When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Added the following as contraindicated for concomitant use with Telzir:
Alfuzosin, sildenafil, simvastatin or lovastatin
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.
· 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
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.
4.8 Undesirable effects
Updated in line with SPC guidelines; no changes have been made to the actual undesirable effects
Section 4.4 - Special warnings and precautions for use, Section 4.5 - Interaction with other medicinal products and other forms of interaction, S ection 4.8 - Undesirable effects
Telzir 50 mg/ml oral suspension (EU/1/04/282/002) Changes in Red Section 2 Included the following excipients: Methyl parahydroxybenzoate (E218) 1.5 mg/ml Propyl parahydroxybenzoate (E216) 0.2 mg/ml Section 4.2 ‘Telzir (fosamprenavir)’ changed to ‘Fosamprenavir’ Statement Regarding use in ‘Elderly (over 65 years of age)’ updated to clarify that ‘no recommendations can be made in this patient population’. Section 4.3 Statement ‘Hypersensitivity to fosamprenavir, amprenavir or to any of the excipients of Telzir, or to ritonavir.’ updated to read: ‘Hypersensitivity to fosamprenavir, amprenavir, or ritonavir, or to any of the excipients’ Section 4.4 Description ‘adverse event’ changed to ‘adverse reaction’. Correction to spelling from ‘etiology’ to ‘aetiology’ Section 4.5 Description ‘adverse event’ changed to ‘adverse reaction’. Section 4.8 Statement added: ‘The most frequently (> 5% of adult subjects treated) reported adverse reactions 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.’ Description ‘adverse event’ changed to ‘adverse reaction’. List of adverse reactions under ‘Skin and subcutaneous tissue disorders’ rearranged, no change to content. Added adverse reactions ‘Alanine aminotransferase increased, Aspartate aminotransferase increased, Lipase increased, Blood triglycerides increased, Blood cholesterol increased’ under the heading ‘Investigations’. Section 4.9 Changed ‘overdosage’ to ‘overdose’ Section 10 Changed to 15/05/2009
Section 2
Included the following excipients: Methyl parahydroxybenzoate (E218) 1.5 mg/ml
Propyl parahydroxybenzoate (E216) 0.2 mg/ml
Section 4.2
‘Telzir (fosamprenavir)’ changed to ‘Fosamprenavir’
Statement Regarding use in ‘Elderly (over 65 years of age)’ updated to clarify that ‘no recommendations can be made in this patient population’. Section 4.3 Statement ‘Hypersensitivity to fosamprenavir, amprenavir or to any of the excipients of Telzir, or to ritonavir.’ updated to read: ‘Hypersensitivity to fosamprenavir, amprenavir, or ritonavir, or to any of the excipients’ Section 4.4 Description ‘adverse event’ changed to ‘adverse reaction’. Correction to spelling from ‘etiology’ to ‘aetiology’ Section 4.5 Description ‘adverse event’ changed to ‘adverse reaction’. Section 4.8 Statement added: ‘The most frequently (> 5% of adult subjects treated) reported adverse reactions 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.’ Description ‘adverse event’ changed to ‘adverse reaction’. List of adverse reactions under ‘Skin and subcutaneous tissue disorders’ rearranged, no change to content. Added adverse reactions ‘Alanine aminotransferase increased, Aspartate aminotransferase increased, Lipase increased, Blood triglycerides increased, Blood cholesterol increased’ under the heading ‘Investigations’. Section 4.9 Changed ‘overdosage’ to ‘overdose’ Section 10 Changed to 15/05/2009
Section 4.3
Statement ‘Hypersensitivity to fosamprenavir, amprenavir or to any of the excipients of Telzir, or to ritonavir.’ updated to read:
‘Hypersensitivity to fosamprenavir, amprenavir, or ritonavir, or to any of the excipients’
Section 4.4
Description ‘adverse event’ changed to ‘adverse reaction’.
Correction to spelling from ‘etiology’ to ‘aetiology’
Section 4.5
Section 4.8
Statement added:
‘The most frequently (> 5% of adult subjects treated) reported adverse reactions 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.’
List of adverse reactions under ‘Skin and subcutaneous tissue disorders’ rearranged, no change to content.
Added adverse reactions ‘Alanine aminotransferase increased, Aspartate aminotransferase increased, Lipase increased, Blood triglycerides increased, Blood cholesterol increased’ under the heading ‘Investigations’.
Section 4.9
Changed ‘overdosage’ to ‘overdose’
Section 10
Changed to 15/05/2009
4.8 Addition of the side effect oral paraesthesia.
4.2, 4.3, 4.4 and 5.2 Updates to the dosage recommendations for patients with severe hepatic impairment.
Section 4.2: Doasage instructions have been removed from the body text and tabulated with additional details added to instructions for use in 6-17yrs, 25-32 kg, 33-38 kg and = 39 kg.
Sections 4.3: Reworded statement regarding coadministration of rifampicin with Telzir and low dose ritonavir, i.e. contraindicated.
Section 4.5: Statement regarding interaction with rifampicin updated to highlight the resulting decrease in amprenavir AUC can result in virological failure and resistance development. Attempts to overcome decreased exposure by increasing the dose of other protease inhibitors with ritonavir resulted in a high frequency of liver reactions.
Change to 5.1 Pharmacodynamic properties
Alignment of resistance wording to indications
Change to 4.5 Interaction with other medicinal products and other forms of interaction
Addition of paroxetine interaction
Change to 5.3 Preclinical safety data
Repeat dose in rats - thyroid neoplasms
Change to Kaletra (lopinavir + ritonavir) interaction wording
Change to 10 Date of revision of text
Change to July 2008
Changes to Section 4.8: Addition of angiodema (uncommon) and Steven Johnson Syndrome (rare).
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 Ct,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 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 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
No resistance data is available for boosted amprenavir in PI naives.
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
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.
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.
Osteonecrosis:
Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Osteonecrosis
Section 5.3
In long-term carcinogenicity studies with fosamprenavir in mice and rats, there were increases in hepatocellular adenomas and hepatocellular carcinomas in mice at exposure levels equivalent to 0.1 to 0.3-fold those in humans given 700 mg of fosamprenavir plus 100mg ritonavir twice daily, and increases in hepatocellular adenomas and thyroid follicular cell adenomas in rats at exposure levels equivalent to 0.3 to 0.6-fold those in humans given 700 mg of fosamprenavir plus 100mg ritonavir twice daily. The relevance of the hepatocellular findings in the rodents for humans is uncertain; however, there is no evidence from clinical trials or marketed use to suggest that these findings are of clinical significance. 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.
Section 5.1 : additional text added
In a subsequent randomised open-label study (ESS100732) 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%].
The median plasma HIV-1 RNA had decreased by 3.34 log10 copies/ml and 3.33 log10 copies/ml at Week 48 in the fosamprenavir with ritonavir and lopinavir / ritonavir arms respectively.
Median increase in CD4 cell count was 176 cells/mm3 in the fosamprenavir with ritonavir arm and 191 cells/mm3 in the lopinavir / ritonavir arm respectively by Week 48.