ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Telzir 700 mg film-coated tablets
2.
Each film-coated tablet contains 700 mg of fosamprenavir as fosamprenavir calcium (equivalent to
approximately 600 mg of amprenavir).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Pink film coated, capsule shaped, biconvex tablets, marked with GXLL7 on one side.
Telzir in combination with low dose ritonavir is indicated for the treatment of Human
Immunodeficiency Virus Type 1 (HIV-1) infected adults, adolescents and children of 6 years 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).
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).
2
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. 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 sever
e
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.
Even with these dose adjustments for adults, 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.
No dose recommendation can be made for children and adolescents with hepatic impairment
as no studies have been conducted in these age groups.
3
Hypersensitivity to fosamprenavir, amprenavir, or ritonavir, or to any of the excipients.
Telzir must not be administered concurrently with medicinal products with narrow therapeutic
windows that are substrates of cytochrome P450 3A4 (CYP3A4), e.g. amiodarone, astemizole,
bepridil, cisapride, dihydroergotamine, ergotamine, pimozide, quinidine, terfenadine, oral midazolam
(for caution on parenterally administered midazolam, see section 4.5), oral triazolam.
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).
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. Current antiretroviral therapies, including Telzir, have not been proven to prevent the risk of
transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions
should continue to be taken.
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).
4
The use of Telzir concomitantly with PDE5 inhibitors (e.g. sildenafil and vardenafil) is not
recommended (see section 4.5).
Concomitant use of Telzir with simvastatin or lovastatin is not recommended due to an increased risk
of myopathy, including rhabdomyolysis (see section 4.5).
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).
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.
5
Hyperglycaemia
New onset of diabetes mellitus, hyperglycaemia or exacerbations of existing diabetes mellitus have
been reported in patients receiving antiretroviral therapy, including protease inhibitors. In some of
these, the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many of
the patients had confounding medical conditions, some of which required therapy with medicinal
products that have been associated with the development of diabetes mellitus or hyperglycaemia.
Blood glucose testing should be performed prior to initiating therapy with Telzir and at periodic
intervals during therapy.
Lipodystrophy
Combination antiretroviral therapy has been associated with the redistribution of body fat
(lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown.
Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and
protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been
hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older
age, and with drug related factors such as longer duration of antiretroviral treatment and associated
metabolic disturbances. Clinical examination should include evaluation for physical signs of fat
redistribution.
Lipid elevations
Treatment with fosamprenavir has resulted in increases in the concentration of triglycerides and
cholesterol. Triglyceride and cholesterol testing should be performed prior to initiating therapy with
Telzir and at periodic intervals during therapy (see section 4.8).
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.
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 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.
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
.
6
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-
administration
Geometric mean change
(%)
(Possible mechanism)
ANTIRETROVIRAL
MEDICINAL PRODUCTS
Non-nucleoside reverse
transcriptase inhibitors:
Efavirenz
600 mg once daily
No clinically significant
interaction is observed.
No dosage adjustment
necessary.
Nevirapine
200 mg twice daily
No clinically significant
interaction is observed.
No dosage adjustment
necessary.
Etravirine
Amprenavir AUC ↑ 69%
Amprenavir C
min
↑ 77%
Amprenavir C
max
↑ 62%
Telzir may require dose
reduction (using oral
suspension)
(Study conducted in 8
patients)
Etravirine AUC ↔
a
Etravirine C
min
↔
a
Etravirine C
max
↔
a
a
Comparison based on
historic control.
Nucleoside / Nucleotide
reverse transcriptase
inhibitors:
Abacavir
Lamivudine
Zidovudine
No clinically significant
interaction is expected.
No dosage adjustment
necessary.
Study performed with
amprenavir.
No FPV/RTV drug
interaction studies.
7
Didanosine chewable tablet
No clinically significant
interaction is expected.
No dose separation or dosage
adjustment necessary (see
Antacids).
No drug interaction studies.
Didanosine gastro-resistant
capsule
No clinically significant
interaction is expected.
No dosage adjustment
necessary.
No drug interaction studies.
Tenofovir
300mg once daily
No clinically significant
interaction observed.
No dosage adjustment
necessary.
Protease Inhibitors:
According to current treatment guidelines, dual therapy with protease inhibitors is generally
not recommended.
Lopinavir / ritonavir
400 mg/100 mg
twice daily
Lopinavir: C
max
Ç
30%
Lopinavir: AUC
Ç
37%
Lopinavir: C
min
Ç
52%
Concomitant use is not
recommended.
Amprenavir: C
max
È
58%
Amprenavir: AUC
È
63%
Amprenavir: C
min
È
65%
Lopinavir: C
max
↔*
Lopinavir: AUC ↔*
Lopinavir: C
min
↔*
* compared to lopinavir /
ritonavir 400 mg/100 mg
twice daily
Lopinavir / ritonavir
533 mg/133 mg twice daily
Amprenavir: C
max
È
13%*
Amprenavir: AUC
È
26%*
Amprenavir: C
min
È
42 %*
* compared to fosamprenavir
/ ritonavir 700 mg/100 mg
twice daily
(Telzir 1400 mg twice daily)
(Mixed CYP3A4
induction/inhibition, Pgp
induction)
Indinavir
Saquinavir
Nelfinavir
No dose recommendations
can be given.
No drug
interaction studies.
8
Atazanavir
Atazanavir: Cmax
È
24%*
Atazanavir: AUC
È
22%*
Atazanavir: C
min
↔*
*compared to atazanavir/
ritonavir 300 mg/ 100 mg
once daily
No dosage adjustment
necessary.
300 mg once daily
Amprenavir: C
max
↔
Amprenavir: AUC ↔
Amprenavir: C
min
↔
ANTIARRHYTHMICS
Amiodarone
Bepridil
Quinidine
Flecainide
Propafenone
Amiodarone:
Ç
expected
Bepridil:
Ç
expected
Quinidine:
Ç
expected
Contraindicated (see section
4.3). Potential for serious
and/or life-threatening
reactions such as cardiac
arrhythmias.
(CYP3A4 inhibition by
FPV/RTV)
Flecainide:
Ç
expected
Propafenone:
Ç
expected
(CYP2D6 inhibition by
RTV)
ERGOT DERIVATIVES
Dihydroergotamine
Ergotamine
Ergonovine
Methylergonovine
Dihydroergotamine:
Ç
expected
Ergonovine:
Ç
expected
Ergotamine:
Ç
expected
Methylergonovine:
Ç
expected
Contraindicated (see section
4.3). Potential for serious
and/or life-threatening
reactions such as acute ergot
toxicity characterized by
peripheral vasospasm and
ischemia of the extremities
and other tissues.
(CYP3A4 inhibition by
FPV/RTV)
GASTROINTESTINAL
MOTILITY AGENTS
Cisapride
Cisapride:
Ç
expected
Contraindicated (see section
4.3). Potential for serious
and/or life-threatening
reactions such as cardiac
arrhythmias.
(CYP3A4 inhibition by
FPV/RTV)
ANTIHISTAMINES
(HISTAMINE H1
RECEPTOR
ANTAGONISTS)
Astemizole
Terfenadine
Astemizole:
Ç
expected
Terfenadine:
Ç
expected
Contraindicated (see section
4.3). Potential for serious
and/or life-threatening
reactions such as cardiac
arrhythmias.
