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Telzir (fosamprenavir calcium) – Summary of product characteristics - J05AE07

Updated on site: 10-Oct-2017

Medication nameTelzir
ATC CodeJ05AE07
Substancefosamprenavir calcium
ManufacturerViiV Healthcare UK Limited  

1.NAME OF THE MEDICINAL PRODUCT

Telzir 700 mg film-coated tablets

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Film-coated tablet

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

4.CLINICAL PARTICULARS

4.1Therapeutic indications

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).

4.2Posology and method of administration

Telzir must only be given with low dose ritonavir as a pharmacokinetic enhancer of amprenavir and in combination with other antiretroviral medicinal products. The Summary of Product Characteristics of ritonavir 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 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. This adjusted dose has not been evaluated in a clinical study and has been derived from extrapolation (see section 5.2). 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.

Overall, even with these dose adjustments for adults with hepatic impairment, some patients 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 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.

4.3Contraindications

Hypersensitivity to fosamprenavir, amprenavir, or ritonavir, or to any of the excipients listed in section 6.1.

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, 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 of sildenafil in patients with erectile dysfunction, see sections 4.4 and 4.5).

Co-administration of paritaprevir and fosamprenavir/ritonavir is contraindicated due to the expected increase of paritaprevir exposure and the lack of clinical data assessing the magnitude of this increase (see section 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).

4.4Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

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.

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).

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 expected due 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 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.

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. 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. Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

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

4.5Interaction with other medicinal products and other forms of interaction

When fosamprenavir and ritonavir are co-administered, the ritonavir metabolic drug interaction profile may predominate because ritonavir is a more potent CYP3A4 inhibitor. The full prescribing information for ritonavir must therefore be consulted prior to initiation of therapy with 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 primarily metabolised in the liver by CYP3A4. Therefore, any medicinal products that either share this metabolic pathway or modify CYP3A4 activity may modify the pharmacokinetics of amprenavir and ritonavir. Similarly administration of fosamprenavir with ritonavir may modify the pharmacokinetics of 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 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.

Drugs by Therapeutic Area

Interaction

Recommendation

 

 

concerning co-

 

Geometric mean change

administration

 

(%)

 

 

(Possible mechanism)

 

ANTIRETROVIRAL

 

 

MEDICINAL PRODUCTS

 

 

Non-nucleoside reverse

 

 

transcriptase inhibitors:

 

 

 

 

 

Efavirenz

No clinically significant

No dosage adjustment

600 mg once daily

interaction is observed.

necessary.

 

 

 

Nevirapine

No clinically significant

No dosage adjustment

200 mg twice daily

interaction is observed.

necessary.

 

 

 

Etravirine

Amprenavir AUC ↑ 69%

Telzir may require dose

 

Amprenavir Cmin ↑ 77%

reduction (using oral

(Study conducted in 8

Amprenavir Cmax ↑ 62%

suspension).

Etravirine AUC ↔a

 

patients)

 

 

Etravirine Cmina

 

 

Etravirine Cmaxa

 

 

a Comparison based on

 

 

historic control.

 

 

 

 

Nucleoside / Nucleotide

 

 

reverse transcriptase

 

 

inhibitors:

 

 

 

 

 

Abacavir

No clinically significant

No dosage adjustment

Lamivudine

interaction is expected.

necessary.

Zidovudine

 

 

Study performed with

 

 

amprenavir.

 

 

No FPV/RTV drug

 

 

interaction studies.

 

 

 

 

 

Didanosine chewable tablet

No clinically significant

No dose separation or dosage

 

interaction is expected.

adjustment necessary (see

No drug interaction studies.

 

Antacids).

 

 

 

Didanosine gastro-resistant

No clinically significant

No dosage adjustment

capsule

interaction is expected.

necessary.

No drug interaction studies.

 

 

Tenofovir

No clinically significant

No dosage adjustment

300 mg once daily

interaction observed.

necessary.

 

 

 

Protease Inhibitors:

According to current treatment guidelines, dual therapy with protease inhibitors is generally not recommended.

Lopinavir / ritonavir

Lopinavir: Cmax30%

Concomitant use is not

400 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 mg

 

 

twice 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 CYP3A4

 

 

induction/inhibition, Pgp

 

 

induction)

 

Indinavir

 

No dose recommendations

Saquinavir

 

can be given.

Nelfinavir

 

 

No drug interaction studies.

 

 

Atazanavir

Atazanavir: Cmax 24%*

No dosage adjustment

 

Atazanavir: AUC22%*

necessary.

300 mg once daily

Atazanavir: Cmin*

 

 

*compared to atazanavir/

 

 

ritonavir 300 mg/ 100 mg

 

 

once daily

 

 

Amprenavir: Cmax

 

 

Amprenavir: AUC

 

 

Amprenavir: Cmin

 

 

 

 

Integrase inhibitors

 

 

 

 

 

Raltegravir

Fasting state

Concomitant use is not

400 mg twice daily

 

recommended. Significant

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)

 

Raltegravir:

may result in virological

 

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 of

50 mg once daily

Cmax 24%

fosamprenavir or

dolutegravir is recommended

 

AUC 35%

based on observed exposure-

 

49%

response relationships of

 

Amprenavir: Cmax

clinical data. Caution is

 

warranted and close

 

Amprenavir: AUC

monitoring is recommended

 

Amprenavir: Cmin

when this combination is

 

 

given in integrase inhibitor-

 

 

resistant patients.

CCR5-receptor antagonists

 

 

 

 

 

Maraviroc

Maraviroc: AUC12 2.49

Concomitant use is not

300 mg twice daily

Maraviroc: Cmax 1.52

recommended. Significant

Maraviroc: C12 4.74

reductions in amprenavir Cmin

 

Amprenavir: AUC12 0.65

observed may result in

 

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

Telaprevir

Amprenavir

Not recommended.

 

AUC 0.53 (0.49-0.58)

 

(PK data from telaprevir

Cmax 0.65 (0.59-0.70)

 

prescribing information)

Cmin 0.44 (0.40-0.50)

 

 

Telaprevir

 

 

AUC 0.68 (0.63-0.72)

 

 

Cmax 0.67 (0.63-0.71)

 

 

Cmin 0.70 (0.64-0.77)

 

 

Mechanism unknown.

 

 

 

 

Boceprevir

Not studied.

Not recommended.

 

Results from studies with

 

 

other HIV protease inhibitors

 

 

and boceprevir suggest that

 

 

co-administration of

 

 

fosamprenavir/ritonavir with

 

 

boceprevir is likely to lead to

 

 

subtherapeutic levels of

 

 

fosamprenavir and

 

 

boceprevir.

