The decrease in amprenavirritonavir) AUC can result in virologicalfailure and resistance

No FPV/RTV drug (CYP3A4 induction by development. Duringinteraction studies rifampicin) attempts to overcome thedecreased exposure byincreasing the dose of otherprotease inhibitors withritonavir, a high frequency ofliver reactions was seen.

Anti-fungals:

Ketoconazole Ketoconazole: Cmax ↑ 25% High doses (> 200 mg/day)200 mg once daily for four Ketoconazole: AUC ↑ 2.69- of ketoconazole ordays fold. itraconazole are notrecommended.

Amprenavir: Cmax ↔

Amprenavir: AUC ↔

Amprenavir: Cmin ↔

Itraconazole Itraconazole: ↑ expected

No drug interaction studies. (CYP3A4 inhibition by

FPV/RTV)

ANTACIDS, HISTAMINE

H2 RECEPTOR

ANTAGONIST AND

PROTON-PUMP

INHIBITORS

Single 30 ml dose of antacid Amprenavir: Cmax ↓ 35% No dosage adjustmentsuspension (equivalent to Amprenavir: AUC ↓ 18% necessary with antacids,3.6 grams aluminium Amprenavir: Cmin (C12h) ↔ proton-pump inhibitors orhydroxide and 1.8 grams histamine H2 receptormagnesium hydroxide antagonists.

(Telzir 1400 mg single dose)

Ranitidine Amprenavir: Cmax ↓ 51%300 mg single dose Amprenavir: AUC ↓ 30%

Amprenavir: Cmin (C12h) ↔(Telzir 1400 mg single dose)

Esomeprazole Amprenavir Cmax ↔20 mg once daily Amprenavir AUC ↔

Amprenavir Cmin (C12h) ↔(Increase in gastric pH)

ANTICONVULSANTS

Phenytoin Phenytoin: Cmax ↓ 20% It is recommended that300 mg once daily Phenytoin: AUC ↓ 22% phenytoin plasma

Phenytoin: Cmin ↓ 29% concentrations be monitoredand phenytoin dose increased(Modest induction of as appropriate.

CYP3A4 by FPV/RTV)

Amprenavir: Cmax ↔

Amprenavir: AUC ↑ 20%

Amprenavir: Cmin ↑ 19%

Phenobarbital Amprenavir: ↓ expected Use with caution (see

Carbamazepine section 4.4).(Modest CYP3A4

No drug interaction studies. induction)

Lidocaine Lidocaine: ↑ expected Concomitant use is not(by systemic route) recommended. It may cause(CYP3A4 inhibition by serious adverse reactions

No drug interaction studies. FPV/RTV) (see section 4.4).

Halofantrine Halofantrine: ↑ expected Concomitant use is notrecommended. It may cause

No drug interaction studies. (CYP3A4 inhibition by serious adverse reactions

FPV/RTV) (see section 4.4).

PDE5 INHIBITORS

Sildenafil PDE5 inhibitors: ↑ expected Concomitant use is not

Vardenafil recommended. It may result

Tadalafil (CYP3A4 inhibition by in an increase in PDE5

FPV/RTV) inhibitor-associated adverse

No drug interaction studies. reactions, includinghypotension, visual changesand priapism (refer to PDE5inhibitor prescribinginformation). Patients shouldbe warned about thesepossible side effects whenusing PDE5 inhibitors with

Telzir/ritonavir (see section4.4). Note that co-administration of Telzir withlow dose ritonavir withsildenafil used for thetreatment of pulmonaryarterial hypertension iscontraindicated (see section4.3).