(CYP3A4 inhibition by
FPV/RTV)
9
NEUROLEPTIC
Pimozide
Pimozide:
Ç
expected
Contraindicated (see section
4.3). Potential for serious
and/or life-threatening
reactions such as cardiac
arrhythmias.
(CYP3A4 inhibition by
FPV/RTV)
INFECTION
Antibacterials:
Clarithromycin
Clarithromycin: moderate
Ç
expected
Use with caution
Study performed with
amprenavir.
(CYP3A4 inhibition)
No FPV/RTV drug
interaction studies.
Erythromycin
Erythromycin:
Ç
expected
Use with caution.
No drug interaction studies.
(CYP3A4 inhibition by
FPV/RTV)
Anti-mycobacterial:
Rifabutin
150 mg every other day
Rifabutin: C
max
È
14%*
Rifabutin: AUC(0-48) ↔*
The increase of 25-O-
desacetylrifabutin (active
metabolite) could potentially
lead to an increase of
rifabutin related adverse
events, notably uveitis.
25-O-desacetylrifabutin:
C
max
Ç
6-fold*
25-O-desacetylrifabutin:
AUC(0-48)
Ç
11-fold*
*compared to rifabutin
300 mg once daily
A 75 % reduction of the
standard rifabutin dose (i.e.
to 150 mg every other day) is
recommended. Further dose
reduction may be necessary
(see section 4.4).
Amprenavir exposure
unchanged when compared
to historical data.
(Mixed CYP3A4
induction/inhibition)
Rifampicin
600mg once daily
Amprenavir: AUC
È
82%
Contraindicated (see section
4.3.)
(Amprenavir without
ritonavir)
Significant
È
APV expected
The decrease in amprenavir
AUC can result in virological
failure and resistance
development. During
attempts to overcome the
decreased exposure by
increasing the dose of other
protease inhibitors with
ritonavir, a high frequency of
liver reactions was seen.
No FPV/RTV drug
interaction studies
(CYP3A4 induction by
rifampicin)
10
Anti-fungals:
Ketoconazole
200 mg once daily for four
days
Ketoconazole: C
max
Ç
25%
Ketoconazole: AUC
Ç
2.69-
fold.
High doses (> 200 mg/day)
of ketoconazole or
itraconazole are not
recommended.
Amprenavir: C
max
↔
Amprenavir: AUC ↔
Amprenavir: C
min
↔
Itraconazole
Itraconazole:
Ç
expected
No drug interaction studies.
(CYP3A4 inhibition by
FPV/RTV)
ANTACIDS, HISTAMINE
H
2
RECEPTOR
ANTAGONIST AND
PROTON-PUMP
INHIBITORS
Single 30 ml dose of antacid
suspension (equivalent to
3.6 grams aluminium
hydroxide and 1.8 grams
magnesium hydroxide
Amprenavir: C
max
È
35%
Amprenavir: AUC
È
18%
Amprenavir: C
min
(C
12h
) ↔
No dosage adjustment
necessary with antacids,
proton-pump inhibitors or
histamine H
2
receptor
antagonists.
(Telzir 1400 mg single dose)
Ranitidine
300 mg single dose
Amprenavir: C
max
È
51%
Amprenavir: AUC
È
30%
Amprenavir: C
min
(C
12h
) ↔
(Telzir 1400 mg single dose)
Esomeprazole
20 mg once daily
Amprenavir C
max
↔
Amprenavir AUC ↔
Amprenavir C
min
(C
12h
) ↔
(Increase in gastric pH)
ANTICONVULSANTS
Phenytoin
300 mg once daily
Phenytoin: C
max
È
20%
Phenytoin: AUC
È
22%
Phenytoin: C
min
È
29%
It is recommended that
phenytoin plasma
concentrations be monitored
and phenytoin dose increased
as appropriate.
(Modest induction of
CYP3A4 by FPV/RTV)
Amprenavir: C
max
↔
Amprenavir: AUC
Ç
20%
Amprenavir: Cmin
Ç
19%
11
Phenobarbital
Carbamazepine
Amprenavir:
È
expected
Use with caution (see
section 4.4).
(Modest CYP3A4
induction)
No drug interaction studies.
Lidocaine
(by systemic route)
Lidocaine:
Ç
expected
Concomitant use is not
recommended. It may cause
serious adverse reactions
(see section 4.4).
(CYP3A4 inhibition by
FPV/RTV)
No drug interaction studies.
Halofantrine
Halofantrine:
Ç
expected
Concomitant use is not
recommended. It may cause
serious adverse reactions
(see section 4.4).
No drug interaction studies.
(CYP3A4 inhibition by
FPV/RTV)
ERECTILE
DYSFUNCTION
MEDICINAL PRODUCTS
(
PDE5 INHIBITORS)
Sildenafil
Vardenafil
PDE5 inhibitors:
Ç
expected
Concomitant use is not
recommended. It may result
in an increase in PDE5
inhibitor associated adverse
reactions, including
hypotension, visual changes
and priapism (see section
4.4).
No drug interaction studies.
(CYP3A4 inhibition by
FPV/RTV)
INHALED/NASAL
STEROIDS
Fluticasone propionate
50 µg intranasal 4 times daily)
for 7 days
Fluticasone propionate:
Ç
Concomitant use is not
recommended unless the
potential benefit of treatment
outweighs the risk of
systemic corticosteroid
effects (see section 4.4). A
dose reduction of the
glucocorticoid with close
monitoring of local and
systemic effects or a switch
to a glucocorticoid, which is
not a substrate for CYP3A4
(e.g. beclomethasone)
should be considered. In
case of withdrawal of
glucocorticoids, progressive
dose reduction may have to
be performed over a longer
period (see section 4.4).
Intrinsic cortisol levels:
È
86 %.
(Ritonavir 100 mg capsules
twice daily for 7 days)
The effects of high
fluticasone systemic
exposure on ritonavir
plasma levels are unknown.
Greater effects may be
expected when fluticasone
propionate is inhaled.
(CYP3A4 inhibition by
FPV/RTV)
12
HERBAL PRODUCTS
St. John’s wort
(Hypericum
perforatum)
Amprenavir
È
expected
Herbal preparations
containing St John’s wort
must not be combined with
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.
(CYP3A4 induction by St.
John’s wort)
HMG-COA REDUCTASE
INHIBITORS
Lovastatin
Simvastatin
Lovastatin:
Ç
expected
Concomitant use is not
recommended.
Increased concentrations of
HMG-CoA reductase
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 (see
section 4.4).
Simvastatin:
Ç
expected
No drug interaction studies.
(CYP3A4 inhibition by
FPV/RTV)
Atorvastatin
10 mg once daily for 4 days
Atorvastatin: C
max
Ç
184%
Atorvastatin: AUC
Ç
153%
Atorvastatin: C
min
Ç
73%
Doses of atorvastatin no
greater than 20 mg/day
should be administered, with
careful monitoring for
atorvastatin toxicity.
Amprenavir: C
max
↔
Amprenavir: AUC ↔
Amprenavir: Cmin ↔
(CYP3A4 inhibition by
FPV/RTV)
IMMUNOSUPPRESSANTS
Cyclosporin
Rapamycin
Tacrolimus
Cyclosporin:
Ç
expected
Rapamycin:
Ç
expected
Tacrolimus:
Ç
expected
Frequent therapeutic
concentration monitoring of
immunosuppressant levels is
recommended until levels
have stabilised (see section
4.4).