 

Simeprevir

Not studied.

Not recommended.

Daclatasvir

Results from studies with

 

 

other HIV protease inhibitors

 

 

and simeprevir or daclatasvir,

 

 

suggest that co-

 

 

administration with

 

 

fosamprenavir/ritonavir is

 

 

likely to lead to increased

 

 

plasma exposures of

 

 

simeprevir or daclatasvir due

 

 

to CYP3A4 enzyme

 

 

inhibition.

 

Paritaprevir

Not studied.

Contraindicated (see section

(co-formulated with

Results from studies with

4.3).

ritonavir and ombitasvir

other HIV protease inhibitors

 

and co-administered with

and paritaprevir/ritonavir/

 

dasabuvir)

ombitasvir +/- dasabuvir

 

 

suggest that co-

 

administration of fosamprenavir/ritonavir with paritaprevir/ritonavir/ ombitasvir+/-dasabuvir is likely to lead to increased plasma exposures of paritaprevir due to CYP3A4 enzyme inhibition and higher ritonavir 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

(CYP3A4 inhibition by

arrhythmias.

 

 

 

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 by

 

expected

peripheral vasospasm and

 

(CYP3A4 inhibition by

ischemia of the extremities

 

and other tissues.

 

FPV/RTV)

 

GASTROINTESTINAL

 

 

MOTILITY AGENTS

 

 

Cisapride

Cisapride: ↑ expected

Contraindicated (see section

 

 

4.3). Potential for serious

 

(CYP3A4 inhibition by

and/or life-threatening

 

FPV/RTV)

reactions such as cardiac

 

 

arrhythmias.

ANTIHISTAMINES

 

 

(HISTAMINE H1

 

 

RECEPTOR

 

 

ANTAGONISTS)

 

 

Astemizole

Astemizole: ↑ expected

Contraindicated (see section

Terfenadine

Terfenadine: ↑ expected

4.3). Potential for serious

 

(CYP3A4 inhibition by

and/or life-threatening

 

reactions such as cardiac

 

FPV/RTV)

arrhythmias.

NEUROLEPTIC

 

 

 

 

 

Pimozide

Pimozide: ↑ expected

Contraindicated (see section

 

 

4.3). Potential for serious

 

(CYP3A4 inhibition by

and/or life-threatening

 

FPV/RTV)

reactions such as cardiac

 

 

arrhythmias.

ANTIPSYCHOTICS

 

 

Quetiapine

Due to CYP3A inhibition by

Concomitant administration

 

Telzir, concentrations of

of Telzir and quetiapine is

 

quetiapine are expected to

contra-indicated as it may

 

increase.

increase quetiapine-related

 

 

toxicity. Increased plasma

 

 

concentrations of quetiapine

 

 

may lead to coma.

INFECTION

 

 

Antibacterials:

 

 

 

 

 

Clarithromycin

Clarithromycin: moderate ↑

Use with caution.

Study performed with

expected

 

(CYP3A4 inhibition)

 

amprenavir.

 

No FPV/RTV drug

 

 

interaction 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 (active

 

 

metabolite) could potentially

 

25-O-desacetylrifabutin:

lead to an increase of

 

Cmax 6-fold*

rifabutin related adverse

 

25-O-desacetylrifabutin:

events, notably uveitis.

 

AUC(0-48)11-fold*

A 75 % reduction of the

 

*compared to rifabutin

 

300 mg once daily

standard rifabutin dose (i.e.

 

 

to 150 mg every other day) is

 

Amprenavir exposure

recommended. Further dose

 

unchanged when compared

reduction may be necessary

 

to historical data.

(see section 4.4).

 

(Mixed CYP3A4

 

 

induction/inhibition)

 

 

 

 

Rifampicin

Amprenavir: AUC ↓ 82%

Contraindicated (see section

600 mg once daily

 

4.3).

(Amprenavir without

Significant ↓ APV expected

The decrease in amprenavir

ritonavir)

 

AUC can result in virological

 

 

failure and resistance

No FPV/RTV drug

(CYP3A4 induction by

development. During

interaction studies

rifampicin)

attempts to overcome the

 

 

decreased exposure by

 

 

increasing the dose of other

 

 

protease inhibitors with

 

 

ritonavir, a high frequency of

 

 

liver 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 or

days

fold.

itraconazole are not

 

Amprenavir: Cmax

recommended.

 

 

 

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 adjustment

suspension (equivalent to

Amprenavir: AUC ↓ 18%

necessary with antacids,

3.6 grams aluminium

Amprenavir: Cmin (C12h) ↔

proton-pump inhibitors or

hydroxide and 1.8 grams

 

histamine H2 receptor

magnesium hydroxide

 

antagonists.

(Telzir 1400 mg single dose)

 

 

Ranitidine

Amprenavir: Cmax ↓ 51%

 

300 mg single dose

Amprenavir: AUC ↓ 30%

 

(Telzir 1400 mg single dose)

Amprenavir: Cmin (C12h) ↔

 

 

 

Esomeprazole

Amprenavir Cmax

 

20 mg once daily

Amprenavir AUC ↔

 

 

Amprenavir Cmin (C12h) ↔

 

 

(Increase in gastric pH)

 

ANTICONVULSANTS

 

 

 

 

 

Phenytoin

Phenytoin: Cmax ↓ 20%

It is recommended that

300 mg once daily

Phenytoin: AUC ↓ 22%

phenytoin plasma

 

Phenytoin: Cmin ↓ 29%

concentrations be monitored

 

(Modest induction of

and phenytoin dose increased

 

as appropriate.

 

CYP3A4 by FPV/RTV)

 

 

 

 

Amprenavir: Cmax

Amprenavir: AUC ↑ 20%

Amprenavir: Cmin ↑ 19%

Phenobarbital

Amprenavir: ↓ expected

Use with caution (see

Carbamazepine

(Modest CYP3A4

section 4.4).

 

 

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 not

 

 

recommended. 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, including

 

 

hypotension, visual changes

 

 

and priapism (refer to PDE5

 

 

inhibitor prescribing

 

 

information). Patients should

 

 

be warned about these

 

 

possible side effects when

 

 

using PDE5 inhibitors with

 

 

Telzir/ritonavir (see section

 

 

4.4). 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).

