Telzir 50mg/ml Oral Suspension

  • Name:

    Telzir 50mg/ml Oral Suspension

  • Company:
    info
  • Active Ingredients:

    Fosamprenavir calcium

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 15/07/19

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Summary of Product Characteristics last updated on medicines.ie: 15/7/2019

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ViiV Healthcare UK Ltd

ViiV Healthcare UK Ltd

Company Products

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Medicine Name Epivir Film-Coated Tablets 150mg Active Ingredients Lamivudine
Medicine Name Epivir Film-Coated Tablets 300mg Active Ingredients Lamivudine
Medicine Name Epivir Oral Solution 10mg/ml Active Ingredients Lamivudine
Medicine Name Juluca 50 mg/25 mg film-coated tablets Active Ingredients Dolutegravir sodium, Rilpivirine Hydrochloride
Medicine Name Kivexa film-coated tablets Active Ingredients Abacavir Sulfate, Lamivudine
Medicine Name Retrovir Capsules 100mg Active Ingredients Zidovudine
Medicine Name Retrovir IV Active Ingredients Zidovudine
Medicine Name Retrovir Oral Solution Active Ingredients Zidovudine
Medicine Name Telzir 50mg/ml Oral Suspension Active Ingredients Fosamprenavir calcium
Medicine Name Telzir 700mg Film-Coated Tablets Active Ingredients Fosamprenavir calcium
Medicine Name Tivicay film-coated tablets Active Ingredients Dolutegravir sodium
Medicine Name Triumeq 50 mg/600 mg/300 mg film-coated tablets Active Ingredients Abacavir Sulfate, Dolutegravir sodium, Lamivudine
Medicine Name Trizivir Film-Coated Tablets Active Ingredients Abacavir Sulfate, Lamivudine, Zidovudine
Medicine Name Ziagen Film-Coated Tablets 300mg Active Ingredients Abacavir Sulfate
Medicine Name Ziagen Oral Solution 20mg/ml Active Ingredients Abacavir Sulfate
1 - 0 of 18 items.Total: Infinity pages

When a pharmaceutical company changes any document, 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.

Updated on 15 July 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 6 - date of revision

Updated on 15 July 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 29 January 2019 PIL

Reasons for updating

  • Change to section 6 - manufacturer
  • Change to section 6 - date of revision

Updated on 23 October 2018 PIL

Reasons for updating

  • Change to section 4 - how to report a side effect
  • Change to section 6 - marketing authorisation holder

Updated on 22 October 2018 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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).

Updated on 19 October 2018 SmPC

Reasons for updating

  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 1 June 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 9 May 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 9 May 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 31 January 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 31 January 2018 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.6 - Pregnancy and lactation
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.3 Contraindications - Abbreviations for actives "fosamprenavir/ritonavir"
Section 4.6 Fertility, Pregnancy and Lactation and 5.2 Pharmacokinetic Properties and 5.3 Preclinical safety data: All updated with new pregnancy information
Section 4.8 SPCs: Update to UK reporting details.

Updated on 30 January 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 30 January 2018 PIL

Reasons for updating

  • Change to section 6 - date of revision
  • Change to other sources of information section

Updated on 6 May 2016 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

SmPC Section 4.3, 4.4, 4.5 updated with drug interaction details. Section 5.1 - formatting updates.

Updated on 5 May 2016 PIL

Reasons for updating

  • Change to drug interactions
  • Change to date of revision

Updated on 5 January 2016 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Sections 4.4 and 4.8 updated in line with PRAC recommendations on lipodystrophy

Updated on 4 January 2016 PIL

Reasons for updating

  • Change to side-effects
  • Change to date of revision

Updated on 2 November 2015 PIL

Reasons for updating

  • Change to date of revision
  • Addition of manufacturer
  • Addition of information on reporting a side effect.

Updated on 8 May 2015 SmPC

Reasons for updating

  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Update Section 4.6 of SmPC  to include WHO Breast-feeding guidance. 

Updated on 6 May 2015 PIL

Reasons for updating

  • Change to information about pregnancy or lactation
  • Change to date of revision
  • Addition of information on reporting a side effect.

Updated on 6 November 2014 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

Description of change to SPC:

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

Updated on 5 November 2014 PIL

Reasons for updating

  • Change to drug interactions
  • Change to date of revision
  • Addition of information on reporting a side effect.
  • Correction of spelling/typing errors

Updated on 15 May 2014 SmPC

Reasons for updating

  • Change to paediatric information
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
  • Change to improve clarity and readability

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.4 - to include warnings regarding HIV transmission risk. 
Section 4.8 & 5.1 - additional information on safety, antiviral response and treatment resistence in HIV-1 infected paediatric subjects based on results of studies.