No drug interaction studies.
(CYP3A4 inhibition by
FPV/RTV)
13
BENZODIAZEPINES
Midazolam
Midazolam:
Ç
expected (3-
4 fold for parenteral
midazolam)
Telzir/ritonavir should not
be co-administered with
orally administered
midazolam (see section 4.3),
whereas
caution should be used with
co-administration of
Telzir/ritonavir and
parenteral midazolam.
No drug interaction studies.
Based on data with other
protease inhibitors plasma
concentrations of
midazolam are expected to
be significantly higher when
midazolam is given orally.
If Telzir/ritonavir is co-
administered with parenteral
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.
(CYP3A4 inhibition by
FPV/RTV)
TRICYCLIC
ANTIDEPRESSANTS
Desipramine
Nortriptyline
Tricyclic antidepressant:
Ç
expected
Careful monitoring of the
therapeutic and adverse
reactions of tricyclic
antidepressants is
recommended (see section
4.4).
No drug interaction studies.
(Mild CYP2D6 inhibition
by RTV)
OPIOIDS
Methadone
≤ 200 mg once daily
(R-) methadone: C
max
È
21%
(R-) methadone: AUC
È
18%
The decrease of (R-)
methadone (active
enantiomer) is not expected
to be clinically significant.
As a precaution, patients
should be monitored for
withdrawal syndrome.
(CYP induction by
FPV/RTV)
14
ORAL ANTICOAGULANTS
Warfarin
Other oral anticoagulants
Possible
È
or
Ç
of
antithrombotic effect.
Reinforced monitoring of the
International Normalised
Ratio is recommended (see
section 4.4).
No drug interaction studies.
(Induction and/or inhibition
of CYP2C9 by RTV)
ORAL CONTRACEPTIVES
Ethinyl estradiol 0.035
mg/norethisterone 0.5 mg
once daily
Ethinyl estradiol: C
max
È
28%
Ethinyl estradiol: AUC
È
37%
Alternative non-hormonal
methods of contraception are
recommended for women of
childbearing potential (see
section 4.4).
Norethisterone: C
max
È
38%
Norethisterone: AUC
È
34%
Norethisterone: C
min
È
26
(CYP3A4 induction by
FPV/RTV)
Amprenavir: C
max
↔*
Amprenavir: AUC ↔*
Amprenavir: C
min
↔*
* compared to historical
data
Ritonavir: C
max
Ç
63%*
Ritonavir: AUC
Ç
45%*
* compared to historical
data
Clinically significant hepatic
transaminase elevations
occurred in some subjects.
SELECTIVE SEROTONIN
REUPTAKE INHIBITORS
(SSRIS)
Paroxetine
Paroxetine: Cmax
È
51%
Paroxetine: AUC
È
55%
Dose titration of paroxetine
based on a clinical
assessment of antidepressant
response is recommended.
Patients on stable dose of
paroxetine who start
treatment with Telzir and
ritonavir should be
monitored for antidepressant
response.
20 mg once daily
Amprenavir: C
max
↔*
Amprenavir: AUC ↔*
Amprenavir: C
min
↔*
* compared to historical
data
Mechanism unknown.
15
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.
Lactation
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 therefore recommended that mothers treated with Telzir do not breast-feed their infants. As a
general rule, it is recommended that HIV-infected women must not breast-feed under any
circumstances to avoid transmission of HIV.
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).
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.
16
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
paraesthesia
Common
Gastrointestinal disorders
Diarrhoea
Very common
Loose stools, nausea, vomiting,
abdominal pain
Common
Skin and subcutaneous tissue
disorders
Stevens Johnson syndrome
Rare
Angioedema
Uncommon
Rash (see text below
“rash/cutaneous reactions”)
Common
General disorders and
administration site conditions
Fatigue
Common
Investigations
Blood cholesterol increased
Very common
Blood triglycerides increased
Common
Alanine aminotransferase
increased
Common
Aspartate aminotransferase
increased
Common
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
).
17
Lipodystrophy
:
combination antiretroviral therapy has been associated with redistribution of body fat
(lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased
intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo
hump) (see section 4.4).
Metabolic abnormalities
:
combination antiretroviral therapy has been associated with metabolic
abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance,
hyperglycaemia and hyperlactataemia (see section 4.4).
Hyperglycaemia
:
new onset of diabetes mellitus, hyperglycaemia or exacerbations of existing diabetes
mellitus have been reported in patients receiving antiretroviral protease inhibitors (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 (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 combination antiretroviral
therapy (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 and APV20003) in which 126 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). 70 % of subjects received greater than 48 weeks of exposure.
Overall the safety profile in these 126 children and adolescents was similar to that observed in the
adult population. Drug-related adverse reactions were more common in APV20003 (55%) where
subjects received once daily fosamprenavir / ritonavir when compared to APV29005 (39%) where
subjects received twice daily fosamprenavir / ritonavir.
Haemophiliac patients:
there have been reports of increased spontaneous bleeding in haemophiliac
patients receiving antiretroviral protease inhibitors (see section 4.4).
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. PHARMACOLOGICALPROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antivirals for systemic use, protease inhibitor, ATC Code: J05AE07
Mechanism of action
18
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 C
min
/IC
50
and C
min
/IC
95
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 (IC
50
) of amprenavir ranged from 0.012 to 0.08 μM in
acutely infected cells and was 0.41 μM in chronically infected cells (1 μM = 0.50 μg/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 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 700mg/ritonavir 100mg 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
Genotypic analysis of isolates from 13 of 14 paediatric patients exhibiting virological failure among
the 59 PI-naïve patients enrolled, demonstrated resistance patterns similar to those observed in adults.
b) PI-experienced patients
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), the following mutations emerged in patients experiencing
19
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, 67 PI-experienced patients were treated with
fosamprenavir / ritonavir and of 22 virological failure isolates genotyped, nine patients were found
with treatment-emergent protease mutations. 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.
20
Table 1 Efficacy Outcome at Week 48 in ESS100732 (ART-Naïve Patients)
FPV/RTV 700 mg/100 mg
BID (n= 434)
LPV/RTV 400 mg/100 mg BID
(n=444)
ITT-E Population
TLOV
R
analysis
Proportion with HIV-1 RNA < 400 copies/ml
All Subjects
72.5 %
71.4%
Baseline HIV-1 RNA <
100,000
copies/
ml
69.5 % (n=197)
69.4% (n=209)
Baseline HIV-1 RNA ≥
100,000
copies/
ml
75.1% (n=237)
73.2% (n=235)
Proportion with HIV-1 RNA < 50 copies/ml
All Subjects
66%
65%
Baseline HIV-1 RNA <
100,000
copies/
ml
67% (n=197)
64% (n=209)
Baseline HIV-1 RNA ≥
100,000
copies/
ml
65% (n=237)
66% (n=235)
Median Change from baseline in CD4 cells (cells/μl)
ITT-E observed analysis
176 (n=323)
191 (n=336)
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.