INHALED/NASAL

STEROIDS

Fluticasone propionate Fluticasone propionate: ↑ Concomitant use is not50 µg intranasal 4 times daily) recommended unless thefor 7 days Intrinsic cortisol levels: ↓ potential benefit of treatment86 %. outweighs the risk of(Ritonavir 100 mg capsules systemic corticosteroidtwice daily for 7 days) The effects of high effects (see section 4.4). Afluticasone systemic dose reduction of theexposure on ritonavir glucocorticoid with closeplasma levels are unknown. monitoring of local andsystemic effects or a switch

Greater effects may be to a glucocorticoid, which isexpected when fluticasone not a substrate for CYP3A4propionate is inhaled. (e.g. beclomethasone)should be considered. In(CYP3A4 inhibition by case of withdrawal of

FPV/RTV) glucocorticoids, progressivedose reduction may have tobe performed over a longerperiod (see section 4.4).

ALPHA 1-

ADRENORECEPTOR

ANTAGONIST

Alfuzosin, Potential for increased Co-administration ofalfuzosin concentrations TELZIR/ritonavir withwhich can result in alfuzosin is contraindicatedhypotension. The (see section 4.3)mechanism of interaction is

CYP3A4 inhibition byfosamprenavir/ritonavir.

HERBAL PRODUCTS

St. John’s wort (Hypericum Amprenavir ↓ expected Herbal preparationsperforatum) containing St John’s wort(CYP3A4 induction by St. must not be combined with

John’s wort) Telzir (see section 4.3). If apatient is already taking St

John’s wort, checkamprenavir, ritonavir and

HIV RNA and stop St John’swort. Amprenavir andritonavir levels may increaseon stopping St John’s wort.

The inducing effect maypersist for at least 2 weeksafter cessation of treatmentwith St John’s wort.

HMG-COA REDUCTASE

INHIBITORS

Lovastatin Lovastatin: ↑ expected Contraindicated (see section

Simvastatin 4.3).

Simvastatin: ↑ expected

Increased concentrations of

No drug interaction studies. (CYP3A4 inhibition by HMG-CoA reductase

FPV/RTV) inhibitors may causemyopathy, includingrhabdomyolysis.

Pravastatin or fluvastatin arerecommended because theirmetabolism is not dependenton CYP 3A4 andinteractions are not expectedwith protease inhibitors.

Atorvastatin Atorvastatin: Cmax ↑ 184% Doses of atorvastatin no10 mg once daily for 4 days Atorvastatin: AUC ↑ 153% greater than 20 mg/day

Atorvastatin: Cmin ↑ 73% should be administered, withcareful monitoring for

Amprenavir: Cmax ↔ atorvastatin toxicity.

Amprenavir: AUC ↔

Amprenavir: Cmin ↔(CYP3A4 inhibition by

FPV/RTV)

IMMUNOSUPPRESSANTS

Cyclosporin Cyclosporin: ↑ expected Frequent therapeutic

Rapamycin Rapamycin: ↑ expected concentration monitoring of

Tacrolimus Tacrolimus: ↑ expected immunosuppressant levels isrecommended until levels

No drug interaction studies. (CYP3A4 inhibition by have stabilised (see section

FPV/RTV) 4.4).

BENZODIAZEPINES

Midazolam Midazolam: ↑ expected (3-4 Telzir/ritonavir should notfold for parenteral be co-administered with

No drug interaction studies. midazolam) orally administeredmidazolam (see section 4.3),

Based on data with other whereasprotease inhibitors plasma caution should be used withconcentrations of co-administration ofmidazolam are expected to Telzir/ritonavir andbe significantly higher when parenteral midazolam.midazolam is given orally.

If Telzir/ritonavir is co-(CYP3A4 inhibition by administered with parenteral

FPV/RTV) midazolam, it should bedone in an intensive careunit (ICU) or similar settingwhich ensures close clinicalmonitoring and appropriatemedical management in caseof respiratory depressionand/or prolonged sedation.

Dosage adjustment formidazolam should beconsidered, especially ifmore than a single dose ofmidazolam is administered.

TRICYCLIC

ANTIDEPRESSANTS

Desipramine Tricyclic antidepressant: ↑ Careful monitoring of the

Nortriptyline expected therapeutic and adversereactions of tricyclic

No drug interaction studies. (Mild CYP2D6 inhibition antidepressants isby RTV) recommended (see section4.4).