INHALED/NASAL

 

 

STEROIDS

 

 

 

 

 

Fluticasone propionate

Fluticasone propionate: ↑

Concomitant use is not

50 µg intranasal 4 times daily)

Intrinsic cortisol levels: ↓

recommended unless the

for 7 days

potential benefit of treatment

 

86 %.

outweighs the risk of

(Ritonavir 100 mg capsules

The effects of high

systemic corticosteroid

twice daily for 7 days)

effects (see section 4.4). A

 

fluticasone systemic

dose reduction of the

 

exposure on ritonavir

glucocorticoid with close

 

plasma levels are unknown.

monitoring of local and

 

 

systemic effects or a switch

 

Greater effects may be

to a glucocorticoid, which is

 

expected when fluticasone

not a substrate for CYP3A4

 

propionate is inhaled.

(e.g. beclomethasone)

 

 

should be considered. In

 

(CYP3A4 inhibition by

case of withdrawal of

 

FPV/RTV)

glucocorticoids, progressive

 

 

dose reduction may have to

 

 

be performed over a longer

 

 

period (see section 4.4).

 

 

 

ALPHA 1-

 

 

ADRENORECEPTOR

 

 

ANTAGONIST

 

 

Alfuzosin,

Potential for increased

Co-administration of

 

alfuzosin concentrations

TELZIR/ritonavir with

 

which can result in

alfuzosin is contraindicated

 

hypotension. The

(see section 4.3)

 

mechanism of interaction is

 

 

CYP3A4 inhibition by

 

 

fosamprenavir/ritonavir.

 

 

 

 

HERBAL PRODUCTS

 

 

 

 

 

St. John’s wort (Hypericum

Amprenavir ↓ expected

Herbal preparations

perforatum)

 

containing St John’s wort

 

(CYP3A4 induction by St.

must not be combined with

 

John’s wort)

Telzir (see section 4.3). If a

 

 

patient is already taking St

 

 

John’s wort, check

 

 

amprenavir, ritonavir and

 

 

HIV RNA and stop St John’s

 

 

wort. Amprenavir and

 

 

ritonavir levels may increase

 

 

on stopping St John’s wort.

 

 

The inducing effect may

 

 

persist for at least 2 weeks

 

 

after cessation of treatment

 

 

with St John’s wort.

HMG-COA REDUCTASE

 

 

INHIBITORS

 

 

 

 

 

Lovastatin

Lovastatin: ↑ expected

Contraindicated (see section

Simvastatin

Simvastatin: ↑ expected

4.3).

 

Increased concentrations of

 

 

No drug interaction studies.

(CYP3A4 inhibition by

HMG-CoA reductase

 

FPV/RTV)

inhibitors may cause

 

 

myopathy, including

 

 

rhabdomyolysis.

 

 

Pravastatin or fluvastatin are

 

 

recommended because their

 

 

metabolism is not dependent

 

 

on CYP 3A4 and

 

 

interactions are not expected

 

 

with protease inhibitors.

Atorvastatin

Atorvastatin: Cmax ↑ 184%

Doses of atorvastatin no

10 mg once daily for 4 days

Atorvastatin: AUC ↑ 153%

greater than 20 mg/day

 

Atorvastatin: Cmin ↑ 73%

should be administered, with

 

Amprenavir: Cmax

careful monitoring for

 

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 is

 

(CYP3A4 inhibition by

recommended until levels

No drug interaction studies.

have stabilised (see section

 

FPV/RTV)

4.4).

 

 

 

BENZODIAZEPINES

 

 

 

 

 

Midazolam

Telzir/ritonavir should not

 

fold for parenteral

be co-administered with

No drug interaction studies.

midazolam)

orally administered

 

Based on data with other

midazolam (see section 4.3),

 

whereas

 

protease inhibitors plasma

caution should be used with

 

concentrations of

co-administration of

 

midazolam are expected to

Telzir/ritonavir and

 

be 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 be

 

 

done in an intensive care

 

 

unit (ICU) or similar setting

 

 

which ensures close clinical

 

 

monitoring and appropriate

 

 

medical management in case

 

 

of respiratory depression

 

 

and/or prolonged sedation.

 

 

Dosage adjustment for

 

 

midazolam should be

 

 

considered, especially if

 

 

more than a single dose of

 

 

midazolam is administered.

TRICYCLIC

 

 

ANTIDEPRESSANTS

 

 

 

 

 

Desipramine

Tricyclic antidepressant: ↑

Careful monitoring of the

Nortriptyline

expected

therapeutic and adverse

 

 

reactions of tricyclic

No drug interaction studies.

(Mild CYP2D6 inhibition

antidepressants is

 

by RTV)

recommended (see section

 

 

4.4).

 

 

 

OPIOIDS

 

 

 

 

 

Methadone

(R-) methadone: Cmax

The decrease of (R-)

≤ 200 mg once daily

21%

methadone (active

 

(R-) methadone: AUC ↓

enantiomer) is not expected

 

18%

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

 

(Induction and/or inhibition

Ratio is recommended (see

No drug interaction studies.

section 4.4).

 

of CYP2C9 by RTV)

 

 

 

 

ORAL CONTRACEPTIVES

 

 

 

 

 

Ethinyl estradiol 0.035

Ethinyl estradiol: Cmax

Alternative non-hormonal

mg/norethisterone 0.5 mg

↓28%

methods of contraception are

once daily

Ethinyl estradiol: AUC

recommended for women of

 

↓37%

childbearing potential (see

 

Norethisterone: Cmax ↓38%

section 4.4).

 

 

 

Norethisterone: AUC ↓34%

 

 

Norethisterone: Cmin ↓ 26

 

 

(CYP3A4 induction by

 

 

FPV/RTV)

 

 

Amprenavir: Cmax ↔*

 

 

Amprenavir: AUC ↔*

 

 

Amprenavir: Cmin ↔*

 

 

* compared to historical

 

 

data

 

 

Ritonavir: Cmax ↑ 63%*

 

 

Ritonavir: AUC ↑ 45%*

 

 

* compared to historical

 

 

data

 

 

Clinically significant hepatic

 

 

transaminase elevations

 

 

occurred in some subjects.

 

SELECTIVE SEROTONIN

 

 

REUPTAKE INHIBITORS

 

 

(SSRIS)

 

 

 

 

 

Paroxetine

Paroxetine: Cmax 51%

Dose titration of paroxetine

 

Paroxetine: AUC 55%

based on a clinical

20 mg once daily

Amprenavir: Cmax *

assessment of antidepressant

 

response is recommended.