21
Table 2 Efficacy Outcome at Weeks 96 and 144 in ESS100732 Extension (ART-Naïve Patients)
FPV/RTV 700 mg/100 mg
BID (n= 105)
LPV/RTV 400 mg/100 mg BID
(n=91)
ITT (Ext) Population
TLOVR analysis
Proportion with HIV-1 RNA < 400 copies/ml
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)
Observed analysis
Median Change from baseline in CD4 cells (cells/μl)
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 (log
10
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:
22
Table 3 Efficacy at Week 48 Outcomes in APV30003 ITT(E) Population (ART-experienced
Patients)
FPV/RTV BID
(N=107)
LPV/RTV BID
(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 OBT
1
0
-1.42 (8)
-1.91 (4)
1
-1.30 (35)
-1.59 (23)
≥ 2
-1.68 (62)
-1.80 (76)
All Patients, RD=F Analysis
2
n (%)
n(%)
Subjects (%) with plasma HIV-1 RNA <50
copies/ml
49 (46%)
52 (50%)
Subjects (%) with plasma HIV-1 RNA
<400 copies/ml
62 (58%)
63 (61%)
Subjects with >1 log
10
change from
baseline in plasma HIV-1
RNA
62 (58%)
71 (69%)
23
Change from baseline in CD4 cells
(cells/μl)
Median (n)
Median (n)
All Patients 81 (79) 91 (85)
Key:
1
GSS to OBT: Genotypic Sensitivity Score to Optimised Background. GSS was derived using
ANRS 2007 guidelines.
2
RD=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
Scor
e in
OBT
All Subjects
Susceptiple to FPV/RTV
< 4 mutations from score
Resistant to FPV/RTV
≥ 4 mutations from score
0
-1.42 (8)
-1.83 (4)
-1.01 (4)
1
-1.30 (35)
-1.42 (29)
-0.69 (6)
≥ 2
-1.68 (62)
-1.76 (56)
-0.89 (6)
All patients
-1.53 (105)
-1.65 (89)
-0.85 (16)
As shown in the above table, there were only 16 patients harbouring baseline virus with resistance to
FPV/RTV according to the ANRS score. Data from this small number further analysed by 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 the ongoing 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 24 weeks of treatment are provided below.
APV29005 enrolled 25 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 29 patients aged 12 to 18 (the
majority of whom were treated with the adult tablet regimen). Overall, 27 (50 %) were PI-naïve, 9 of
whom were ART naïve, and 27 (50 %) were PI-experienced. Prior NRTI exposure was extensive, with
median durations of 421 and 389 weeks for the PI naïve and experienced patients respectively. The
median duration of prior PI exposure was 239 weeks. Overall, patients enrolled with a median 4.6
HIV-1 RNA log10 copies/ml (33 % of whom had > 100,000 copies/ml at baseline) and a median %
CD4+ cell of 18 % (37 % of whom had % CD4+ of < 15% at baseline).
24
Through 24 weeks of therapy, 70 % (19/27) of protease inhibitor naive and 56 % (15/27) of protease
inhibitor experienced patients achieved and maintained a plasma HIV 1 RNA <400 copies/ml (ITT(E),
TLOVR). In the ITT(E) population (Observed analysis) at Week 24 the median % CD4+ cell counts
increased by 8 % in the PI-naïve subjects and 4 % in the PI-experienced subjects.
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 AUC
∞
values and the Telzir oral suspension formulation delivered a 14 % higher plasma
amprenavir C
max
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, C
max
values were approximately 30 %
lower and C
min
values were approximately 28 % higher with fosamprenavir.
Co-administration of ritonavir with fosamprenavir increase plasma amprenavir AUC by approximately
2-fold and plasma C
τ,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 (C
max
) of 6.08 (5.38-6.86) μg/ml occurring approximately 1.5 (0.75-5.0)
hours after dosing (t
max
). The mean steady state plasma amprenavir trough concentration (C
min
) was
2.12 (1.77-2.54) μg/ml and AUC
0-tau
was 39.6 (34.5–45.3) h*μg/ml.
Administration of the fosamprenavir tablet formulation in the fed state (standardised high fat meal:
967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) did not alter plasma amprenavir
pharmacokinetics (C
max
, t
max
or AUC
0-∞
) 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
25
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.
Metabolism
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 C
max
, and 20 % lower C
min
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 C
max
and
C
min
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, C
max
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).
26
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 C
max
(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 C
max
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.
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.
27
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 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. 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.
6.1 List 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)
6.2 Incompatibilities
Not applicable.
28
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
HDPE bottles with a child resistant polypropylene closure containing 60 tablets.
6.6 Special precautions for disposal
Any unused product should be disposed of in accordance with local requirements.
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/04/282/001
Date of first authorisation: 12 July 2004
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA) http://www.ema.europa.eu
29
1.
Telzir 50 mg/ml oral suspension
2.
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 a full list of excipients, see section 6.1.
3.
Oral suspension.
The suspension is white to off-white in colour.
4.
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).
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.
30
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
Capsule or Solution
700 mg (1 tablet or 14 ml
suspension)
100 mg
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
suspension)
100 mg
Oral suspension should be
taken
with
food
31
33-38 kg
Oral suspension
Capsule or Solution
18 mg/kg (0.36 ml/kg );
maximum 700 mg or 14 ml
100 mg
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.
For adults with sever
e
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.
Even with these dose adjustments for adults, 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.
Hypersensitivity to fosamprenavir, amprenavir, or ritonavir, or to any of the excipients.
32
Telzir must not be administered concurrently with medicinal products with narrow therapeutic
windows that are substrates of cytochrome P450 3A4 (CYP3A4), e.g. amiodarone, astemizole,
bepridil, cisapride, dihydroergotamine, ergotamine, pimozide, quinidine, terfenadine, oral midazolam
(for caution on parenterally administered midazolam, see section 4.5), oral triazolam.
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).
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. Current antiretroviral therapies, including Telzir, have not been proven to prevent the
risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate
precautions should continue to be taken.
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.
The use of Telzir concomitantly with PDE5 inhibitors (e.g. sildenafil and vardenafil) is not
recommended (see section 4.5).
33
Concomitant use of Telzir with simvastatin or lovastatin is not recommended due to an increased risk
of myopathy, including rhabdomyolysis (see section 4.5).
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).
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.
Hyperglycaemia
New onset of diabetes mellitus, hyperglycaemia or exacerbations of existing diabetes mellitus have
been reported in patients receiving antiretroviral therapy, including protease inhibitors. In some of
these, the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many of
34
the patients had confounding medical conditions, some of which required therapy with medicinal
products that have been associated with the development of diabetes mellitus or hyperglycaemia.
Blood glucose testing should be performed prior to initiating therapy with Telzir and at periodic
intervals during therapy.
Lipodystrophy
Combination antiretroviral therapy has been associated with the redistribution of body fat
(lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown.
Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and
protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been
hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older
age, and with drug related factors such as longer duration of antiretroviral treatment and associated
metabolic disturbances. Clinical examination should include evaluation for physical signs of fat
redistribution.
Lipid elevations
Treatment with fosamprenavir has resulted in increases in the concentration of triglycerides and
cholesterol. Triglyceride and cholesterol testing should be performed prior to initiating therapy with
Telzir and at periodic intervals during therapy (see section 4.8).
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.
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 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.
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.
