SPC section 4.4, warnings and precautions – addition of the warning on the co-administration of fosamprenavir/ritonavir with other antineoplastics

SPC section 4.5, Interaction with other medicinal products – addition and removal of some medicinal products with interactions

Section 4.4:
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) 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.

Section 4.8:
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment. (see section 4.4).

Description of change to SPC:

Update to section 4.5 (Dolutegravir D/I) and S9 to include latest renewal date.

·         There are a number of editorial changes in sections 2, 4.3, 4.6, 5.2, 6.6 and 10 of the SPC

·         The following text was added to section 4.4 of the SPC with regards to autoimmune disorders

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.

·         The following text was added to section 4.5 of the SPC with regards to interaction with ./Maraviroc

·         The following text was added to section 4.8 of the SPC with regards to autoimmune disorders

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

4.2     Posology and method of administration

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

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

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

Added the following as contraindicated for concomitant use with Telzir:

Alfuzosin, sildenafil, simvastatin or lovastatin

4.4        Special warnings and precautions for use

Added warning that the use of Telzir concomitantly with PDE5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) is not recommended (see section 4.5).

Added the following statement regarding the coadministration of Telzir with low dose ritonavir and PDE5 inhibitors:

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).

Removed the warning regarding concomitant use of Telzir with simvastatin or lovastatin; these have been moved to section 4.3 contraindications.

4.5        Interaction with other medicinal products and other forms of interaction

·                 Added interaction data and recommendations for Raltegravir

·                 Removed the category description ‘Erectile dysfunction medicinal products’ from the category PDE5 Inhibitors

·                 Added interaction data and recommendations for Tadalafil

·                 Added interaction data and recommendations for the Alpha 1-Adrenoreceptor Antagonist alfuzosin

·                 Changed the warning regarding interaction with simvastatin or lovastatin to a contraindication

Applicable to Telzir 50 mg/ml oral suspension (EU/1/04/282/002) only:

6.5        Nature and contents of container

Updated the description of the dosing syringe to read:

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.

Telzir 50 mg/ml oral suspension (EU/1/04/282/002) Changes in Red

Pharmacotherapeutic group: Antivirals for systemic use, protease inhibitor, ATC Code: J05A E07

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 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.

Co‑administration of ritonavir with fosamprenavir increase plasma amprenavir AUC by approximately 2‑fold and plasma C_t,ss by 4‑ to 6‑fold, compared to values obtained when fosamprenavir is administered alone. Administration of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily results in plasma amprenavir concentrations (data from study APV30003 in antiretroviral experienced patients) which results in protein adjusted median ratios of C_min/IC₅₀ and C_min/IC₉₅ of 21.7 (range 1.19-240) and 3.21 (range 0.26-30.0), respectively.

Antiviral activity in vitro

The in vitro antiviral activity of amprenavir was evaluated against HIV-1 IIIB in both acutely and chronically infected lymphoblastic cell lines (MT-4, CEM-CCRF, H9) and in peripheral blood lymphocytes. The 50% inhibitory concentration (IC₅₀) of amprenavir ranged from 0.012 to 0.08 mM in acutely infected cells and was 0.41 mM in chronically infected cells (1 mM = 0.50 mg/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 vitro

HIV-1 isolates with a decreased susceptibility to amprenavir have been selected during in vitro serial passage experiments. Reduced susceptibility to amprenavir was associated with virus that had developed I50V or I84V or V32I+I47V or I54M mutations.

In vivo

a) PI-naïve patients, unboosted amprenavir/fosamprenavir

Amprenavir

During studies of PI-naïve patients treated with unboosted amprenavir in the phase II studies  PRO2001 (n=10), PRO2002 (n=84) receiving amprenavir ranging from 1800 to 2400 mg per day and the Phase III pivotal studies PRO3001 (n=112) and PRO3006 (n=245) receiving amprenavir 1200 mg twice daily in adults or in study PRO2004 in children (n=26) receiving 15 mg/kg three times daily or 20 mg/kg twice daily, the following PI-mutations emerged: L10V/F/R, I13V, G16E, K20R/T, I32V, L33F/V, M36I, M46I/L, I47V/L, I50V, I54L/M, Q58E, D60E, I62V, L63P, I64M, H69K, A71V/T, G73S, L76V, V77I, V82I, I84V, I85V, N88S and I93L.

Fosamprenavir

During studies of PI-naïve subjects treated with unboosted fosamprenavir in APV30001 with 166 patients on fosamprenavir 1400 mg twice daily, the following PI-mutations emerged in patients failing fosamprenavir therapy: L10I/F/V, K20R, V32I, L33F, E35G, M46I/L, I47V, I50V, I54L/M, I62V, L63P, A71T and V77I.

b) PI-naïve patients, boosted amprenavir/fosamprenavir

Amprenavir

No resistance data is available for boosted amprenavir in PI naives.

Fosamprenavir

During studies of PI-naïve patients treated with boosted fosamprenavir in studies APV30002, APV30005 (APV30002 extension after Week 48) and ESS100732 with 332, 213 and 434 patients respectively on fosamprenavir 700 mg / ritonavir 100 mg twice daily or fosamprenavir 1400 mg / ritonavir 200 mg once daily the following PI-mutations emerged: after 96 to 204 weeks therapy in study APV30005 in failing patients: L10F, V32I, L33F, M36I, M46I, I47V, I50V, I54M, A71V and I84V; in study ESS100732, the mutations K20R, I54L and I93L had emerged by Week 48; in study APV30002, PI resistance-associated mutations did not emerge by Week 48.

c) PI-experienced patients, boosted amprenavir/fosamprenavir

Amprenavir

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

Fosamprenavir

In the studies of PI-experienced patients, APV30003 and its extension, APV30005 (fosamprenavir 700 mg / ritonavir 100 mg twice daily: n=107; fosamprenavir 1400 mg / ritonavir 200 mg once daily: n=105), the following mutations emerged in patients with virological failure: L10F/I, V11I, I13V, G16E, L24I, V32I, L33F, M36I, M46I/L, I47V, I50V, I54L/M/S, Q58E, I62V, I64V, A71I/T/V, G73C/S, L76V, V82A, I84V, I85V, L90M and I93L/M.

Analyses based on 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.

Cross‑Resistance

HIV-1 isolates with a decreased susceptibility to amprenavir have been selected during in vitro serial passage experiments. Reduced susceptibility to amprenavir was associated with virus that had developed I50V or I84V or V32I+I47Vor I54M mutations. Each of these four genetic patterns associated with reduced susceptibility to amprenavir produces some cross-resistance to ritonavir but susceptibility to indinavir, nelfinavir and saquinavir is generally retained. There are currently insufficient data on cross-resistance between amprenavir and other protease inhibitors. Based on data from thirteen antiretroviral naïve patients failing a fosamprenavir containing regimen and on limited in vitro data (site directed mutagenesis) the resistance pathways associated with amprenavir produce limited cross-resistance to lopinavir (clinical data available from thirteen isolates) while susceptibility to atazanavir (from four isolates) and tipranavir (from two isolates) is generally retained. Conversely amprenavir retains activity against some isolates with resistance to other PIs and this retained activity would depend on the number and type of protease resistance mutations present in the isolates.

The number of key PI-resistance mutations increases markedly the longer a failing PI-containing regimen is continued. Early discontinuation of failing therapies is recommended in order to limit the accumulation of multiple mutations, which may be detrimental to a subsequent rescue regimen.

Cross-resistance between amprenavir and reverse transcriptase inhibitors is unlikely to occur because the enzyme targets are different.

Telzir is not recommended for use as monotherapy, due to the rapid emergence of resistant virus.