OPIOIDS

Methadone (R-) methadone: Cmax ↓ The decrease of (R-)≤ 200 mg once daily 21% methadone (active(R-) methadone: AUC ↓ enantiomer) is not expected18% to be clinically significant.

As a precaution, patients(CYP induction by should be monitored for

FPV/RTV) withdrawal syndrome.

ORAL ANTICOAGULANTS

Warfarin Possible ↓ or ↑ of Reinforced monitoring of the

Other oral anticoagulants antithrombotic effect. International Normalised

Ratio is recommended (see

No drug interaction studies. (Induction and/or section 4.4).

inhibition of CYP2C9 by

RTV)

ORAL CONTRACEPTIVES

Ethinyl estradiol 0.035 Ethinyl estradiol: Cmax Alternative non-hormonalmg/norethisterone 0.5 mg once ↓28% methods of contraception aredaily Ethinyl estradiol: AUC recommended for women of↓37% childbearing potential (seesection 4.4).

Norethisterone: Cmax↓38%

Norethisterone: AUC↓34%

Norethisterone: Cmin ↓ 26(CYP3A4 induction by

FPV/RTV)

Amprenavir: Cmax ↔*

Amprenavir: AUC ↔*

Amprenavir: Cmin ↔*

* compared to historicaldata

Ritonavir: Cmax ↑ 63%*

Ritonavir: AUC ↑ 45%*

* compared to historicaldata

Clinically significanthepatic transaminaseelevations occurred insome subjects.

SELECTIVE SEROTONIN

REUPTAKE INHIBITORS(SSRIS)

Paroxetine Paroxetine: Cmax ↓ 51% Dose titration of paroxetine

Paroxetine: AUC ↓55% based on a clinical assessment20 mg once daily of antidepressant response is

Amprenavir: Cmax ↔* recommended. Patients on

Amprenavir: AUC ↔* stable dose of paroxetine who

Amprenavir: Cmin ↔* start treatment with Telzir and

* compared to historical ritonavir should be monitoreddata for antidepressant response.

Mechanism unknown.

ANTINEOPLASTIC AGENTS

METABOLISED BY CYP3A

Examples of antineoplastic dasatinib: ↑ expected When antineoplastic agentsagents: nilotinib: ↑ expected that are metabolised bydasatinib ibrutinib: ↑ expected CYP3A are co-administerednilotinib vinblastine: ↑ expected with fosamprenavir/ritonavir,ibrutinib everolimus: ↑ expected plasma concentrations ofvinblastine (CYP3A4 inhibition) these antineoplasticeverolimus medications may be increasedand could increase the risk of

No FPV/RTV drug interaction adverse events usuallystudies associated with theseantineoplastic agents. In caseof concomitant administrationwith antineoplastic agentsmetabolized by CYP3A,please refer to the relevantproduct information for thesemedications.

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection inpregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn,the animal data (see section 5.3) as well as the clinical experience in pregnant women should be takeninto account.

There is limited clinical experience (less than 300 pregnancy outcomes) from the use of fosamprenavirin pregnant women. Placental transfer of amprenavir has been shown to occur in humans.

In animal studies at systemic plasma exposures (AUC) to amprenavir lower than therapeutic exposurein patients treated with Telzir, some developmental toxicity was observed (see section 5.3). In view ofthe low exposure in reproductive toxicity studies, the potential developmental toxicity of Telzir hasnot been fully determined.

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

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

It is recommended that women living with HIVdo not breast-feed their infants in order to avoidtransmission of HIV.

No human data on the effect of fosamprenavir on fertility are available. In rats, there was no majoreffect on fertillty or reproductive performance with fosamprenavir (see section 5.3).

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

The adverse reaction profile was similar across all the respective adult studies: antiretroviral naïvepatients (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 inthese three studies.

The most frequently (> 5% of adult subjects treated) reported adverse reactions withfosamprenavir/ritonavir combination were gastrointestinal reactions (nausea, diarrhoea, abdominalpain and vomiting) and headache. Most adverse reactions associated with fosamprenavir/ritonavircombination 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 havealso been reported (cf paragraph Description of selected adverse reactions).