35
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-
administration
Geometric mean change
(%)
(Possible mechanism)
ANTIRETROVIRAL
MEDICINAL PRODUCTS
Non-nucleoside reverse
transcriptase inhibitors:
Efavirenz
600 mg once daily
No clinically significant
interaction is observed.
No dosage adjustment
necessary.
Nevirapine
200mg twice daily
No clinically significant
interaction is observed.
No dosage adjustment
necessary.
Etravirine
Amprenavir AUC ↑ 69%
Amprenavir C
min
↑ 77%
Amprenavir C
max
↑ 62%
Telzir may require dose
reduction (using oral
suspension)
(Study conducted in 8
patients)
Etravirine AUC ↔
a
Etravirine C
min
↔
a
Etravirine C
max
↔
a
a
Comparison based on
historic control.
Nucleoside / Nucleotide
reverse transcriptase
inhibitors:
Abacavir
Lamivudine
Zidovudine
No clinically significant
interaction is expected.
No dosage adjustment
necessary.
Study performed with
amprenavir.
No FPV/RTV drug
interaction studies.
Didanosine chewable tablet
No clinically significant
interaction is expected.
No dose separation or dosage
adjustment necessary (see
Antacids).
No drug interaction studies.
36
Didanosine gastro-resistant
capsule
No clinically significant
interaction is expected.
No dosage adjustment
necessary.
No drug interaction studies.
Tenofovir
300mg once daily
No clinically significant
interaction observed.
No dosage adjustment
necessary.
Protease Inhibitors:
According to current treatment guidelines, dual therapy with protease inhibitors is generally
not recommended.
Lopinavir / ritonavir
400 mg/100 mg
twice daily
Lopinavir: C
max
Ç
30%
Lopinavir: AUC
Ç
37%
Lopinavir: C
min
Ç
52%
Concomitant use is not
recommended.
Amprenavir: C
max
È
58%
Amprenavir: AUC
È
63%
Amprenavir: C
min
È
65%
Lopinavir: C
max
↔*
Lopinavir: AUC ↔*
Lopinavir: C
min
↔*
* compared to lopinavir /
ritonavir 400 mg/100 mg
twice daily
Lopinavir / ritonavir
533 mg/133 mg twice daily
Amprenavir: C
max
È
13%*
Amprenavir: AUC
È
26%*
Amprenavir: C
min
È
42 %*
* compared to fosamprenavir
/ ritonavir 700 mg/100 mg
twice daily
(Telzir 1400 mg twice daily)
(Mixed CYP3A4
induction/inhibition, Pgp
induction)
Indinavir
Saquinavir
Nelfinavir
No dose recommendations
can be given.
No drug
interaction studies.
37
Atazanavir
Atazanavir: Cmax
È
24%*
Atazanavir: AUC
È
22%*
Atazanavir: C
min
↔*
*compared to atazanavir/
ritonavir 300 mg/ 100 mg
once daily
No dosage adjustment
necessary.
300 mg once daily
Amprenavir: C
max
↔
Amprenavir: AUC ↔
Amprenavir: C
min
↔
ANTIARRHYTHMICS
Amiodarone
Bepridil
Quinidine
Flecainide
Propafenone
Amiodarone:
Ç
expected
Bepridil:
Ç
expected
Quinidine:
Ç
expected
Contraindicated (see section
4.3). Potential for serious
and/or life-threatening
reactions such as cardiac
arrhythmias.
(CYP3A4 inhibition by
FPV/RTV)
Flecainide:
Ç
expected
Propafenone:
Ç
expected
(CYP2D6 inhibition by
RTV)
ERGOT DERIVATIVES
Dihydroergotamine
Ergotamine
Ergonovine
Methylergonovine
Dihydroergotamine:
Ç
expected
Ergonovine:
Ç
expected
Ergotamine:
Ç
expected
Methylergonovine:
Ç
expected
Contraindicated (see section
4.3). Potential for serious
and/or life-threatening
reactions such as acute ergot
toxicity characterized by
peripheral vasospasm and
ischemia of the extremities
and other tissues.
(CYP3A4 inhibition by
FPV/RTV)
GASTROINTESTINAL
MOTILITY AGENTS
Cisapride
Cisapride:
Ç
expected
Contraindicated (see section
4.3). Potential for serious
and/or life-threatening
reactions such as cardiac
arrhythmias.
(CYP3A4 inhibition by
FPV/RTV)
ANTIHISTAMINES
(HISTAMINE H1
RECEPTOR
ANTAGONISTS)
Astemizole
Terfenadine
Astemizole:
Ç
expected
Terfenadine:
Ç
expected
Contraindicated (see section
4.3). Potential for serious
and/or life-threatening
reactions such as cardiac
arrhythmias.
(CYP3A4 inhibition by
FPV/RTV)
38
NEUROLEPTIC
Pimozide
Pimozide:
Ç
expected
Contraindicated (see section
4.3). Potential for serious
and/or life-threatening
reactions such as cardiac
arrhythmias.
(CYP3A4 inhibition by
FPV/RTV)
INFECTION
Antibacterials:
Clarithromycin
Clarithromycin: moderate
Ç
expected
Use with caution
Study performed with
amprenavir.
(CYP3A4 inhibition)
No FPV/RTV drug
interaction studies.
Erythromycin
Erythromycin:
Ç
expected
Use with caution.
No drug interaction studies.
(CYP3A4 inhibition by
FPV/RTV
Anti-mycobacterial:
Rifabutin
150 mg every other day
Rifabutin: C
max
È
14%*
Rifabutin: AUC(0-48) ↔*
The increase of 25-O-
desacetylrifabutin (active
metabolite) could potentially
lead to an increase of
rifabutin related adverse
events, notably uveitis.
25-O-desacetylrifabutin:
C
max
Ç
6-fold*
25-O-desacetylrifabutin:
AUC(0-48)
Ç
11-fold*
*compared to rifabutin
300 mg once daily
A 75 % reduction of the
standard rifabutin dose (i.e.
to 150 mg every other day) is
recommended. Further dose
reduction may be necessary
(see section 4.4).
Amprenavir exposure
unchanged when compared
to historical data.
(Mixed CYP3A4
induction/inhibition)
Rifampicin
600mg once daily
Amprenavir: AUC
È
82%
Contraindicated (see section
4.3.)
(Amprenavir without
ritonavir)
Significant
È
APV expected
The decrease in amprenavir
AUC can result in virological
failure and resistance
development. During
attempts to overcome the
decreased exposure by
increasing the dose of other
protease inhibitors with
ritonavir, a high frequency of
liver reactions was seen.
No FPV/RTV drug
interaction studies
(CYP3A4 induction by
rifampicin)
39
Anti-fungals:
Ketoconazole
200 mg once daily for four
days
Ketoconazole: C
max
Ç
25%
Ketoconazole: AUC
Ç
2.69-
fold.
High doses (> 200 mg/day)
of ketoconazole or
itraconazole are not
recommended.
Amprenavir: C
max
↔
Amprenavir: AUC ↔
Amprenavir: C
min
↔
Itraconazole
Itraconazole:
Ç
expected
No drug interaction studies.