 

Amprenavir: AUC *

Patients on stable dose of

 

Amprenavir: Cmin *

paroxetine who start

 

* compared to historical

treatment with Telzir and

 

data

ritonavir should be

 

 

monitored for antidepressant

 

Mechanism unknown.

response.

4.6Fertility, pregnancy and lactation

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.

Breast-feeding

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 recommended that HIV-infected women must not breast-feed under any circumstances to avoid transmission of HIV.

4.7Effects on ability to drive and use machines

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).

4.8Undesirable effects

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.

Body System

Adverse reaction

Frequency

Nervous system disorders

Headache, dizziness, oral

Common

 

paraesthesia

 

 

 

 

Gastrointestinal disorders

Diarrhoea

Very common

 

Loose stools, nausea, vomiting,

Common

 

abdominal pain

 

Skin and subcutaneous tissue

Stevens Johnson syndrome

Rare

disorders

Angioedema

Uncommon

 

 

Rash (see text below

Common

 

“rash/cutaneous reactions”)

 

 

 

 

General disorders and

Fatigue

Common

administration site conditions

 

 

 

 

 

Investigations

Blood cholesterol increased

Very common

 

Blood triglycerides increased

Common

 

Alanine aminotransferase

Common

 

increased

 

 

Aspartate aminotransferase

Common

 

increased

 

 

Lipase increased

Common

 

 

 

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).

Metabolic parameters: Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (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. Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is 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 generally acknowledged risk factors, advanced HIV disease or long-term exposure to 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 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 with ritonavir with background nucleoside reverse transcriptase inhibitor therapy (see section 5.1 for information on dosing regimens applied for each age group). 79 % of subjects received greater than 48 weeks of exposure.

Overall the safety profile in these 158 children and adolescents was similar to that observed in the adult population. Vomiting occurred more frequently amongst paediatric patients. Drug-related adverse reactions were more common in APV20003 (57%) where subjects received once daily fosamprenavir / ritonavir when compared to APV29005 (33%) where subjects received twice daily fosamprenavir / 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 received only single doses of fosamprenavir with or without ritonavir.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9Overdose

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.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

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 Cmin/IC50 and Cmin/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 M in acutely infected cells and was 0.41 M in chronically infected cells (1 M = 0.50 g/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 adult 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 700 mg/ritonavir 100 mg 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

Among the 81 PI-naïve paediatric patients treated with fosamprenavir / ritonavir, 15 patients met protocol-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 virus isolated 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 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 adult 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, 77 PI-experienced patients were treated with fosamprenavir / ritonavir-based regimens and 43 patients met study-defined virologic failure criteria through 48 weeks in APV29005 and up to 108 weeks in APV20003. Treatment-emergent major protease or APV-associated mutations were observed in virus isolated from 1 patient in APV29005 and 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 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)

 

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/ l)

 

 

 

ITT-E observed

176 (n=323)

191 (n=336)

analysis

 

 

 

 

 

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)

 

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/ l)

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 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)

 

 

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

-1.42 (8)

-1.91 (4)

 

-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/ l)

 

 

 

 

 

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/RTV

in OBT

 

 

< 4 mutations from

≥ 4 mutations from

 

 

 

 

 

 

score

score

 

 

 

 

-1.42 (8)

-1.83 (4)

-1.01 (4)

 

 

 

 

 

-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 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 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 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 (the majority 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

PI

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

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 dosage regimen than that of study APV29005 was used.

5.2Pharmacokinetic properties

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 AUCvalues and the Telzir oral suspension formulation delivered a 14 % higher plasma amprenavir Cmax 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, 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 approximately 2-fold and plasma Cτ,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 (Cmax) of 6.08 (5.38-6.86) g/ml occurring approximately 1.5 (0.75-5.0) hours after dosing (tmax). The mean steady state plasma amprenavir trough concentration (Cmin) was 2.12 (1.77-2.54) g/ml and AUC0-tau was 39.6 (34.5–45.3) h* g/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 (Cmax, tmax or AUC0-∞) 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.

Biotransformation

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 Cmax, and 20 % lower Cmin 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 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 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-τ) was approximately 48 % lower, Cmax 26 % lower, and Cτ 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 Cmax (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 Cmax 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. Predicted exposures are based on extrapolation from data observed following administration of fosamprenavir 300 mg twice daily with ritonavir

100 mg once daily in subjects with moderate hepatic impairment.

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.

5.3Preclinical safety data

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 100 mg 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 100 mg 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.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

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)

6.2Incompatibilities

Not applicable.

6.3Shelf life

3 years.

6.4Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5Nature and contents of container

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

6.6Special precautions for disposal

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

7.MARKETING AUTHORISATION HOLDER

ViiV Healthcare UK Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

8.MARKETING AUTHORISATION NUMBER

EU/1/04/282/001

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 12 July 2004

Date of renewal of authorisation: 15 May 2009.

10.DATE OF REVISION OF THE TEXT

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

1. NAME OF THE MEDICINAL PRODUCT

Telzir 50 mg/ml oral suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of oral suspension contains 50 mg fosamprenavir as fosamprenavir calcium (equivalent to approximately 43 mg amprenavir).

Excipients:

 

Methyl parahydroxybenzoate (E218)

1.5 mg/ml

Propyl parahydroxybenzoate (E216)

0.2 mg/ml

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oral suspension

The suspension is white to off-white in colour.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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).

4.2 Posology and method of administration

Telzir must only be given with low dose ritonavir as a pharmacokinetic enhancer of amprenavir and in combination with other antiretroviral medicinal products. The Summary of Product Characteristics of ritonavir 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 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 dose of fosamprenavir with ritonavir detailed below are exceeded (see section 4.4).

Telzir suspension is administered orally.

Shake the bottle vigorously for 20 seconds before first dose is removed and 5 seconds before each subsequent dose.

Telzir is also available as 700 mg film-coated tablets.

Adults

In adults, the oral suspension should be taken without food and on an empty stomach.

Please refer to the table below for the dosing recommendations in adults.

Paediatric patients (from 6 years of age)

In paediatric patients, the oral suspension should be taken with food in order to aid palatability and assist compliance (see section 5.2).

Telzir oral suspension is the recommended option for the most accurate dosing in children based on body weight.

Please refer to the table below for the dosing recommendations in paediatric patients.

No dosing recommendations can be made for children weighing less than 25 kg.

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).