Adverse reactions are listed by MedDRA system organ class and absolute frequency. Frequencies aredefined 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 postmarketingdata.

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

Body System Adverse reaction Frequency

Nervous system disorders Headache, dizziness, oral Commonparaesthesia

Gastrointestinal disorders Diarrhoea Very common

Loose stools, nausea, vomiting, Commonabdominal pain

Skin and subcutaneous tissue Stevens Johnson syndrome Raredisorders

Angioedema Uncommon

Rash (see text below Common“rash/cutaneous reactions”)

General disorders and Fatigue Commonadministration site conditions

Investigations Blood cholesterol increased Very common

Blood triglycerides increased Common

Alanine aminotransferase Commonincreased

Aspartate aminotransferase Commonincreased

Lipase increased Common

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

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

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

Metabolic parameters: Weight and levels of blood lipids and glucose may increase duringantiretroviral therapy (see section 4.4).

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

Immune Reactivation Syndrome: in HIV-infected patients with severe immune deficiency at the timeof initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomaticor residual opportunistic infections may arise. Autoimmune disorders (such as Graves’ disease) havealso been reported to occur in the setting of immune reactivation; however, the reported time to onsetis more variable and these events can occur many months after initiation of treatment (see section 4.4).

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

Paediatric/other populations

Children and adolescents: The adverse reaction profile in children and adolescents is based onintegrated safety data from two studies (APV29005 Week 24 data and APV20003 Week 168 data[final data]) in which 158 HIV-1 infected subjects 2 to 18 years of age received fosamprenavir withritonavir with background nucleoside reverse transcriptase inhibitor therapy (see section 5.1 forinformation on dosing regimens applied for each age group). 79 % of subjects received greater than 48weeks of exposure.

Overall the safety profile in these 158 children and adolescents was similar to that observed in theadult population. Vomiting occurred more frequently amongst paediatric patients. Drug-relatedadverse reactions were more common in APV20003 (57%) where subjects received once dailyfosamprenavir/ritonavir when compared to APV29005 (33%) where subjects received twice dailyfosamprenavir/ritonavir.

No new safety concerns were identified from analyses of 48 week data from studies APV29005 or

APV20002, in which 54 subjects 4 weeks to <2 years of age received twice daily fosamprenavir /ritonavir with background nucleoside reverse transcriptase inhibitor therapy and 5 subjects receivedonly single doses of fosamprenavir with or without ritonavir.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

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

Administration of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily results inplasma amprenavir concentrations (data from study APV30003 in antiretroviral experienced patients)which results in protein adjusted median ratios of Cmin/IC50 and Cmin/IC95 of 21.7 (range 1.19-240) and3.21 (range 0.26-30.0), respectively.

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

In vivoa) ART-naïve or PI-naïve patients

Various regimens have been assessed in the amprenavir/fosamprenavir development programs withand without co-administration of ritonavir. Analysis of the virological failure samples across theseregimens defined four main resistance pathways: V32I+I47V, I50V, I54L/M and I84V. Additionalmutations 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 adult patients were treated with the currently approved doses offosamprenavir/ritonavir, as for other ritonavir boosted PI regimens, the mutations described wereinfrequently observed. Sixteen of 434 ART-naïve patients who received fosamprenavir 700mg/ritonavir 100 mg twice daily in ESS100732 experienced virological failure by Week 48 with 14isolates genotyped. Three of 14 isolates had protease resistance mutations. One resistance mutationwas observed in each of 3 isolates: K20K/R, I54I/L and I93I/L respectively

Among the 81 PI-naïve paediatric patients treated with fosamprenavir/ritonavir, 15 patients metprotocol-defined virological failure through 48 weeks in APV29005 and up to 108 weeks in

APV20003. Treatment-emergent major or APV-associated protease mutations were observed in virusisolated from 2 patients. Resistance patterns were similar to those observed in adults.

b) PI-experienced patients

Amprenavir

In the studies of PI-experienced adult patients, PRO30017 (amprenavir 600 mg/ritonavir 100 mgtwice daily in sub-study A and B with 80 and 37 patients respectively), the following mutationsemerged 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.