(CYP3A4 inhibition by
FPV/RTV)
ANTACIDS, HISTAMINE
H
2
RECEPTOR
ANTAGONIST AND
PROTON-PUMP
INHIBITORS
Single 30 ml dose of antacid
suspension (equivalent to
3.6 grams aluminium
hydroxide and 1.8 grams
magnesium hydroxide
Amprenavir: C
max
È
35%
Amprenavir: AUC
È
18%
Amprenavir: C
min
(C
12h
) ↔
No dosage adjustment
necessary with antacids,
proton-pump inhibitors or
histamine H
2
receptor
antagonists.
(Telzir 1400 mg single dose)
Ranitidine
300 mg single dose
Amprenavir: C
max
È
51%
Amprenavir: AUC
È
30%
Amprenavir: C
min
(C
12h
) ↔
(Telzir 1400 mg single dose)
Esomeprazole
20 mg once daily
Amprenavir C
max
↔
Amprenavir AUC ↔
Amprenavir C
min
(C
12h
) ↔
(Increase in gastric pH)
ANTICONVULSANTS
Phenytoin
300 mg once daily
Phenytoin: C
max
È
20%
Phenytoin: AUC
È
22%
Phenytoin: C
min
È
29%
It is recommended that
phenytoin plasma
concentrations be monitored
and phenytoin dose increased
as appropriate.
(Modest induction of
CYP3A4 by FPV/RTV)
Amprenavir: C
max
↔
Amprenavir: AUC
Ç
20%
Amprenavir: Cmin
Ç
19%
40
Phenobarbital
Carbamazepine
Amprenavir:
È
expected
Use with caution (see
section 4.4).
(Modest CYP3A4
induction)
No drug interaction studies.
Lidocaine
(by systemic route)
Lidocaine:
Ç
expected
Concomitant use is not
recommended. It may cause
serious adverse reactions
(see section 4.4).
(CYP3A4 inhibition by
FPV/RTV)
No drug interaction studies.
Halofantrine
Halofantrine:
Ç
expected
Concomitant use is not
recommended. It may cause
serious adverse reactions
(see section 4.4).
No drug interaction studies.
(CYP3A4 inhibition by
FPV/RTV)
ERECTILE
DYSFUNCTION
MEDICINAL PRODUCTS
(
PDE5 INHIBITORS)
Sildenafil
Vardenafil
PDE5 inhibitors:
Ç
expected
Concomitant use is not
recommended. It may result
in an increase in PDE5
inhibitor associated adverse
reactions, including
hypotension, visual changes
and priapism (see section
4.4).
No drug interaction studies.
(CYP3A4 inhibition by
FPV/RTV)
INHALED/NASAL
STEROIDS
Fluticasone propionate
50 µg intranasal 4 times daily)
for 7 days
Fluticasone propionate:
Ç
Concomitant use is not
recommended unless the
potential benefit of treatment
outweighs the risk of
systemic corticosteroid
effects (see section 4.4). A
dose reduction of the
glucocorticoid with close
monitoring of local and
systemic effects or a switch
to a glucocorticoid, which is
not a substrate for CYP3A4
(e.g. beclomethasone)
should be considered. In
case of withdrawal of
glucocorticoids, progressive
dose reduction may have to
be performed over a longer
period (see section 4.4).
Intrinsic cortisol levels:
È
86 %.
(Ritonavir 100 mg capsules
twice daily for 7 days)
The effects of high
fluticasone systemic
exposure on ritonavir
plasma levels are unknown.
Greater effects may be
expected when fluticasone
propionate is inhaled.
(CYP3A4 inhibition by
FPV/RTV)
41
HERBAL PRODUCTS
St. John’s wort
(Hypericum
perforatum)
Amprenavir
È
expected
Herbal preparations
containing St John’s wort
must not be combined with
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.
(CYP3A4 induction by St.
John’s wort)
HMG-COA REDUCTASE
INHIBITORS
Lovastatin
Simvastatin
Lovastatin:
Ç
expected
Concomitant use is not
recommended.
Increased concentrations of
HMG-CoA reductase
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 (see
section 4.4).
Simvastatin:
Ç
expected
No drug interaction studies.
(CYP3A4 inhibition by
FPV/RTV)
Atorvastatin
10 mg once daily for 4 days
Atorvastatin: C
max
Ç
184%
Atorvastatin: AUC
Ç
153%
Atorvastatin: C
min
Ç
73%
Doses of atorvastatin no
greater than 20 mg/day
should be administered, with
careful monitoring for
atorvastatin toxicity.
Amprenavir: C
max
↔
Amprenavir: AUC ↔
Amprenavir: Cmin ↔
(CYP3A4 inhibition by
FPV/RTV)
IMMUNOSUPPRESSANTS
Cyclosporin
Rapamycin
Tacrolimus
Cyclosporin:
Ç
expected
Rapamycin:
Ç
expected
Tacrolimus:
Ç
expected
Frequent therapeutic
concentration monitoring of
immunosuppressant levels is
recommended until levels
have stabilised (see section
4.4).
No drug interaction studies.
(CYP3A4 inhibition by
FPV/RTV)
42
BENZODIAZEPINES
Midazolam
Midazolam:
Ç
expected (3-
4 fold for parenteral
midazolam)
Telzir/ritonavir should not
be co-administered with
orally administered
midazolam (see section 4.3),
whereas
caution should be used with
co-administration of
Telzir/ritonavir and
parenteral midazolam.
No drug interaction studies.
Based on data with other
protease inhibitors plasma
concentrations of
midazolam are expected to
be significantly higher when
midazolam is given orally.
If Telzir/ritonavir is co-
administered with parenteral
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.
(CYP3A4 inhibition by
FPV/RTV)
TRICYCLIC
ANTIDEPRESSANTS
Desipramine
Nortriptyline
Tricyclic antidepressant:
Ç
expected
Careful monitoring of the
therapeutic and adverse
reactions of tricyclic
antidepressants is
recommended (see section
4.4).
No drug interaction studies.
(Mild CYP2D6 inhibition
by RTV)
OPIOIDS
Methadone
≤ 200 mg once daily
(R-) methadone: C
max
È
21%
(R-) methadone: AUC
È
18%
The decrease of (R-)
methadone (active
enantiomer) is not expected
to be clinically significant.
As a precaution, patients
should be monitored for
withdrawal syndrome.
(CYP induction by
FPV/RTV)
ORAL ANTICOAGULANTS
Warfarin
Other oral anticoagulants
Possible
È
or
Ç
of
antithrombotic effect.
Reinforced monitoring of the
International Normalised
Ratio is recommended (see
section 4.4).
No drug interaction studies.
(Induction and/or inhibition
of CYP2C9 by RTV)
43
ORAL CONTRACEPTIVES
Ethinyl estradiol 0.035
mg/norethisterone 0.5 mg
once daily
Ethinyl estradiol: C
max
È
28%
Ethinyl estradiol: AUC
È
37%
Alternative non-hormonal
methods of contraception are
recommended for women of
childbearing potential (see
section 4.4).
Norethisterone: C
max
È
38%
Norethisterone: AUC
È
34%
Norethisterone: C
min
È
26
(CYP3A4 induction by
FPV/RTV)
Amprenavir: C
max
↔*
Amprenavir: AUC ↔*
Amprenavir: C
min
↔*
* compared to historical
data
Ritonavir: C
max
Ç
63%*
Ritonavir: AUC
Ç
45%*
* compared to historical
data
Clinically significant hepatic
transaminase elevations
occurred in some subjects.