Dosing recommendations for Telzir with ritonavir

Age

Body

Telzir dose

Ritonavir dose

 

weight

(TWICE DAILY)

(TWICE DAILY)

 

 

 

 

Adult

 

Tablet or Oral suspension

Capsule or Solution

(>18

 

 

 

years)

 

700 mg (1 tablet or 14 ml

100 mg

 

 

suspension)

 

 

 

Oral suspension should be

 

 

 

taken without food

 

6-17 years

>39 kg

Tablet or Oral suspension

Capsule or Solution

 

 

700 mg (1 tablet or 14 ml

100 mg

 

 

suspension)

 

 

 

Oral suspension should be

 

 

 

taken with food

 

 

33-38 kg

Oral suspension

Capsule or Solution

 

 

18 mg/kg (0.36 ml/kg );

100 mg

 

 

maximum 700 mg or 14 ml

 

 

 

Oral suspension should be

 

 

 

taken with food

 

 

25-32 kg

Oral suspension

Solution

 

 

18 mg/kg (0.36 ml/kg )

3 mg/kg

 

 

Oral suspension should be

 

 

 

taken with food

 

 

<25 kg

No dosing recommendations

 

 

 

 

 

<6 years

 

Not recommended

 

 

 

 

 

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 (i.e. 9 ml Telzir oral suspension) twice daily with 100 mg ritonavir once daily. This adjusted dose has not been evaluated in a clinical study and has been derived from extrapolation (see section 5.2).

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.

Overall, even with these dose adjustments for adults with hepatic impairment, some patients 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 close monitoring of safety and virologic response is warranted.

In this patient population, the oral suspension should be taken without food and on an empty stomach.

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

4.3 Contraindications

Hypersensitivity to fosamprenavir, amprenavir, or ritonavir, or to any of the excipients listed in section 6.1.

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, 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 of sildenafil in patients with erectile dysfunction, see sections 4.4 and 4.5).

Co-administration of paritaprevir and fosamprenavir/ritonavir is contraindicated due to the expected increase of paritaprevir exposure and the lack of clinical data assessing the magnitude of this increase (see section 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).

4.4 Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Patients should be advised that treatment with the 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.

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.

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

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.

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 co-administered with Telzir (see section 4.5).

When warfarin or other oral anticoagulants are co-administered 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).

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 expected due to inhibition or induction of CYP3A4 enzyme activity (see section 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 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.

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. 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. Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

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

4.5 Interaction with other medicinal products and other forms of interaction

When fosamprenavir and ritonavir are co-administered, the ritonavir metabolic drug interaction profile may predominate because ritonavir is a more potent CYP3A4 inhibitor. The full prescribing information for ritonavir must therefore be consulted prior to initiation of therapy with 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 primarily metabolised in the liver by CYP3A4. Therefore, any medicinal products that either share this metabolic pathway or modify CYP3A4 activity may modify the pharmacokinetics of amprenavir and ritonavir. Similarily, administration of fosamprenavir with ritonavir may modify the pharmacokinetics of 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 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,

Drugs by Therapeutic Area

Interaction

Recommendation

 

 

concerning co-

 

Geometric mean change

administration

 

(%)

 

 

(Possible mechanism)

 

ANTIRETROVIRAL

 

 

MEDICINAL PRODUCTS

 

 

Non-nucleoside reverse

 

 

transcriptase inhibitors:

 

 

 

 

 

Efavirenz

No clinically significant

No dosage adjustment

600 mg once daily

interaction is observed.

necessary.

 

 

 

Nevirapine

No clinically significant

No dosage adjustment

200 mg twice daily

interaction is observed.

necessary.

 

 

 

Etravirine

Amprenavir AUC ↑↑ 69%

Telzir may require dose

 

Amprenavir Cmin ↑ 77%

reduction (using oral

(Study conducted in 8

Amprenavir Cmax ↑ 62%

suspension).

Etravirine AUC ↔a

 

patients)

 

 

Etravirine Cmina

 

 

Etravirine Cmaxa

 

 

a Comparison based on

 

 

historic control.

 

Nucleoside / Nucleotide

 

 

reverse transcriptase

 

 

inhibitors:

 

 

 

 

 

Abacavir

No clinically significant

No dosage adjustment

Lamivudine

interaction is expected.

necessary.

Zidovudine

 

 

Study performed with

 

 

amprenavir.

 

 

No FPV/RTV drug

 

 

interaction studies.

 

 

 

 

 

Didanosine chewable tablet

No clinically significant

No dose separation or dosage

 

interaction is expected.

adjustment necessary (see

No drug interaction studies.

 

Antacids).

 

 

 

Didanosine gastro-resistant

No clinically significant

No dosage adjustment

capsule

interaction is expected.

necessary.

No drug interaction studies.

 

 

 

 

 

Tenofovir

No clinically significant

No dosage adjustment

300 mg once daily

interaction observed.

necessary.

 

 

 

Protease Inhibitors:

According to current treatment guidelines, dual therapy with protease inhibitors is generally not recommended.

Lopinavir / ritonavir

Lopinavir: Cmax 30%

Concomitant use is not

400 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 mg

 

 

twice 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 CYP3A4

 

 

induction/inhibition, Pgp

 

 

induction)

 

Indinavir

 

No dose recommendations

Saquinavir

 

can be given.

Nelfinavir

 

 

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 mg

 

 

once daily

 

 

Amprenavir: Cmax

 

 

Amprenavir: AUC

 

 

Amprenavir: Cmin

 

 

 

 

Integrase inhibitors

 

 

 

 

 

Raltegravir

Fasting state

Concomitant use is not

400 mg twice daily

 

recommended. Significant

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)

 

Raltegravir:

may result in virological

 

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 of

50 mg once daily

Cmax 24%

fosamprenavir or

dolutegravir is recommended

 

AUC 35%

based on observed exposure-

 

49%

response relationships of

 

Amprenavir: Cmax

clinical data. Caution is

 

warranted and close

 

Amprenavir: AUC

monitoring is recommended

 

Amprenavir: Cmin

when this combination is

 

 

given in integrase inhibitor-

 

 

resistant patients.

CCR5-receptor antagonists

 

 

 

 

 

Maraviroc

Maraviroc: AUC12 2.49

Concomitant use is not

300 mg twice daily

Maraviroc: Cmax 1.52

recommended. Significant

Maraviroc: C12 4.74

reductions in amprenavir Cmin

 

Amprenavir: AUC12 0.65

observed may result in

 

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

Telaprevir

Amprenavir

Not recommended.

 

AUC 0.53 (0.49-0.58)

 

(PK data from telaprevir

Cmax 0.65 (0.59-0.70)

 

prescribing information)

Cmin 0.44 (0.40-0.50)

 

 

Telaprevir

 

 

AUC 0.68 (0.63-0.72)

 

 

Cmax 0.67 (0.63-0.71)

 

 

Cmin 0.70 (0.64-0.77)

 

 

Mechanism unknown.