In the studies of PI-experienced adult patients, APV30003 and its extension, APV30005(fosamprenavir 700 mg/ritonavir 100 mg twice daily: n=107), the following mutations emerged inpatients 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, 77 PI-experienced patients were treated withfosamprenavir/ritonavir-based regimens and 43 patients met study-defined virologic failure criteriathrough 48 weeks in APV29005 and up to 108 weeks in APV20003. Treatment-emergent majorprotease or APV-associated mutations were observed in virus isolated from 1 patient in APV29005and 6 patients from APV20003. 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 orfosamprenavir/ritonavir in subjects with PI-resistant isolates. The current (July 2006) ANRS AC-11algorithm 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 tofosamprenavir with ritonavir as well as reduced likelihood of virological response (resistance).

Conclusions regarding the relevance of particular mutations or mutational patterns are subject tochange with additional data, and it is recommended to always consult current interpretation systemsfor analysing resistance test results.

Phenotypic resistance testing

Clinically validated phenotypic interpretation systems may be used in association with the genotypicdata 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-offsfor FPV/RTV that can be used to interpret resistance test results.

Clinical experience with fosamprenavir boosted with ritonavir is mainly based on two open labelstudies one in antiretroviral naïve patients (study ESS100732), and one study in antiretroviralexperienced patients (study APV30003). Both of these studies compared fosamprenavir/ritonavir withlopinavir/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 regimenincluding abacavir/lamivudine (600 mg/300 mg) fixed dose combination tablet once daily showedcomparable efficacy over 48 weeks to lopinavir/ritonavir (400 mg/100 mg) given twice daily incombination 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 at48 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 thefosamprenavir 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)

FPV/RTV 700 mg/100 mg LPV/RTV 400 mg/100 mg BID

BID (n= 434) (n=444)

ITT-E Population Proportion with HIV-1 RNA < 400 copies/ml

TLOVR analysis

All Subjects 72.5 % 71.4%

Baseline HIV-1 RNA 69.5 % (n=197) 69.4% (n=209)< 100,000 copies/ml

Baseline HIV-1 RNA 75.1% (n=237) 73.2% (n=235)≥ 100,000 copies/ml

Proportion with HIV-1 RNA < 50 copies/ml

All Subjects 66% 65%

Baseline HIV-1 RNA 67% (n=197) 64% (n=209)< 100,000 copies/ml

Baseline HIV-1 RNA 65% (n=237) 66% (n=235)≥ 100,000 copies/ml

Median Change from baseline in CD4 cells (cells/µl)

ITT-E observed 176 (n=323) 191 (n=336)analysis

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

Efficacy outcomes are described in the table below.

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

FPV/RTV 700 mg/100 mg LPV/RTV 400 mg/100 mg BID

BID (n= 105) (n=91)

ITT (Ext) Population Proportion with HIV-1 RNA < 400 copies/ml

TLOVR analysis

Week 96 93% 87%

Week 144 83% 70%

Proportion with HIV-1 RNA < 50 copies/ml

Week 96 85% 75%

Week 144 73% 60%

ITT (Ext) Median Change from baseline in CD4 cells (cells/µl)

Observed analysis

Week 96 292 (n=100) 286 (n=84)

Week 144 300 (n=87) 335 (n=66)

Antiretroviral Experienced Adult Patients

In a randomised open-label study (APV30003) in protease inhibitor experienced patients withvirological 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 minusbaseline (AAUCMB) for plasma HIV-1 RNA over 48 weeks (the primary end point). Results were infavour of the lopinavir/ritonavir arm as detailed below.

