Agenerase

1.

NAME OF THE MEDICINAL PRODUCT

Agenerase 50 mg soft capsules.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 50 mg of amprenavir.

Excipients:

d-sorbitol (E420)

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Soft capsule.

Oblong, opaque, off-white to cream coloured, printed with ‘GX CC1’.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Agenerase, in combination with other antiretroviral agents, is indicated for the treatment of protease

inhibitor (PI) experienced HIV-1 infected adults and children above the age of 4 years. Agenerase

capsules should normally be administered with low dose ritonavir as a pharmacokinetic enhancer of

amprenavir (see sections 4.2 and 4.5). The choice of amprenavir should be based on individual viral

resistance testing and treatment history of patients (see section 5.1).

The benefit of Agenerase boosted with ritonavir has not been demonstrated in PI naïve patients (see

section 5.1)

4.2 Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

The importance of complying with the full recommended dosing regimen should be stressed to all

patients.

Agenerase is administered orally and can be taken with or without food.

Agenerase is also available as an oral solution for use in children or adults unable to swallow capsules.

Amprenavir is 14 % less bioavailable from the oral solution than from the capsules; therefore,

Agenerase capsules and Agenerase oral solution are not interchangeable on a milligram per milligram

basis (see section 5.2).

Adults and adolescents of 12 years of age and older (greater than 50 kg body weight): the

recommended dose of Agenerase capsules is 600 mg twice daily with ritonavir, 100 mg twice daily, in

combination with other antiretroviral agents.

If Agenerase capsules are used without the boosting effect of ritonavir higher doses of Agenerase

(1200 mg twice daily) should be used.

2

Children (4 to 12 years) and patients less than 50 kg body weight: the recommended dose of

Agenerase capsules is 20 mg/kg body weight twice a day, in combination with other antiretroviral

agents, without exceeding a total daily dose of 2400 mg (see section 5.1).

The pharmacokinetics, efficacy and safety of Agenerase in combination with low doses of ritonavir or

other protease inhibitors have not yet been evaluated in children. Therefore, such combinations should

be avoided in children.

Children less than 4 years of age: Agenerase is not recommended in children below 4 years due to lack

of data on safety and efficacy (see section 5.2).

Elderly: the pharmacokinetics, efficacy and safety of amprenavir have not been studied in patients

over 65 years of age (see section 5.2).

Renal impairment: no dose adjustment is considered necessary in patients with renal impairment (see

section 5.2).

Hepatic impairment: the principal route of metabolism of amprenavir is via the liver. Agenerase

capsules should be used with caution in patients with hepatic impairment. Clinical efficacy and safety

have not been determined in this patient group. For subjects with hepatic impairment, pharmacokinetic

data are available for the use of Agenerase capsules without the boosting effect of ritonavir. Based on

pharmacokinetic data, the dose of Agenerase capsules should be reduced to 450 mg twice a day for

adult patients with moderate hepatic impairment and to 300 mg twice a day for adult patients with

severe hepatic impairment. No dose recommendation can be made in children with hepatic impairment

(see section 5.2).

The use of amprenavir in combination with ritonavir has not been studied in patients with hepatic

impairment. No dose recommendations can be made regarding this combination. Concomitant

administration should be used with caution in patients with mild and moderate hepatic impairment and

is contraindicated in patients with severe hepatic impairment (see section 4.3).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Agenerase must not be administered concurrently with medicinal products with narrow therapeutic

windows that are substrates of cytochrome P450 3A4 (CYP3A4). Co-administration may result in

competitive inhibition of the metabolism of these medicinal products and create the potential for

serious and/or life-threatening adverse events such as cardiac arrhythmia (e.g. amiodarone, bepridil,

quinidine, terfenadine, astemizole, cisapride, pimozide), respiratory depression and /or prolonged

sedation (e.g. oral triazolam and oral midazolam (for caution on parenterally administered midazolam,

see section 4.5)) or peripheral vasospasm or ischaemia and ischaemia of other tissues, including

cerebral or myocardial ischaemia (e.g. ergot derivatives).

Agenerase in combination with ritonavir is contraindicated in patients with severe hepatic impairment.

Combination of rifampicin with Agenerase with concomitant low-dose ritonavir is contraindicated.

(see section 4.5).

Agenerase 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).

Herbal preparations containing St John’s wort ( Hypericum perforatum ) must not be used while taking

amprenavir due to the risk of decreased plasma concentrations and reduced clinical effects of

amprenavir (see section 4.5).

3

4.4 Special warnings and precautions for use

Patients should be advised that Agenerase, 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 Agenerase, 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.

On the basis of current pharmacodynamic data, amprenavir should be used in combination with at

least two other antiretrovirals. When amprenavir is administered as monotherapy, resistant viruses

rapidly emerge (see section 5.1). Agenerase capsules should normally be given in combination with

low dose ritonavir and in combination with other antiretroviral agents (see section 4.2).