 

 

 

 

Boceprevir

Not studied.

Not recommended.

 

Results from studies with

 

 

other HIV protease inhibitors

 

 

and boceprevir suggest that

 

 

co-administration of

 

 

fosamprenavir/ritonavir with

 

 

boceprevir is likely to lead to

 

 

subtherapeutic levels of

 

 

fosamprenavir and

 

 

boceprevir.

 

Simeprevir

Not studied.

Not recommended.

Daclatasvir

Results from studies with

 

 

other HIV protease inhibitors

 

 

and simeprevir or daclatasvir,

 

 

suggest that co-

 

 

administration with

 

 

fosamprenavir/ritonavir is

 

 

likely to lead to increased

 

 

plasma exposures of

 

 

simeprevir or daclatasvir due

 

 

to CYP3A4 enzyme

 

 

inhibition.

 

Paritaprevir

Not studied.

Contraindicated (see section

(co-formulated with

Results from studies with

4.3).

ritonavir and ombitasvir

other HIV protease inhibitors

 

and co-administered with

and paritaprevir/ritonavir/

 

dasabuvir)

ombitasvir +/- dasabuvir

 

 

suggest that co-

 

administration of fosamprenavir/ritonavir with paritaprevir/ritonavir/ ombitasvir +/- dasabuvir is likely to lead to increased plasma exposures of paritaprevir due to CYP3A4 enzyme inhibition and higher ritonavir 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

(CYP3A4 inhibition by

arrhythmias.

 

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 by

 

expected

peripheral vasospasm and

 

(CYP3A4 inhibition by

ischemia of the extremities

 

and other tissues.

 

FPV/RTV)

 

GASTROINTESTINAL

 

 

MOTILITY AGENTS

 

 

 

 

 

Cisapride

Cisapride: ↑ expected

Contraindicated (see section

 

 

4.3). Potential for serious

 

(CYP3A4 inhibition by

and/or life-threatening

 

FPV/RTV)

reactions such as cardiac

 

 

arrhythmias.

ANTIHISTAMINES

 

 

(HISTAMINE H1

 

 

RECEPTOR

 

 

ANTAGONISTS)

 

 

Astemizole

Astemizole: ↑ expected

Contraindicated (see section

Terfenadine

Terfenadine: ↑ expected

4.3). Potential for serious

 

(CYP3A4 inhibition by

and/or life-threatening

 

reactions such as cardiac

 

FPV/RTV)

arrhythmias.

NEUROLEPTIC

 

 

 

 

 

Pimozide

Pimozide: ↑ expected

Contraindicated (see section

 

 

4.3). Potential for serious

 

(CYP3A4 inhibition by

and/or life-threatening

 

FPV/RTV)

reactions such as cardiac

 

 

arrhythmias.

ANTIPSYCHOTICS

 

 

Quetiapine

Due to CYP3A inhibition by

Concomitant administration

 

Telzir, concentrations of

of Telzir and quetiapine is

 

quetiapine are expected to

contra-indicated as it may

 

increase.

increase quetiapine-related

 

 

toxicity. Increased plasma

 

 

concentrations of quetiapine

 

 

may lead to coma.

 

 

 

INFECTION

 

 

Antibacterials:

 

 

 

 

 

Clarithromycin

Clarithromycin: moderate ↑

Use with caution.

Study performed with

expected

 

(CYP3A4 inhibition)

 

amprenavir.

 

No FPV/RTV drug

 

 

interaction 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 (active

 

 

metabolite) could potentially

 

25-O-desacetylrifabutin: Cmax

lead to an increase of

 

6-fold*

rifabutin related adverse

 

25-O-desacetylrifabutin:

events, notably uveitis.

 

AUC(0-48)11-fold*

A 75 % reduction of the

 

*compared to rifabutin

 

300 mg once daily

standard rifabutin dose (i.e.

 

 

to 150 mg every other day) is

 

Amprenavir exposure

recommended. Further dose

 

unchanged when compared

reduction may be necessary

 

to historical data.

(see section 4.4).

 

(Mixed CYP3A4

 

 

induction/inhibition)

 

Rifampicin

Amprenavir: AUC ↓ 82%

Contraindicated (see section

600 mg once daily

 

4.3.)

(Amprenavir without

Significant ↓ APV expected

The decrease in amprenavir

ritonavir)

 

AUC can result in virological

 

 

failure and resistance

No FPV/RTV drug

(CYP3A4 induction by

development. During

interaction studies

rifampicin)

attempts to overcome the

 

 

decreased exposure by

 

 

increasing the dose of other

 

 

protease inhibitors with

 

 

ritonavir, a high frequency of

 

 

liver 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 or

days

fold.

itraconazole are not

 

Amprenavir: Cmax

recommended.

 

 

 

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 adjustment

suspension (equivalent to

Amprenavir: AUC ↓ 18%

necessary with antacids,

3.6 grams aluminium

Amprenavir: Cmin (C12h) ↔

proton-pump inhibitors or

hydroxide and 1.8 grams

 

histamine H2 receptor

magnesium hydroxide

 

antagonists.

(Telzir 1400 mg single dose)

 

 

Ranitidine

Amprenavir: Cmax ↓ 51%

 

300 mg single dose

Amprenavir: AUC ↓ 30%

 

(Telzir 1400 mg single dose)

Amprenavir: Cmin (C12h) ↔

 

 

 

Esomeprazole

Amprenavir Cmax

 

20 mg once daily

Amprenavir AUC ↔

 

 

Amprenavir Cmin (C12h) ↔

 

 

(Increase in gastric pH)

 

ANTICONVULSANTS

 

 

 

 

 

Phenytoin

Phenytoin: Cmax ↓ 20%

It is recommended that

300 mg once daily

Phenytoin: AUC ↓ 22%

phenytoin plasma

 

Phenytoin: Cmin ↓ 29%

concentrations be monitored

 

(Modest induction of

and phenytoin dose increased

 

as appropriate.

 

CYP3A4 by FPV/RTV)

 

 

Amprenavir: Cmax

 

Amprenavir: AUC ↑ 20%

Amprenavir: Cmin ↑ 19%

Phenobarbital

Amprenavir: ↓ expected

Use with caution (see

Carbamazepine

(Modest CYP3A4

section 4.4).