All patients in this study had failed treatment with a previous protease inhibitor regimen (defined asplasma HIV-1 RNA that never went below 1,000 copies/ml after at least 12 consecutive weeks oftherapy, 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. Themedian durations of prior exposure to NRTIs were 257 weeks for patients receiving fosamprenavirwith ritonavir twice daily (79 % had ≥ 3 prior NRTIs) and 210 weeks for patients receivinglopinavir/ritonavir (64 % had ≥ 3 prior NRTIs). The median durations of prior exposure to proteaseinhibitors 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 (primaryend-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)

FPV/RTV BID LPV/RTV BID(N=107) (N=103)

AAUCMB Observed Analysis Mean (n) Mean (n)

All Patients -1.53 (105) -1.76 (103)1000 - 10,000 copies/ml -1.53 (41) -1.43 (43)>10,000 - 100,000 copies/ml -1.59 (45) -1.81 (46)>100,000 copies/ml -1.38 (19) -2.61 (14)

FPV/RTV BID vs LPV/RTV BID AAUCMB Mean Diff (97.5% CI)

All Patients 0.244 (-0.047, 0.536)1000 - 10,000 copies/ml -0.104 (-0.550, 0.342)>10,000 - 100,000 copies/ml 0.216 (-0.213, 0.664)>100,000 copies/ml 1.232 (0.512, 1.952)

AAUCMB Observed Analysis Mean (n) Mean (n)

All Patients -1.53 (105) -1.76 (103)

CD4-count <50 -1.28 (7) -2.45 (8)≥50 -1.55 (98) -1.70 (95)<200 -1.68 (32) -2.07 (38)≥ 200 -1.46 (73) -1.58 (65)

GSS to OBT1 0 -1.42 (8) -1.91 (4)1 -1.30 (35) -1.59 (23)≥ 2 -1.68 (62) -1.80 (76)

All Patients, RD=F Analysis2 n (%) n(%)

Subjects (%) with plasma HIV-1 RNA 49 (46%) 52 (50%)<50 copies/ml

Subjects (%) with plasma HIV-1 RNA 62 (58%) 63 (61%)<400 copies/ml

Subjects with >1 log10 change from 62 (58%) 71 (69%)baseline in plasma HIV-1 RNA

Change from baseline in CD4 cells Median (n) Median (n)(cells/µl)

All Patients 81 (79) 91 (85)

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

Week 48 AAUCMB(n)

Genotypic All Subjects Susceptiple to Resistant to

Sensitivity Score FPV/RTV FPV/RTVin OBT< 4 mutations from ≥ 4 mutations fromscore score0 -1.42 (8) -1.83 (4) -1.01 (4)1 -1.30 (35) -1.42 (29) -0.69 (6)≥ 2 -1.68 (62) -1.76 (56) -0.89 (6)

All patients -1.53 (105) -1.65 (89) -0.85 (16)

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 GSSsubgroups need to be interpreted with caution.

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

Children and adolescent patients above the age of six

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

APV29005 enrolled 30 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 40 patients aged 12 to 18 (themajority of whom were treated with the adult tablet regimen).

Table 5 Baseline Characteristics and Efficacy Outcomes at Week 48 in APV29005 ITT(E)

Population

Patients aged 6 to 11 Patients aged 12 to 18

N=30 N=40

Baseline Characteristics

ART/PI status, n (%)

ART-naïve 2 (7) 14 (35)

ART-experienced, PI-naïve 8 (27) 12 (30)

PI-experienced 20 (67) 14 (35)

Median duration of prior ART exposure, weeks

NRTI 386 409

PI 253 209

Median plasma HIV-1 RNA log10 copies/mL 4.6 (n=29) 4.7>100,000 copies/ml, n (%) 9 (31) 13 (33)

Median CD4 cells/μl 470 250

CD4 count < 350 cells/μl, n (%) 10 (33) 27 (68)

Efficacy Outcomes

Patients with plasma HIV-1 RNA <400 16 (53%) 25 (63%)copies/ml, Snapshot analysis

Median change from baseline in CD4 cells 210 (n=21) 140 (n=35)(cells/μl), observed analysis

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

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

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

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

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

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

Co-administration of ritonavir with fosamprenavir increase plasma amprenavir AUC by approximately2-fold and plasma Cτ,ss by 4- to 6-fold, compared to values obtained when fosamprenavir isadministered 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 plasmaamprenavir concentration (Cmax) of 6.08 (5.38-6.86) µg/ml occurring approximately 1.5 (0.75-5.0)hours after dosing (tmax). The mean steady state plasma amprenavir trough concentration (Cmin) was2.12 (1.77-2.54) µg/ml and AUC0-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 amprenavirpharmacokinetics (Cmax, tmax or AUC0-∞) compared to the administration of this formulation in thefasted state. Telzir tablets may be taken without regard to food intake.