Liver Disease: The safety and efficacy of amprenavir has not been established in patients with

significant underlying liver disorders. Agenerase capsules are contraindicated in patients with severe

hepatic impairment when used in combination with ritonavir (see section 4.3). 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 events. In case of concomitant antiviral therapy for hepatitis B or

C, please refer also to the relevant product information 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

Concomitant use of Agenerase 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).

The HMG-CoA reductase inhibitors lovastatin and simvastatin are highly dependent on CYP3A4 for

metabolism, thus concomitant use of Agenerase with simvastatin or lovastatin is not recommended

due to an increased risk of myopathy, including rhabdomyolysis. Caution must also be exercised if

Agenerase is used concurrently with atorvastatin, which is metabolized to a lesser extent by CYP3A4.

In this situation, a reduced dose of atorvastatin should be considered. If treatment with a HMG-CoA

reductase inhibitor is indicated, pravastatin or fluvastatin are recommended (see section 4.5).

For some medicinal products that can cause serious or life-threatening undesirable effects, such as

carbamazepine, phenobarbital, phenytoin, tricyclic antidepressants and warfarin (monitor International

Normalised Ratio), concentration monitoring is available; this should minimise the risk of potential

safety problems with concomitant use.

The use of Agenerase concomitantly with halofantrine or lidocaine (systemic) is not recommended

(see section 4.5).

Anticonvulsants (carbamazepine, phenobarbital, phenytoin) should be used with caution. Agenerase

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 Agenerase (see section 4.5).

Caution is advised when Agenerase is used concomitantly with PDE5 inhibitors (e.g. sildenafil and

vardenafil) (see section 4.5).

4

Caution is advised when Agenerase is used concomitantly with delavirdine (see section 4.5).

A reduction of rifabutin dosage of at least 50 % is recommended when administered with Agenerase.

When ritonavir is co-administered further dose reduction may be necessary (see section 4.5).

Because of the potential for metabolic interactions with amprenavir, the efficacy of hormonal

contraceptives may be modified, but there is insufficient information to predict the nature of the

interactions. Therefore, alternative reliable methods of contraception are recommended for women of

childbearing potential (see section 4.5).

Co-administration of amprenavir with methadone leads to a decrease of methadone concentrations.

Therefore, when methadone is co-administered with amprenavir, patients should be monitored for

opiate abstinence syndrome, in particular if low-dose ritonavir is also given. No recommendations can

currently be made regarding adjustment of amprenavir dose when amprenavir is co-administered with

methadone.

Agenerase capsules contain vitamin E (36 IU/50 mg capsule), therefore additional vitamin E

supplementation is not recommended.

Agenerase capsules also contain sorbitol (E420). Patients with rare hereditary problems of fructose

intolerance should not take this medicine.

Due to the potential risk of toxicity from the high propylene glycol content of Agenerase oral solution,

this formulation is contraindicated in children below the age of four years and should be used with

caution in certain other patient populations. The Summary of Product Characteristics of Agenerase

oral solution should be consulted for full prescribing information.

Rash / cutaneous reactions

Most patients with mild or moderate rash can continue Agenerase. Appropriate antihistamines (e.g.

cetirizine dihydrochloride) may reduce pruritus and hasten the resolution of rash. Agenerase should be

permanently discontinued when rash is accompanied with systemic symptoms or allergic symptoms or

mucosal involvement (see section 4.8).

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 agents that

have been associated with the development of diabetes mellitus or hyperglycaemia.

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. Consideration should be given to the measurement of fasting serum lipids and blood

glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

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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. In some

patients, additional factor VIII was given. 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 made aware of the possibility of increased bleeding.

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 etiology is considered to be multifactorial (including corticosteroid use, alcohol

consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been

reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination

antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience

joint aches and pain, joint stiffness or difficulty in movement.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have been performed with amprenavir as the sole protease inhibitor. When

amprenavir and ritonavir are co-administered, the ritonavir metabolic drug interaction profile may

predominate because ritonavir is a more potent CYP3A4 inhibitor. Ritonavir also inhibits CYP2D6

and induces CYP3A4, CYP1A2, CYP2C9 and glucuronosyl transferase. The full prescribing

information for ritonavir must therefore be consulted prior to initiation of therapy with Agenerase and

ritonavir.

Amprenavir and ritonavir are primarily metabolised in the liver by CYP3A4. Therefore, medicinal

products that either share this metabolic pathway or modify CYP3A4 activity may modify the

pharmacokinetics of amprenavir. Similarly, amprenavir and ritonavir might also modify the

pharmacokinetics of other medicinal products that share this metabolic pathway.

Associations contraindicated (see section 4.3)

CYP3A4 substrates with narrow therapeutic index

Agenerase must not be administered concurrently with medicinal products with narrow therapeutic

windows containing active substances that are substrates of cytochrome P450 3A4 (CYP3A4).