 

 

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 not

 

 

recommended. 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, including

 

 

hypotension, visual changes

 

 

and priapism (refer to PDE5

 

 

inhibitor prescribing

 

 

information). Patients should

 

 

be warned about these

 

 

possible side effects when

 

 

using PDE5 inhibitors with

 

 

Telzir/ritonavir (see section

 

 

4.4). 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).

INHALED/NASAL

 

 

STEROIDS

 

 

 

 

 

Fluticasone propionate

Fluticasone propionate: ↑

Concomitant use is not

50 µg intranasal 4 times daily)

Intrinsic cortisol levels: ↓

recommended unless the

for 7 days

potential benefit of treatment

 

86 %.

outweighs the risk of

(Ritonavir 100 mg capsules

 

systemic corticosteroid

twice daily for 7 days)

The effects of high

effects (see section 4.4). A

 

fluticasone systemic

dose reduction of the

 

exposure on ritonavir

glucocorticoid with close

 

plasma levels are unknown.

monitoring of local and

 

 

systemic effects or a switch

 

 

to a glucocorticoid, which is

 

Greater effects may be

not a substrate for CYP3A4

 

expected when fluticasone

(e.g. beclomethasone)

 

propionate is inhaled.

should be considered. In

 

(CYP3A4 inhibition by

case of withdrawal of

 

glucocorticoids, progressive

 

FPV/RTV)

dose reduction may have to

 

 

be performed over a longer

 

 

period (see section 4.4).

ALPHA 1-

 

 

ADRENORECEPTOR

 

 

ANTAGONIST

 

 

Alfuzosin,

Potential for increased

Co-administration of

 

alfuzosin concentrations

TELZIR/ritonavir with

 

which can result in

alfuzosin is contraindicated

 

hypotension. The

(see section 4.3).

 

mechanism of interaction is

 

 

CYP3A4 inhibition by

 

 

fosamprenavir/ritonavir.

 

 

 

 

HERBAL PRODUCTS

 

 

 

 

 

St. John’s wort (Hypericum

Amprenavir ↓ expected

Herbal preparations

perforatum)

 

containing St John’s wort

 

(CYP3A4 induction by St.

must not be combined with

 

John’s wort)

Telzir (see section 4.3). If a

 

 

patient is already taking St

 

 

John’s wort, check

 

 

amprenavir, ritonavir and

 

 

HIV RNA and stop St John’s

 

 

wort. Amprenavir and

 

 

ritonavir levels may increase

 

 

on stopping St John’s wort.

 

 

The inducing effect may

 

 

persist for at least 2 weeks

 

 

after cessation of treatment

 

 

with St John’s wort.

HMG-COA REDUCTASE

 

 

INHIBITORS

 

 

 

 

 

Lovastatin

Lovastatin: ↑ expected

Contraindicated (see section

Simvastatin

Simvastatin: ↑ expected

4.3).

 

Increased concentrations of

 

 

HMG-CoA reductase

No drug interaction studies.

(CYP3A4 inhibition by

inhibitors may cause

 

FPV/RTV)

myopathy, including

 

 

rhabdomyolysis.

 

 

Pravastatin or fluvastatin are

 

 

recommended because their

 

 

metabolism is not dependent

 

 

on CYP 3A4 and

 

 

interactions are not expected

 

 

with protease inhibitors.

Atorvastatin

Atorvastatin: Cmax ↑ 184%

Doses of atorvastatin no

10 mg once daily for 4 days

Atorvastatin: AUC ↑ 153%

greater than 20 mg/day

 

Atorvastatin: Cmin 73%

should be administered, with

 

Amprenavir: Cmax

careful monitoring for

 

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 is

 

(CYP3A4 inhibition by

recommended until levels

No drug interaction studies.

have stabilised (see section

 

FPV/RTV)

4.4).

 

 

 

BENZODIAZEPINES

 

 

 

 

 

Midazolam

Telzir/ritonavir should not

 

fold for parenteral

be co-administered with

No drug interaction studies.

midazolam)

orally administered

 

Based on data with other

midazolam (see section 4.3),

 

whereas

 

protease inhibitors plasma

caution should be used with

 

concentrations of

co-administration of

 

midazolam are expected to

Telzir/ritonavir and

 

be 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 be

 

 

done in an intensive care

 

 

unit (ICU) or similar setting

 

 

which ensures close clinical

 

 

monitoring and appropriate

 

 

medical management in case

 

 

of respiratory depression

 

 

and/or prolonged sedation.

 

 

Dosage adjustment for

 

 

midazolam should be

 

 

considered, especially if

 

 

more than a single dose of

 

 

midazolam is administered.

TRICYCLIC

 

 

ANTIDEPRESSANTS

 

 

 

 

 

Desipramine

Tricyclic antidepressant:

Careful monitoring of the

Nortriptyline

expected

therapeutic and adverse

 

(Mild CYP2D6 inhibition

reactions of tricyclic

No drug interaction studies.

antidepressants is

 

by RTV)

recommended (see section

 

 

4.4).

OPIOIDS

 

 

 

 

 

Methadone

(R-) methadone: Cmax

The decrease of (R-)

≤ 200 mg once daily

21%

methadone (active

 

(R-) methadone: AUC

enantiomer) is not expected

 

18%

to be clinically significant.

 

(CYP induction by

As a precaution, patients

 

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

 

(Induction and/or inhibition

Ratio is recommended (see

No drug interaction studies.

section 4.4).

 

of CYP2C9 by RTV)

 

 

 

 

ORAL CONTRACEPTIVES

 

 

 

 

 

Ethinyl estradiol 0.035

Ethinyl estradiol: Cmax

Alternative non-hormonal

mg/norethisterone 0.5 mg

28%

methods of contraception are

once daily

Ethinyl estradiol: AUC

recommended for women of

 

37%

childbearing potential (see

 

Norethisterone: Cmax 38%

section 4.4).

 

 

 

Norethisterone: AUC 34%

 

 

Norethisterone: Cmin 26

 

 

(CYP3A4 induction by

 

 

FPV/RTV)

 

 

Amprenavir: Cmax *

 

 

Amprenavir: AUC *

 

 

Amprenavir: Cmin *

 

 

* compared to historical

 

 

data

 

 

Ritonavir: Cmax 63%*

 

 

Ritonavir: AUC 45%*

 

 

* compared to historical

 

 

data

 

 

Clinically significant hepatic

 

 

transaminase elevations

 

 

occurred in some subjects.