Updated on 12 May 2014 PIL

Reasons for updating

  • Correction of spelling/typing errors

Updated on 9 May 2014 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to date of revision
  • Addition of information on reporting a side effect.

Updated on 25 October 2013 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Changes to:

Section 4.3 - Contraindications
Section 4.5 - Interaction with other medicinal products and other forms of interaction,

Updated on 24 October 2013 PIL

Reasons for updating

  • Change of contraindications
  • Change to drug interactions
  • Change to MA holder contact details

Updated on 9 April 2013 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.6 - Special precautions for disposal and other handling

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

·         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

Maraviroc

 

300 mg twice daily

Maraviroc: AUC12 á 2.49

Maraviroc: Cmaxá 1.52

Maraviroc: C12 á 4.74

 

Amprenavir: AUC12 â 0.65

Amprenavir: Cmax â 0.66

Amprenavir: C12 â 0.64

 

Ritonavir AUC12 â 0.66

Ritonavir Cmax â 0.61

Ritonavir C12 « 0.86

 

Concomitant use is not recommended.  Significant reductions in amprenavir Cmin observed may result in virological failure in patients

 

·         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

Updated on 4 April 2013 PIL

Reasons for updating

  • Change to side-effects
  • Change to drug interactions

Updated on 21 February 2013 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration

Legal category: Product subject to medical prescription which may not be renewed (A)

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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 weight

Telzir dose

(TWICE DAILY)

 

Ritonavir dose

(TWICE DAILY)

Adult

(>18 years)

 

Tablet or Oral suspension

 

700 mg (1 tablet or 14 ml suspension)

 

Oral suspension should be taken without food

Capsule or Solution

 

100 mg

6-17 years

>39 kg

Tablet or Oral suspension

 

700 mg (1 tablet or 14 ml suspension)

 

Oral suspension should be taken with food

Capsule or Solution

 

100 mg

 

 

 

 

 

 

 

33-38 kg

Oral suspension

 

18 mg/kg (0.36 ml/kg );

maximum 700 mg or 14 ml

 

Oral suspension should be taken with food

Capsule or Solution

 

100 mg

25-32 kg

Oral suspension

 

18 mg/kg (0.36 ml/kg )

 

Oral suspension should be taken with food

Solution

 

3 mg/kg

 

<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, 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.

Updated on 16 September 2011 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to name of manufacturer

Updated on 4 July 2011 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 6.5 - Nature and contents of container

Legal category: Product subject to medical prescription which may not be renewed (A)

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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.

Updated on 10 December 2010 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may not be renewed (A)

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4.8 Undesirable effects

Updated in line with SPC guidelines; no changes have been made to the actual undesirable effects

Updated on 23 August 2010 PIL

Reasons for updating

  • Change to marketing authorisation holder

Updated on 16 August 2010 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder

Legal category: Product subject to medical prescription which may not be renewed (A)

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Change to Section 7

Updated on 9 April 2010 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Changes to the following sections:

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

Updated on 21 July 2009 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 10 - Date of revision of the text
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use

Legal category: Product subject to medical prescription which may not be renewed (A)

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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

Updated on 12 May 2009 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.2 - Pharmacokinetic properties

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company



 

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.

Updated on 28 January 2009 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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.

Updated on 27 August 2008 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to date of revision

Updated on 26 August 2008 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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 4.5 Interaction with other medicinal products and other forms of interaction

Change to Kaletra (lopinavir + ritonavir) interaction wording

Change to 10 Date of revision of text

Change to July 2008

Updated on 12 February 2008 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Changes to Section 4.8: Addition of angiodema (uncommon) and Steven Johnson Syndrome (rare).

Updated on 19 October 2007 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to dosage and administration

Updated on 28 September 2007 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications

Legal category: Product subject to medical prescription which may not be renewed (A)

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change to therapeutic indications

Updated on 28 August 2007 SmPC

Reasons for updating

  • Improved electronic presentation

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 4 April 2007 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may not be renewed (A)

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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

 

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.

 

Updated on 4 April 2007 PIL

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  • Change to warnings or special precautions for use

Updated on 20 February 2007 SmPC

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  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.3 - Preclinical safety data

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Section 4.4

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.

Section 4.8

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

 

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.

Updated on 29 January 2007 SmPC

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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.

Updated on 27 July 2006 SmPC

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  • Improved electronic presentation

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Updated on 30 May 2005 PIL

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  • New PIL for medicines.ie

Updated on 11 August 2004 SmPC

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  • New SPC for new product

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