Co-administration may result in competitive inhibition of the metabolism of these active substances

thus increasing their plasma level and leading to serious and / or life-threatening adverse reactions

such as cardiac arrhythmia (e.g. amiodarone, astemizole, bepridil, cisapride, pimozide, quinidine,

terfenadine) or peripheral vasospasm or ischaemia (e.g. ergotamine, dihydroergotamine).

CYP2D6 substrates with narrow therapeutic index

Agenerase with ritonavir must not be co-administered with medicinal products containing active

substances that are highly dependent on CYP2D6 metabolism and for which elevated plasma

concentrations are associated with serious and / or life-threatening adverse reactions. These active

substances include flecainide and propafenone.

Rifampicin

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Rifampicin is a strong CYP3A4 inducer and has been shown to cause an 82% decrease in amprenavir

AUC, which 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. The combination of rifampicin and Agenerase with concomitant

low-dose ritonavir is contraindicated (see section 4.3).

St John’s wort ( Hypericum perforatum )

Serum levels of amprenavir can be reduced by concomitant use of the herbal preparation St John’s

wort ( Hypericum perforatum ). This is due to induction of drug metabolising enzymes by St John’s

wort. Herbal preparations containing St John’s wort should therefore not be combined with Agenerase.

If a patient is already taking St John’s wort, check amprenavir and if possible viral levels and stop St

John’s wort. Amprenavir levels may increase on stopping St John’s wort. The dose of amprenavir may

need adjusting. The inducing effect may persist for at least 2 weeks after cessation of treatment with St

John’s wort.

• Other combinations

Of note, the following interaction data was obtained in adults.

Antiretroviral agents

•

Protease inhibitors (PIs):

Indinavir : the AUC, C min and C max of indinavir were decreased by 38 %, 27 %, and 22 %, respectively,

when given with amprenavir. The clinical relevance of these changes is unknown. The AUC, C min and

C max of amprenavir were increased by 33 %, 25 %, and 18 %, respectively. No dose adjustment is

necessary for either medicinal product when indinavir is administered in combination with

amprenavir.

Saquinavir : the AUC, C min and C max of saquinavir were decreased by 19 % and 48 % and increased by

21 %, respectively, when given with amprenavir. The clinical relevance of these changes is unknown.

The AUC, C min and C max of amprenavir were decreased by 32 %, 14 %, and 37 %, respectively. No

dose adjustment is necessary for either medicinal product when saquinavir is administered in

combination with amprenavir.

Nelfinavir : the AUC, C min and C max of nelfinavir were increased by 15 %, 14 %, and 12 %,

respectively, when given with amprenavir. The C max of amprenavir was decreased by 14 % whilst the

AUC and C min were increased by 9 % and 189 %, respectively. No dose adjustment is necessary for

either medicinal product when nelfinavir is administered in combination with amprenavir (see also

efavirenz below).

Ritonavir : the AUC and C min of amprenavir were increased by 64% and 508% respectively and the

C max decreased by 30% when ritonavir (100 mg twice daily) was co-administered with amprenavir

capsule (600 mg twice daily) compared to values achieved after 1200 mg twice daily doses of

amprenavir capsules. In clinical trials, doses of amprenavir 600 mg twice daily and ritonavir 100 mg

twice daily have been used; confirming the safety and efficacy of this regimen.

Lopinavir / ritonavir (Kaletra) : in an open-label, non-fasting pharmacokinetic study, the AUC, C max

and C min of lopinavir were decreased by 38%, 28% and 52% respectively when amprenavir (750 mg

twice daily) was given in combination with Kaletra (400 mg lopinavir + 100 mg ritonavir twice daily).

In the same study, the AUC, C max , and C min of amprenavir were increased 72%, 12%, and 483%,

respectively, when compared to values after standard doses of amprenavir (1200 mg twice daily).

The amprenavir plasma C min values achieved with the combination of amprenavir (600 mg twice daily)

in combination with Kaletra (400 mg lopinavir + 100 mg ritonavir twice daily) are approximately 40-

50% lower than when amprenavir (600 mg twice daily) is given in combination with ritonavir 100 mg

twice daily. Adding additional ritonavir to an amprenavir plus Kaletra regimen increase lopinavir C min

values, but not amprenavir C min values. No dose recommendation can be given for the co-

7

administration of amprenavir and Kaletra, but close monitoring is advised because the safety and

efficacy of this combination is unknown.

•

Nucleoside analogue reverse transcriptase inhibitors (NRTIs):

Zidovudine : the AUC and C max of zidovudine were increased by 31 % and 40 %, respectively, when

given with amprenavir. The AUC and the C max of amprenavir were unaltered. No dose adjustment for

either medicinal product is necessary when zidovudine is administered in combination with

amprenavir.

Lamivudine : the AUC and C max of lamivudine and amprenavir, respectively, were both unaltered

when these two medicinal products were given concomitantly. No dose adjustment is necessary for

either medicinal product when lamivudine is administered in combination with amprenavir.

Abacavir : the AUC, C min and C max of abacavir were unaltered when given with amprenavir. The AUC,

C min and C max of amprenavir were increased by 29 %, 27 %, and 47 %, respectively. No dose

adjustment is necessary for either medicinal product when abacavir is administered in combination

with amprenavir.