SELECTIVE SEROTONIN
REUPTAKE INHIBITORS
(SSRIS)
Paroxetine
Paroxetine: Cmax
È
51%
Paroxetine: AUC
È
55%
Dose titration of paroxetine
based on a clinical
assessment of antidepressant
response is recommended.
Patients on stable dose of
paroxetine who start
treatment with Telzir and
ritonavir should be
monitored for antidepressant
response.
20 mg once daily
Amprenavir: C
max
↔*
Amprenavir: AUC ↔*
Amprenavir: C
min
↔*
* compared to historical
data
Mechanism unknown.
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
44
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.
Lactation
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 therefore recommended that mothers treated with Telzir do not breast-feed their infants. As a
general rule, it is recommended that HIV-infected women must not breast-feed under any
circumstances to avoid transmission of HIV.
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).
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.
45
Body System
Adverse reaction
Frequency
Nervous system disorders
Headache, dizziness, oral
paraesthesia
Common
Gastrointestinal disorders
Diarrhoea
Very common
Loose stools, nausea, vomiting,
abdominal pain
Common
Skin and subcutaneous tissue
disorders
Stevens Johnson syndrome
Rare
Angioedema
Uncommon
Rash (see text below
“rash/cutaneous reactions”)
Common
General disorders and
administration site conditions
Fatigue
Common
Investigations
Blood cholesterol increased
Very common
Blood triglycerides increased
Common
Alanine aminotransferase
increased
Common
Aspartate aminotransferase
increased
Common
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
).
46
Lipodystrophy:
combination antiretroviral therapy has been associated with redistribution of body fat
(lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased
intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo
hump) (see section 4.4).
Metabolic abnormalities:
combination antiretroviral therapy has been associated with metabolic
abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance,
hyperglycaemia and hyperlactataemia (see section 4.4).
Hyperglycaemia:
new onset of diabetes mellitus, hyperglycaemia or exacerbations of existing diabetes
mellitus have been reported in patients receiving antiretroviral protease inhibitors (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 (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 combination antiretroviral
therapy (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 and APV20003) in which 126 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). 70 % of subjects received greater than 48 weeks of exposure.
Overall the safety profile in these 126 children and adolescents was similar to that observed in the
adult population. Drug-related adverse reactions were more common in APV20003 (55%) where
subjects received once daily fosamprenavir / ritonavir when compared to APV29005 (39%) where
subjects received twice daily fosamprenavir / ritonavir.
Haemophiliac patients
: there have been reports of increased spontaneous bleeding in haemophiliac
patients receiving antiretroviral protease inhibitors (see section 4.4).
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.
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
47
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 C
min
/IC
50
and C
min
/IC
95
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 (IC
50
) of amprenavir ranged from 0.012 to 0.08 μM in
acutely infected cells and was 0.41 μM in chronically infected cells (1 μM = 0.50 μg/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 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 700mg/ritonavir 100mg 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
Genotypic analysis of isolates from 13 of 14 paediatric patients exhibiting virological failure among
the 59 PI-naïve patients enrolled, demonstrated resistance patterns similar to those observed in adults.
b) PI-experienced patients
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), 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.
48
In the paediatric studies APV20003 and APV29005, 67 PI-experienced patients were treated with
fosamprenavir / ritonavir and of 22 virological failure isolates genotyped, nine patients were found
with treatment-emergent protease mutations. 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.
49
Table 1 Efficacy Outcome at Week 48 in ESS100732 (ART-Naïve Patients)
FPV/RTV 700 mg/100 mg
BID (n= 434)
LPV/RTV 400 mg/100 mg BID
(n=444)
ITT-E Population
TLOV
R
analysis
Proportion with HIV-1 RNA < 400 copies/ml
All Subjects
72.5 %
71.4%
Baseline HIV-1 RNA <
100,000
copies/
ml
69.5 % (n=197)
69.4% (n=209)
Baseline HIV-1 RNA ≥
100,000
copies/
ml
75.1% (n=237)
73.2% (n=235)
Proportion with HIV-1 RNA < 50 copies/ml
All Subjects
66%
65%
Baseline HIV-1 RNA <
100,000
copies/
ml
67% (n=197)
64% (n=209)
Baseline HIV-1 RNA ≥
100,000
copies/
ml
65% (n=237)
66% (n=235)
Median Change from baseline in CD4 cells (cells/μl)
ITT-E observed analysis
176 (n=323)
191 (n=336)
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.
50
Table 2 Efficacy Outcome at Weeks 96 and 144 in ESS100732 Extension (ART-Naïve Patients)
FPV/RTV 700 mg/100 mg
BID (n= 105)
LPV/RTV 400 mg/100 mg BID
(n=91)
ITT (Ext) Population
TLOVR analysis
Proportion with HIV-1 RNA < 400 copies/ml
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)
Observed analysis
Median Change from baseline in CD4 cells (cells/μl)
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 (log
10
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:
51
Table 3 Efficacy at Week 48 Outcomes in APV30003 ITT(E) Population (ART-experienced
Patients)
FPV/RTV BID
(N=107)
LPV/RTV BID
(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 OBT
1
0
-1.42 (8)
-1.91 (4)
1
-1.30 (35)
-1.59 (23)
≥ 2
-1.68 (62)
-1.80 (76)
All Patients, RD=F Analysis
2
n (%)
n(%)
Subjects (%) with plasma HIV-1 RNA <50
copies/ml
49 (46%)
52 (50%)
Subjects (%) with plasma HIV-1 RNA
<400 copies/ml
62 (58%)
63 (61%)
Subjects with >1 log
10
change from
baseline in plasma HIV-1
RNA
62 (58%)
71 (69%)
52
Change from baseline in CD4 cells
(cells/μl)
Median (n)
Median (n)
All Patients 81 (79) 91 (85)
Key:
1
GSS to OBT: Genotypic Sensitivity Score to Optimised Background. GSS was derived using
ANRS 2007 guidelines.
2
RD=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
Scor
e in
OBT
All Subjects
Susceptiple to FPV/RTV
< 4 mutations from score
Resistant to FPV/RTV
≥ 4 mutations from score
0
-1.42 (8)
-1.83 (4)
-1.01 (4)
1
-1.30 (35)
-1.42 (29)
-0.69 (6)
≥ 2
-1.68 (62)
-1.76 (56)
-0.89 (6)
All patients
-1.53 (105)
-1.65 (89)
-0.85 (16)
As shown in the above table, there were only 16 patients harbouring baseline virus with resistance to
FPV/RTV according to the ANRS score. Data from this small number further analysed by 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 the ongoing 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 24 weeks of treatment are provided below.
APV29005 enrolled 25 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 29 patients aged 12 to 18 (the
majority of whom were treated with the adult tablet regimen). Overall, 27 (50 %) were PI-naïve, 9 of
whom were ART naïve, and 27 (50 %) were PI-experienced. Prior NRTI exposure was extensive, with
median durations of 421 and 389 weeks for the PI naïve and experienced patients respectively. The
median duration of prior PI exposure was 239 weeks. Overall, patients enrolled with a median 4.6
HIV-1 RNA log10 copies/ml (33 % of whom had > 100,000 copies/ml at baseline) and a median %
CD4+ cell of 18 % (39 % of whom had % CD4+ of < 15% at baseline).