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

The apparent volume of distribution of amprenavir following administration of Telzir is approximately430 l (6 l/kg assuming a 70 kg body weight), suggesting a large volume of distribution, withpenetration of amprenavir freely into tissues beyond the systemic circulation. This value is decreasedby approximately 40 % when Telzir is co-administered with ritonavir, most likely due to an increase inamprenavir 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 havebeen shown to decrease during the course of antiretroviral therapy. This change will decrease the totalactive substance concentration in the plasma, however the amount of unbound amprenavir, which isthe 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.

Fosamprenavir is rapidly and almost completely hydrolysed to amprenavir and inorganic phosphate asit is absorbed through the gut epithelium, following oral administration. Amprenavir is primarilymetabolised by the liver with less than 1 % excreted unchanged in the urine. The primary route ofmetabolism is via the cytochrome P450 3A4 enzyme. Amprenavir metabolism is inhibited byritonavir, 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 thanritonavir. Therefore medicinal products that are inducers, inhibitors or substrates of CYP3A4 must beused with caution when administered concurrently with Telzir with ritonavir (see sections 4.3 and 4.5).

Following administration of Telzir, the half-life of amprenavir is 7.7 hours. When Telzir isco-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 % excretedunchanged in the urine and no detectable amprenavir in faeces. Metabolites account for approximately14 % of the administered amprenavir dose in the urine, and approximately 75 % in the faeces.

Paediatrics

In a clinical study on pharmacokinetics of fosamprenavir in paediatric patients, eight subjects 12 to 18years of age received the standard fosamprenavir adult tablet dose of 700 mg twice daily (withritonavir 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 Cmax, and 20 % lower Cmin values. Children 6 to 11 years of age (n=9) receivingfosamprenavir/ritonavir 18/3 mg/kg twice daily had 26 % higher AUC(0-24) and similar Cmax and

Cmin 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 4weeks to < 2 years of age. Compared to the historical adult population receiving fosamprenavir withritonavir 700 mg/100 mg twice daily, a subset of five pediatric subjects ages 6 to < 24-monthsreceiving fosamprenavir/ritonavir 45/7 mg/kg twice daily demonstrated that despite an approximate5-fold increase in fosamprenavir and ritonavir doses on a mg/kg basis, plasma amprenavir AUC(0-τ)was approximately 48 % lower, Cmax 26 % lower, and Cτ 29 % lower in the paediatric subjects. Nodosing recommendations can be made for the very young (children < 2 years of age) and Telzir withritonavir is not recommended for this patient population (see section 4.2).

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

Patients with renal impairment have not been specifically studied. Less than 1 % of the therapeuticdose 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

Fosamprenavir is converted in man to amprenavir. The principal route of amprenavir and ritonavirelimination is hepatic metabolism.

The plasma amprenavir pharmacokinetics were evaluated in a 14 day repeat-dose study in HIV-1infected adult subjects with mild, moderate, or severe hepatic impairment receiving fosamprenavirwith 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 offosamprenavir 700 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once dailyprovided slightly higher plasma amprenavir Cmax (17 %), slightly higher plasma amprenavir

AUC(0-12) (22 %), similar plasma total amprenavir C12 values and approximately 117 % higherplasma unbound amprenavir C12 values compared to subjects with normal hepatic function receivingthe 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 offosamprenavir 450 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily ispredicted to deliver similar plasma amprenavir Cmax and AUC(0-12), but approximately 35 % lowerplasma total amprenavir C12 values and approximately 88 % higher plasma unbound amprenavir C12values than achieved in subjects with normal hepatic function receiving the standard fosamprenavirwith ritonavir 700 mg/100 mg twice daily regimen. Predicted exposures are based on extrapolationfrom data observed following administration of fosamprenavir 300 mg twice daily with ritonavir100 mg once daily in subjects with moderate hepatic impairment.