Didanosine : no pharmacokinetic study has been performed with Agenerase in combination with

didanosine, however, due to its antacid component, it is recommended that didanosine and Agenerase

should be administered at least one hour apart (see Antacids below).

•

Non-nucleoside reverse transcriptase inhibitors (NNRTIs):

Efavirenz : efavirenz has been seen to decrease the C max , AUC and C min,ss of amprenavir by

approximately 40 % in adults. When amprenavir is combined with ritonavir, the effect of efavirenz is

compensated by the pharmacokinetic booster effect of ritonavir. Therefore, if efavirenz is given in

combination with amprenavir (600 mg twice daily) and ritonavir (100 mg twice daily), no dose

adjustment is necessary.

Further, if efavirenz is given in combination with amprenavir and nelfinavir, no dosage adjustment is

necessary for any of the medicinal products.

Treatment with efavirenz in combination with amprenavir and saquinavir is not recommended, as the

exposure to both protease inhibitors would be decreased.

No dose recommendation can be given for the co-administration of amprenavir with another protease

inhibitor and efavirenz in children. Such combinations should be avoided in patients with hepatic

impairment.

Nevirapine : The effect of nevirapine on other protease inhibitors and the limited evidence available

suggest that nevirapine may decrease the serum concentrations of amprenavir.

Delavirdine : the AUC, C max and C min of delavirdine were decreased by 61%, 47% and 88%

respectively when given with amprenavir. The AUC, C max and C min of amprenavir were increased by

130%, 40% and 125% respectively.

No dose recommendations can be given for the co-administration of amprenavir and delavirdine. If

these medicinal products are used concomitantly care is advised, as delavirdine may be less effective

due to decreased and potentially sub-therapeutic plasma concentrations.

No dose recommendations can be given for the co-administration of amprenavir and low dose

ritonavir with delavirdine. If these medicinal products are used concomitantly care is advised, and

close clinical and virological monitoring should be performed since it is difficult to predict the effect

of the combination of amprenavir and ritonavir on delavirdine.

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Antibiotics/antifungals

Rifabutin : co-administration of amprenavir with rifabutin resulted in a 193 % increase in rifabutin

AUC and an increase of rifabutin-related adverse events. The increase in rifabutin plasma

concentration is likely to result from inhibition of rifabutin CYP3A4 mediated metabolism by

amprenavir. When it is clinically necessary to co-administer rifabutin with Agenerase, a dosage

reduction of at least half the recommended dose of rifabutin is advised, although no clinical data are

available. When ritonavir is co-administered a larger increase in rifabutin concentration may occur.

Clarithromycin : the AUC and C min of clarithromycin were unaltered and the C max decreased by 10 %

when given with amprenavir. The AUC, C min and C max of amprenavir were increased by 18 %, 39 %

and 15 %, respectively. No dose adjustment is necessary for either medicinal product when

clarithromycin is administered in combination with amprenavir. When ritonavir is co-administered an

increase in clarithromycin concentrations may occur.

Erythromycin : no pharmacokinetic study has been performed with Agenerase in combination with

erythromycin, however, plasma levels of both medicinal products may be increased when

co-administered.

Ketoconazole / Itraconazole : the AUC and C max of ketoconazole were increased by 44 % and 19 %,

respectively when given with amprenavir alone. The AUC and C max of amprenavir were increased by

31 % and decreased by 16 %, respectively. Itraconazole concentrations are expected to increase in the

same manner as ketoconazole. No dose adjustment for any of the medicinal products is necessary

when either ketoconazole or itraconazole is administered in combination with amprenavir. Co-

administration of fosamprenavir 700 mg with ritonavir 100 mg twice daily and ketoconazole 200 mg

once daily increased plasma ketoconazole C max by 25 % and increased AUC(0-τ) to values 2.69-fold

those observed on administration of ketoconazole 200 mg once daily without concurrent

fosamprenavir with ritonavir. The C max , AUC and C min of amprenavir were unchanged. When used

with Agenerase with ritonavir, high doses (>200 mg/day) of ketoconazole or itraconazole are not

recommended .

Other possible interactions

Other medicinal products, listed below, including examples of substrates, inhibitors or inducers of

CYP3A4, may lead to interactions when administered with Agenerase. The clinical significance of

these possible interactions is not known and has not been investigated. Patients should therefore be

monitored for toxic reactions associated with these medicinal products when these are administered in

combination with Agenerase.

Antacids : on the basis of the data for other protease inhibitors, it is advisable not to take antacids at the

same time as Agenerase, since its absorption may be impaired. It is recommended that antacids and

Agenerase should be administered at least one hour apart.

Anticonvulsant active substances : concomitant administration of anticonvulsant active substances

known as enzymatic inductors (phenytoin, phenobarbital, carbamazepine) with amprenavir may lead

to a decrease in the plasma concentrations of amprenavir. These combinations should be used with

caution and therapeutic concentration monitoring is recommended (see section 4.4).