53
Through 24 weeks of therapy, 70 % (19/27) of protease inhibitor naive and 56 % (15/27) of protease
inhibitor experienced patients achieved and maintained a plasma HIV 1 RNA <400 copies/ml (ITT(E),
TLOVR). In the ITT(E) population (Observed analysis) at Week 24 the median % CD4+ cell counts
increased by 8 % in the PI-naïve subjects and 4 % in the PI-experienced subjects.
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 AUC
∞
values and the Telzir oral suspension formulation delivered a 14 % higher plasma
amprenavir C
max
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, C
max
values were approximately 30 %
lower and C
min
values were approximately 28 % higher with fosamprenavir.
Co-administration of ritonavir with fosamprenavir increase plasma amprenavir AUC by approximately
2-fold and plasma C
τ,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 (C
max
) of 6.08 (5.38-6.86) μg/ml occurring approximately 1.5 (0.75-5.0)
hours after dosing (t
max
). The mean steady state plasma amprenavir trough concentration (C
min
) was
2.12 (1.77-2.54) μg/ml and AUC
0-tau
was 39.6 (34.5–45.3) h*μg/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 C
max
by 46% and delayed T
max
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.
54
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.
Metabolism
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 C
max
, and 20 % lower C
min
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 C
max
and
C
min
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, C
max
26 % lower, and Cτ 29 % lower in the paediatric subjects. No
55
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 C
max
(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 C
max
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.
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
56
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 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. 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.
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
57
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.
A 10 ml graduated polypropylene dosing syringe and polyethylene adapter are provided in the pack.
6.6 Special precautions for disposal
Any unused product should be disposed of in accordance with local requirements.
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/04/282/002
Date of first authorisation: 12 July 2004
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA) http://www.ema.europa.eu
58
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
59
A
MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Film-coated tablets
Glaxo Wellcome Operations, Priory Street, Ware, Hertfordshire SG12 0DJ, United Kingdom
Oral suspension
Glaxo Wellcome GmbH & Co KG, Industriestrasse 32-36, D-23843, Bad Oldesloe, Germany
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B
CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 7.2 presented in
Module 1.8.1 of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the pharmacovigilance activities detailed in the Pharmacovigilance
Plan as agreed in version 6 of the Risk Management Plan (RMP) presented in Module 1.8.2. of the
Marketing Authorisation Application and any subsequent updates of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMA
60
Periodic Safety Updates
The MAH will submit yearly PSURs until otherwise instructed by the CHMP.
61
ANNEX III
LABELLING AND PACKAGE LEAFLET
62
A. LABELLING
63
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON FOR TABLETS
1.
Telzir 700 mg film-coated tablets
Fosamprenavir
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 700 mg fosamprenavir as fosamprenavir calcium (equivalent to
approximately 600 mg of amprenavir)
3.
LIST OF EXCIPIENTS
4.
60 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
64
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/04/282/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
telzir 700 mg
65
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
BOTTLE LABEL FOR TABLETS
1.
FURTHER INFORMATION
What Telzir contains
•
The active substance is fosamprenavir.
Each ml of suspension contains 50 mg of fosamprenavir
as fosamprenavir calcium salt (equivalent to approximately 43 mg of amprenavir).
•
The other ingredients are: hypromellose, sucralose, polysorbate 80, calcium chloride dihydrate,
artificial grape bubblegum flavour, natural peppermint flavour, purified water, propylene glycol,
methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216).
What Telzir looks like and contents of the pack
Telzir is supplied in plastic bottles containing 225 ml oral suspension. A 10 ml graduated dosing
syringe and an adapter are also included in the pack. The suspension is white to off-white.
Telzir is also available as 700 mg film-coated tablets.
Marketing Authorisation Holder and Manufacturer
Manufacturer
Marketing Authorisation Holder
Glaxo Wellcome GmbH & Co.
KG.
Industriestrasse 32-36
D-23843 Bad Oldesloe
Germany
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
For any information about this medicinal product please contact the local representative of the
Marketing Authorisation Holder.
België/Belgique/Belgien
ViiV Healthcare sprl/bvba
Tél/Tel: + 32 (0)2 656 25 11
Luxembourg/Luxemburg
ViiV Healthcare sprl/bvba
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 25 11
България
ГлаксоСмитКлайн ЕООД
Teл.: + 359 2 953 10 34
Magyarország
GlaxoSmithKline Kft.
Tel.: + 36 1 225 5300
Česká republika
GlaxoSmithKline s.r.o.
Tel: + 420 222 001 111
gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00
info@glaxosmithkline.dk
Nederland
ViiV Healthcare BV
Tel: + 31 (0)30 6986060
c
ontact-nl@viivhealthcare.com
Deutschland
ViiV Healthcare GmbH
Tel.: + 49 (0)89 203 0038-10
viiv.med.info@viivhealthcare.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00
firmapost@gsk.no
89
Eesti
GlaxoSmithKline Eesti OÜ
Tel: + 372 6676 900
estonia@gsk.com
Österreich
GlaxoSmithKline Pharma GmbH
Tel: + 43 (0)1 97075 0
at.info@gsk.com
Ελλάδα
GlaxoSmithKline A.E.B.E.
Τηλ: + 30 210 68 82 100
Polska
GSK Commercial Sp. z o.o.
Tel.: + 48 (0)22 576 9000
España
Laboratorios ViiV Healthcare, S.L.
Tel: + 34 902 051 260
es-ci@viivhealthcare.com
Portugal
VIIVHIV HEALTHCARE, UNIPESSOAL,
LDA.
Tel: + 351 21 094 08 01
viiv.fi.pt@viivhealthcare.com
France
ViiV Healthcare SAS
Tél: + 33 (0)1 39 17 6969
Infomed@viivhealthcare.com
România
GlaxoSmithKline (GSK) S.R.L.
Tel: + 4021 3028 208
Ireland
GlaxoSmithKline (Ireland) Limited
Tel: + 353 (0)1 4955000
Slovenija
GlaxoSmithKline d.o.o.
Tel: + 386 (0)1 280 25 00
medical.x.si@gsk.com
Ísland
GlaxoSmithKline ehf.
Sim: + 354 530 3700
Slovenská republika
GlaxoSmithKline Slovakia s. r. o.
Tel: + 421 (0)2 49 10 33 11
recepcia.sk@gsk.com
Italia
ViiV Healthcare S.r.l.
Tel: + 39 (0)45 9212611
Suomi/Finland
GlaxoSmithKline Oy
Puh/Tel: + 358 (0)10 30 30 30
Finland.tuoteinfo@gsk.com
Κύπρος
GlaxoSmithKline (Cyprus) Ltd
Τηλ: + 357 22 89 95 01
Sverige
GlaxoSmithKline AB
Tel: + 46 (0)8 638 93 00
info.produkt@gsk.com
Latvija
GlaxoSmithKline Latvia SIA
Tel: + 371 67312687
lv-epasts@gsk.com
United Kingdom
ViiV Healthcare UK Ltd
Tel: + 44 (0)800 221441
customercontactuk@gsk.com
Lietuva
GlaxoSmithKline Lietuva UAB
Tel: + 370 5 264 90 00
info.lt@gsk.com
This leaflet was last approved on
Detailed information on this product is available on the website of the European Medicines Agency
(EMA)
http://www.ema.europa.eu
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Source: European Medicines Agency
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