In subjects with severe hepatic impairment (Child-Pugh score of 10-13), a reduced dose offosamprenavir 300 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once dailydelivered 19% lower plasma amprenavir Cmax, 23% lower AUC(0-12), and 38% lower C12 values, butsimilar unbound plasma amprenavir C12 values than achieved in subjects with normal hepaticfunction 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 insubjects 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 severehepatic impairment, and these regimens had similar adverse event and clinical laboratory profiles asprevious studies of HIV-1 infected subjects with normal hepatic function.

Amprenavir (APV) pharmacokinetics were studied in pregnant women receiving FPV/RTV 700/100mg twice daily during the second trimester (n=6) or third trimester (n=9) and postpartum. APVexposure was 25-35% lower during pregnancy. APV geometric mean (95% CI) and Ctau values were1.31 (0.97, 1.77), 1.34 (0.95, 1.89), and 2.03 (1.46, 2.83) µg/mL for the second trimester, thirdtrimester, and postpartum, respectively and within the range of values in non-pregnant patients on thesame FPV/RTV containing regimens.

Toxicity was similar to that of amprenavir and occurred at amprenavir plasma exposure levels belowhuman exposure after treatment with fosamprenavir in combination with ritonavir at the recommendeddose.

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

In reproductive toxicity studies with fosamprenavir in rats, male fertility was not affected. In females,at the high dose, there was a reduction in the weight of gravid uterus (0 to 16%) probably due to areduction of the number of ovarian corporea lutea and implantations. In pregnant rats and rabbits therewere no major effects on embryo-foetal development. However, the number of abortions increased. Inrabbits, systemic exposure at the high dose level was only 0.3 times human exposure at the maximumclinical dose and thus the developmental toxicity of fosamprenavir has not been fully determined. Inrats exposed pre- and post-natally to fosamprenavir, pups showed impaired physical and functionaldevelopment and reduced growth. Pup survival was decreased. In addition, decreased number ofimplantation sites per litter and a prolongation of gestation were seen when pups were mated afterreaching maturity.

Fosamprenavir was not mutagenic or genotoxic in a standard battery of in vitro and in vivo assays. Inlong-term carcinogenicity studies with fosamprenavir in mice and rats, there were increases inhepatocellular adenomas and hepatocellular carcinomas in mice at exposure levels equivalent to 0.1 to0.3-fold those in humans given 700 mg of fosamprenavir plus 100 mg ritonavir twice daily, andincreases in hepatocellular adenomas and thyroid follicular cell adenomas in rats at exposure levelsequivalent to 0.3 to 0.6-fold those in humans given 700 mg of fosamprenavir plus 100 mg ritonavirtwice 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 ofclinical significance. Repeat dose studies with fosamprenavir in rats produced effects consistent withhepatic enzyme induction, which predisposes rats to thyroid neoplasms. The thyroid tumorigenicpotential is regarded to be species-specific. The clinical relevance of these findings is unknown. In ratsonly 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 anexposure level equivalent to 1.1-fold those in humans. The incidence of endometrial findings wasslightly increased over concurrent controls, but within background range for female rats. Therelevance of the uterine endometrial adenocarcinomas for humans is uncertain; however there is noevidence from clinical trials or marketed use to suggest that these findings are of clinical significance.

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 medicinal product should be disposed of in accordance with local requirements.

ViiV Healthcare BV

Van Asch van Wijckstraat 55H3811 LP Amersfoort

Netherlands

EU/1/04/282/001

Date of first authorisation: 12 July 2004

Date of renewal of authorisation: 15 May 2009.

Detailed information on this medicinal product is available on the website of the European Medicines

Agency (EMA) http://www.ema.europa.eu