Calcium-channel blockers : amprenavir may lead to increased serum concentrations of calcium

channel blockers such as amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine,

nimodipine, nisoldipine and verapamil, possibly resulting in enhanced activity and toxicity of these

medicinal products.

Erectile dysfunction agents : based on data for other protease inhibitors caution should be used when

prescribing PDE5 inhibitors (e.g. sildenafil and vardenafil) to patients receiving Agenerase. Co-

administration with Agenerase may substantially increase PDE5 inhibitor plasma concentrations and

associated adverse events, including hypotension, visual changes and priapism (see section 4.4).

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Fluticasone propionate (interaction with ritonavir) : in a clinical study where ritonavir 100 mg

capsules bid were co-administered with 50 µg intranasal fluticasone propionate (4 times daily) for 7

days in healthy subjects, the fluticasone propionate plasma levels increased significantly, whereas the

intrinsic cortisol levels decreased by approximately 86 % (90 % confidence interval 82-89 %). Greater

effects may be expected when fluticasone propionate is inhaled. Systemic corticosteroid effects

including Cushing’s syndrome and adrenal suppression have been reported in patients receiving

ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with

other corticosteroids metabolised via the P450 3A pathway e.g. budesonide. Consequently,

concomitant administration of Agenerase with ritonavir and these glucocorticoids 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 should be considered with close monitoring of

local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g.

beclomethasone). Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may

have to be performed over a longer period. The effects of high fluticasone systemic exposure on

ritonavir plasma levels is yet unknown.

HMG-CoA reductase inhibitors : HMG-CoA reductase inhibitors which are highly dependent on

CYP3A4 for metabolism, such as lovastatin and simvastatin, are expected to have markedly increased

plasma concentrations when co-administered with Agenerase. Since increased concentrations of

HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis, the combination of

these medicinal products with Agenerase is not recommended. Atorvastatin is less dependent on

CYP3A4 for metabolism. When used with Agenerase, the lowest possible dose of atorvastatin should

be administered. The metabolism of pravastatin and fluvastatin is not dependent on CYP3A4, and

interactions are not expected with protease inhibitors. If treatment with a HMG-CoA reductase

inhibitor is indicated, pravastatin or fluvastatin is recommended.

Immunosuppressants : frequent therapeutic concentration monitoring of immunosuppresant levels is

recommended until levels have stabilised as plasma concentrations of cyclosporin, rapamycin and

tacrolimus may be increased when co-administered with amprenavir (see section 4.4).

Midazolam : midazolam is extensively metabolized by CYP3A4. Coadministration with Agenerase

with or without ritonavir may cause a large increase in the concentration of this benzodiazepine. No

drug interaction study has been performed for the co-administration of Agenerase with

benzodiazepines. Based on data for other CYP3A4 inhibitors, plasma concentrations of midazolam are

expected to be significantly higher when midazolam is given orally. Therefore Agenerase should not

be co-administered with orally administered midazolam (see section 4.3), whereas caution should be

used with co-administration of Agenerase and parenteral midazolam. Data from concomitant use of

parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam

plasma levels. If Agenerase with or without 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.

Methadone and opiate derivatives : co-administration of methadone with amprenavir resulted in a

decrease in the C max and AUC of the active methadone enantiomer (R-enantiomer) of 25% and 13%

respectively, whilst the C max , AUC and C min of the inactive methadone enantiomer (S-enantiomer)

were decreased by 48%, 40% and 23% respectively. When methadone is co-administered with

amprenavir, patients should be monitored for opiate abstinence syndrome, in particular if low-dose

ritonavir is also given.

As compared to a non-matched historical control group, co-administration of methadone and

amprenavir resulted in a 30%, 27% and 25% decrease in serum amprenavir AUC, C max and C min

respectively. No recommendations can currently be made regarding adjustment of amprenavir dose

when amprenavir is co-administered with methadone due to the inherent low reliability of non-

matched historical controls.

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Oral anticoagulants : a reinforced monitoring of the International Normalised Ratio is recommended in

case of administration of Agenerase with warfarin or other oral anticoagulants, due to a possible

decrease or increase of their antithrombotic effect (see section 4.4).

Steroids : oestrogens and progestogens may interact with amprenavir. However, the information

currently available is not sufficient for determining the nature of the interaction. Co-administration of

0.035 mg ethinyl estradiol plus 1.0 mg norethindrone resulted in a decrease of the amprenavir AUC

and C min of 22% and 20% respectively, C max being unchanged. The C min of ethinyl estradiol was

increased by 32%, whilst the AUC and C min of norethindrone were increased by 18% and 45%

respectively. Alternative methods of contraception are recommended for women of childbearing

potential. When ritonavir is co-administered, the effect on hormonal contraceptive concentrations

cannot be predicted, therefore, alternative methods of contraception are also recommended.