 

 

 

 

SELECTIVE SEROTONIN

 

 

REUPTAKE INHIBITORS

 

 

(SSRIS)

 

 

 

 

 

Paroxetine

Paroxetine: Cmax 51%

Dose titration of paroxetine

 

Paroxetine: AUC 55%

based on a clinical

20 mg once daily

Amprenavir: Cmax *

assessment of antidepressant

 

response is recommended.

 

Amprenavir: AUC *

Patients on stable dose of

 

Amprenavir: Cmin *

paroxetine who start

 

* compared to historical

treatment with Telzir and

 

data

ritonavir should be

 

 

monitored for antidepressant

 

Mechanism unknown.

response.

4.6 Fertility, pregnancy and lactation

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.

Breast-feeding

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 recommended that HIV-infected women must not breast-feed under any circumstances to avoid transmission of HIV.

4.7 Effects on ability to drive and use machines

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).

4.8 Undesirable effects

It should be noted that the Telzir oral suspension has not been evaluated clinically in adults and that the adverse reaction profile detailed in this section is based on the experience in adults with the Telzir film coated tablets.

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.

Body System

Adverse reaction

Frequency

Nervous system disorders

Headache, dizziness, oral

Common

 

paraesthesia

 

 

 

 

Gastrointestinal disorders

Diarrhoea

Very common

 

Loose stools, nausea, vomiting,

Common

 

abdominal pain

 

Skin and subcutaneous tissue

Stevens Johnson syndrome

Rare

disorders

Angioedema

Uncommon

 

 

Rash (see text below

Common

 

“rash/cutaneous reactions”)

 

 

 

 

General disorders and

Fatigue

Common

administration site conditions

 

 

 

 

 

Investigations

Blood cholesterol increased

Very common

 

Blood triglycerides increased

Common

 

Alanine aminotransferase

Common

 

increased

 

 

Aspartate aminotransferase

Common

 

increased

 

 

Lipase increased

Common

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).

Metabolic parameters: weight and levels of blood lipids and glucose may increase during antiretroviral therapy (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. Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is 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 generally acknowledged risk factors, advanced HIV disease or long-term exposure to 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 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 with ritonavir with background nucleoside reverse transcriptase inhibitor therapy (see section 5.1 for information on dosing regimens applied for each age group). 79 % of subjects received greater than 48 weeks of exposure.

Overall the safety profile in these 158 children and adolescents was similar to that observed in the adult population. Vomiting occurred more frequently amongst paediatric patients. Drug-related adverse reactions were more common in APV20003 (57%) where subjects received once daily fosamprenavir / ritonavir when compared to APV29005 (33%) where subjects received twice daily fosamprenavir / 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 received only single doses of fosamprenavir with or without ritonavir.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9Overdose

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 Cmin/IC50 and Cmin/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 M in acutely infected cells and was 0.41 M in chronically infected cells (1 M = 0.50 g/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 adult 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 700 mg/ritonavir 100 mg 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

Among the 81 PI-naïve paediatric patients treated with fosamprenavir / ritonavir, 15 patients met protocol-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 virus isolated 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 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 adult 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, 77 PI-experienced patients were treated with fosamprenavir / ritonavir-based regimens and 43 patients met study-defined virologic failure criteria through 48 weeks in APV29005 and up to 108 weeks in APV20003. Treatment-emergent major protease or APV-associated mutations were observed in virus isolated from 1 patient in APV29005 and 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 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)

 

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/ l)

 

 

 

ITT-E observed

176 (n=323)

191 (n=336)

analysis

 

 

 

 

 

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)

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/ l)

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 with virological failure (less than or equal to two PIs) the fosamprenavir with ritonavir (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)

 

 

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

-1.42 (8)

-1.91 (4)

 

-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/ l)

 

 

 

 

 

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 Sensitivity

All Subjects

Susceptiple to

Resistant to

Score in OBT

 

FPV/RTV

FPV/RTV

 

 

< 4 mutations from

≥ 4 mutations from

 

 

score

score

 

 

 

 

-1.42 (8)

-1.83 (4)

-1.01 (4)

 

 

 

 

-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 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 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 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 (the majority 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

PI

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

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 dosage regimen than that of study APV29005 was used.

5.2 Pharmacokinetic properties

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 AUCvalues and the Telzir oral suspension formulation delivered a 14 % higher plasma amprenavir Cmax as compared to the oral tablet formulation. However, the bioequivalence could not be demonstrated when the oral suspension was given with food. Therefore for adult patients the Telzir oral suspension should be taken without food and on an empty stomach (see section 4.2).

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, 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 approximately 2-fold and plasma Cτ,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 (Cmax) of 6.08 (5.38-6.86) g/ml occurring approximately 1.5 (0.75-5.0)

hours after dosing (tmax). The mean steady state plasma amprenavir trough concentration (Cmin) was 2.12 (1.77-2.54) g/ml and AUC0-tau was 39.6 (34.5–45.3) h*g/ml.

Administration of the fosamprenavir oral suspension formulation with a high fat meal (967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) reduced plasma amprenavir AUC(0-∞) by 28% and Cmax by 46% and delayed Tmax by 0.72 hours. For adult patients the fosamprenavir oral suspension should be taken without food and on an empty stomach. In children and adolescents the fosamprenavir oral suspension should be taken with food. The dose recommendations for this population therefore take into account the observed food effect (see section 4.2).

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.

Biotransformation

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 Cmax, and 20 % lower Cmin 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 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 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-τ) was approximately 48 % lower, Cmax 26 % lower, and Cτ 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 Cmax (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 Cmax 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. Predicted exposures are based on extrapolation from data observed following administration of fosamprenavir 300 mg twice daily with ritonavir

100 mg once daily in subjects with moderate hepatic impairment.

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.

5.3 Preclinical safety data

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 development 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 100 mg 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 100 mg 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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Hypromellose

Sucralose

Propylene glycol

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Polysorbate 80

Calcium chloride dihydrate

Artificial grape bubblegum flavour

Natural peppermint flavour

Purified water

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

2 years.

Discard 28 days after first opening.

6.4 Special precautions for storage

Do not freeze.

6.5 Nature and contents of container

HDPE bottle with a child resistant polypropylene closure containing 225 millilitres oral suspension. The pack also includes a polyethylene syringe-adapter and a 10 ml oral dosing syringe comprised of a polypropylene barrel (with ml graduations) and a polyethylene plunger.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

ViiV Healthcare UK Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

8. MARKETING AUTHORISATION NUMBER

EU/1/04/282/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 12 July 2004

Date of renewal of authorisation: 15 May 2009.

10. DATE OF REVISION OF THE TEXT

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

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