Tricyclic antidepressants : careful monitoring of the therapeutic and adverse reactions of tricyclic

antidepressants is recommended when they (for example desipramine and nortriptyline) are

concomitantly administered with Agenerase (see section 4.4).

Paroxetine : plasma concentrations of paroxetine may be significantly decreased when co-administered

with amprenavir and ritonavir. The mechanism of this interaction remains unknown. Based on

historical comparison, amprenavir pharmacokinetic parameters were not altered by paroxetine.

Therefore, if paroxetine is co-administered with Agenerase and ritonavir, the recommended approach

is a dose titration of paroxetine based on a clinical assessment of antidepressant response. In addition,

patients on stable dose of paroxetine who start treatment with Agenerase and ritonavir should be

monitored for antidepressant response.

Other substances : plasma concentrations of other substances may be increased by amprenavir. These

include substances such as: clozapine, cimetidine, dapsone and loratadine.

S ome substances (e.g. lidocaine (by systemic route) and halofantrine) given with Agenerase may

cause serious adverse reactions. Concomitant use is not recommended (see section 4.4).

4.6

Pregnancy and lactation

Pregnancy: there are no adequate data from the use of amprenavir in pregnant women. Studies in

animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

This medicinal product should be used during pregnancy only after careful weighing of the potential

benefits compared to 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. A reproduction study in pregnant rats dosed from the time of uterine

implantation through lactation showed reduced body weight gains in the offspring during the nursing

period. The systemic exposure to the dams associated with this finding was similar to exposure in

humans, following administration of the recommended dose. The subsequent development of the

offspring, including fertility and reproductive performance, was not affected by the maternal

administration of amprenavir.

It is therefore recommended that mothers being treated with Agenerase do not breast-feed their

infants. Additionally, it is recommended that HIV infected women do not breast feed their infants in

order to avoid transmission of HIV.

4.7 Effects on ability to drive and use machines

No studies on the effects on ability to drive and use machines have been performed (see section 4.8).

4.8 Undesirable effects

11

The safety of Agenerase has been studied in adults and children at least 4 years of age, in controlled

clinical trials, in combination with various other antiretroviral agents. Adverse events considered

associated with the use of Agenerase are gastro-intestinal symptoms, rash and oral/peri-oral

paraesthesia. Most undesirable effects associated with Agenerase therapy were mild to moderate in

severity, early in onset, and rarely treatment limiting. For many of these events, it is unclear whether

they are related to Agenerase, to concomitant treatment used in the management of HIV disease or to

the disease process.

In children, the nature of the safety profile is similar to that seen in adults.

Adverse reactions are listed below by MedDRA body system organ class and by frequency. The

frequency categories used are:

Very common ≥ 1 in 10

Common

≥ 1 in 100 and < 1 in 10

Uncommon

≥ 1 in 1,000 and < 1 in 100

Rare

≥1 in 10,000 and < 1 in 1,000

Frequency categories for the events below have been based on clinical trials and postmarketing data.

Most of the adverse events below come from two clinical trials (PROAB3001, PROAB3006)

involving PI naïve subjects receiving Agenerase 1200mg twice daily. Events (grade 2-4) reported by

study investigators as attributable to study medication and occurring in >1% of patients, are included

as well as grade 3-4 treatment emergent laboratory abnormalities. Note that the background rates in

comparator groups were not taken into account.

Metabolism and nutrition disorders

Common:

Elevated triglycerides, elevated amylase, abnormal fat redistribution, anorexia

Uncommon:

Hyperglycaemia, hypercholesterolaemia

Elevated triglycerides, elevated amylase and hyperglycaemia (grade 3-4) were reported primarily in

patients with abnormal values at baseline.

Elevations in cholesterol were of grade 3-4 intensity.

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).

Symptoms of abnormal fat redistribution were infrequent in PROAB3001 with amprenavir. Only one

case (a buffalo hump) was reported in 113 (< 1 %) antiretroviral naive subjects treated with

amprenavir in combination with lamivudine/zidovudine for a median duration of 36 weeks. In study

PROAB3006, seven cases (3 %) were reported in 245 NRTI-experienced subjects treated with

amprenavir and in 27 (11 %) of 241 subjects treated with indinavir, in combination with various

NRTIs for a median duration of 56 weeks (p< 0.001).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as

hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and

hyperlactataemia (see section 4.4).

Psychiatric disorders

Common:

Mood disorders, depressive disorders

Nervous system disorders

12

Very Common:

Oral/perioral paraesthesia, tremors, sleep disorders

Gastrointestinal disorders

Very Common:

Diarrhoea, nausea, flatulence, vomiting

Common:

Abdominal pain, abdominal discomfort, dyspeptic symptoms, loose stools

Hepatobiliary disorders

Common:

Elevated transaminases

Uncommon:

Hyperbilirubinaemia

Elevated transaminases and hyperbilirubinaemia (grade 3-4) were reported primarily in patients with

abnormal values at baseline. Almost all subjects with abnormal liver function tests were co-infected

with Hepatitis B or C virus.

Skin and subcutaneous tissue disorders

Very Common:

Rash

Uncommon:

Stevens Johnson syndrome

Rashes were usually mild to moderate, erythematous or maculopapular cutaneous eruptions, with or

without pruritus, occurring during the second week of therapy and resolving spontaneously within two

weeks, without discontinuation of treatment with amprenavir. A higher incidence of rash was reported

in patients treated with amprenavir in combination with efavirenz. Severe or life-threatening skin

reactions have also occurred in patients treated with amprenavir (see section 4.4).

Musculoskeletal and connective tissue disorders

Increased CPK, myalgia, myositis, and rarely rhabdomyolysis have been reported with protease

inhibitors, particularly in combination with nucleoside analogues.

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).

General disorders and administration site conditions

Very Common:

Fatigue

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).

In PI experienced patients receiving Agenerase capsules 600 mg twice daily and low dose ritonavir,

100 mg twice daily, the nature and frequency of adverse events (grade 2-4) and Grade 3/4 laboratory

abnormalities were similar to those observed with Agenerase alone, with the exception of elevated

triglyceride levels, and elevated CPK levels which were very common in patients receiving Agenerase

and low dose ritonavir.

4.9 Overdose

There are limited reports of overdose with Agenerase. If overdose occurs, the patient should be

monitored for evidence of toxicity (see section 4.8) and standard supportive treatment provided as

13

Common:

Headache

Rare:

Angioedema

necessary. Since amprenavir is highly protein bound, dialysis is unlikely to be helpful in reducing

blood levels of amprenavir.

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group; protease inhibitor; ATC Code: J05A E05

Mechanism of Action

Amprenavir is a competitive inhibitor of 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. The in vitro antiviral activity observed with

fosamprenavir is due to the presence of trace amounts of amprenavir.

Antiviral activity in vitro

The in vitro antiviral activity of amprenavir was evaluated against HIV-1 IIIB in both acutely and

chronically infected lymphoblastic cell lines (MT-4, CEM-CCRF, H9) and in peripheral blood

lymphocytes. The 50% inhibitory concentration (IC50) of amprenavir ranged from 0.012 to 0.08 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 vitro

HIV-1 isolates with decreased susceptibility to amprenavir have been selected during in vitro serial

passage experiments. Reduced susceptibility to amprenavir was associated with virus that had

developed I50V or I84V or V32I+I47V or I54M mutations.

In vivo

a) ART-naïve or PI-naïve patients

(Note: Agenerase is not approved in ART-naive or PI-naive 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.

14

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.

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.

Analyses based on genotypic resistance testing.

Genotypic interpretation systems may be used to estimate the activity of amprenavir / ritonavir or

fosamprenavir / ritonavir in subjects with PI-resistant isolates. The current (July 2006) ANRS AC-11

algorithm for fosamprenavir / ritonavir defines resistance as the presence of the mutations

V32I+I47A/V, or I50V, or at least four mutations among: L10F/I/V, L33F, M36I, I54A/L/M/S/T/V,

I62V, V82A/C/F/G, I84V and L90M and is associated with increased phenotypic resistance to

fosamprenavir with ritonavir as well as reduced likelihood of virological response (resistance).

Conclusions regarding the relevance of particular mutations or mutational patterns are subject to

change with additional data, and it is recommended to always consult current interpretation systems

for analysing resistance test results.

Analyses based on 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.

Cross-Resistance

HIV-1 isolates with a decreased susceptibility to amprenavir have been selected during in vitro serial

passage experiments. Reduced susceptibility to amprenavir was associated with virus that had

developed I50V or I84V or V32I+I47V or I54M mutations. Each of these four genetic patterns

associated with reduced susceptibility to amprenavir produces some cross-resistance to ritonavir but

susceptibility to indinavir, nelfinavir and saquinavir is generally retained. There are currently data on

cross-resistance between amprenavir and other protease inhibitors for all 4 fosamprenavir resistance

pathways, either alone or in combination with other mutations. Based on data from twenty-five

antiretroviral naïve patients failing a fosamprenavir containing regimen (one of whom showed

Baseline resistance to lopinavir and saquinavir and another to tipranavir) the resistance pathways

associated with amprenavir produce limited cross-resistance to atazanavir/ritonavir (three of 25

15

isolates), darunavir/ritonavir (four of 25 isolates), indinavir/ritonavir (one of 25 isolates),

lopinavir/ritonavir (three of 24 isolates), saquinavir (three of 24 isolates) and tipranavir/ritonavir (four

of 24 isolates).. Conversely amprenavir retains activity against some isolates with resistance to other

PIs and this retained activity would depend on the number and type of protease resistance mutations

present in the isolates

The number of key PI-resistance mutations increases markedly the longer a failing PI-containing

regimen is continued. Early discontinuation of failing therapies is recommended in order to limit the

accumulation of multiple mutations, which may be detrimental to a subsequent rescue regimen.

Cross resistance between amprenavir and reverse transcriptase inhibitors is unlikely to occur because

the enzyme targets are different.

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

Clinical experience:

PI-experienced adults, boosted Agenerase capsules

The evidence of efficacy of Agenerase in combination with ritonavir 100 mg twice daily is based on

study PRO30017, a randomized, open-label study, in which PI-experienced adults experiencing

virological failure (viral load ≥1000 copies/ml) received either Agenerase (600 mg twice daily) in

combination with ritonavir (100 mg twice daily) and nucleoside analogues (NRTI) or a standard of

care (SOC) PI, predominantly boosted with low-dose RTV.

One hundred and sixty-three (163) patients with virus sensitive to Agenerase, at least one other PI, and

at least one NRTI were included in PRO30017 substudy A. The primary analysis assessed the non-

inferiority of APV/r to the SOC PI group with respect to time-weighted average change from baseline

(AAUCMB) in plasma viral load (HIV-1 RNA) at week 16 using a non-inferiority margin of 0.4 log10

copies/ml.

16

Results at week 16

Amprenavir / ritonavir

(n = 80)

SOC PI (n = 83):

Indinavir / RTV (29%)

Lopinavir / RTV (36%)

Saquinavir / RTV(20%)

Treatment

difference

Baseline

characteristics

Median HIV-1 RNA

(log 10 copies/ml)

(range)

4.11 (2.51–5.97)

4.10 (2.34–6.07)

Median CD4 (cells/ml)

(range)

265 (8–837)

322 (36–955)

Prior number of PIs

taken [n (%)]

1

2

≥ 3

27 (34)

18 (23)

35 (44)

25 (30)

29 (35)

Median number of PI

primary mutations 1

1.0 (range 0-2)

Prior number of NRTIs

taken [n (%)]

≥ 4

49 (61)

40 (48)

Outcomes a

Mean plasma HIV-1

RNA AAUCMB

(log 10 copies/ml)

− 1.315

− 1.343

0.043 b

(−0.250, 0.335) c

Plasma HIV-1 RNA

below 400 copies/ml

(%)

66

70

6

(−21, 9) c

a Intent To Treat (Exposed) Population: Observed analysis

b Mean stratified difference

c 95% confidence interval

1 Primary mutations were as defined by the IAS USA at the time of the original analysis, 2002 D30N,

M46I/L, G48V, I50V, V82A/F/T/S, I84V, L90M.

Heavily pre-treated children, unboosted Agenerase

The evidence of efficacy of unboosted Agenerase was based on two uncontrolled clinical studies

involving 288 HIV infected children aged between 2 and 18 years, 152 of whom were PI experienced.

The studies evaluated Agenerase oral solution and capsules at doses of 15 mg/kg three times daily, 20

mg/kg three times daily, 20 mg/kg twice daily and 22.5 mg/kg twice daily although the majority

received 20 mg/kg twice daily. Those of at least 13 years of age and weighing at least 50 kg received

1200 mg Agenerase twice daily. Concomitant low dose ritonavir was not administered and the

majority of the PI experienced subjects had prior exposure to at least one (78 %) or two (42 %) of the

NRTIs co-administered with Agenerase. At Week 48, approximately 25 % of those enrolled had

plasma HIV-1 RNA < 10,000 copies/ml and 9 % < 400 copies/ml with a median change from baseline

in CD4+ cells of 26 cells/mm 3 (n=74).

Based on these data, careful consideration should be given to the expected benefit of unboosted

Agenerase when optimising therapy for PI experienced children.

There is no data on the efficacy of boosted Agenerase in children.

17

5.2 Pharmacokinetic properties

Absorption: after oral administration, amprenavir is rapidly and well absorbed. The absolute

bioavailability is unknown due to the lack of an acceptable intravenous formulation for use in man.

Approximately 90 % of an orally administered radiolabelled amprenavir dose was recovered in the

urine and the faeces, primarily as amprenavir metabolites. Following oral administration, the mean

time (t max ) to maximal serum concentrations of amprenavir is between 1-2 hours for the capsule and

0.5 to 1 hour for the oral solution. A second peak is observed after 10 to 12 hours and may represent

either delayed absorption or enterohepatic recirculation.

At therapeutic dosages (1200 mg twice daily), the mean maximum steady state concentration (C max,ss )

of amprenavir capsules is 5.36 μg/ml (0.92-9.81) and the minimum steady state concentration (C min,ss )

is 0.28 μg/ml (0.12-0.51). The mean AUC over a dosing interval of 12 hours is 18.46 μg.h/ml (3.02-

32.95). The 50 mg and 150 mg capsules have been shown to be bioequivalent. The bioavailability of

the oral solution at equivalent doses is lower than that of the capsules, with an AUC and C max

approximately 14 % and 19 % lower, respectively (see section 4.2).

The AUC and C min of amprenavir were increased by 64% and 508% respectively and the C max

decreased by 30% when ritonavir (100 mg twice daily) was coadministered with amprenavir (600 mg

twice daily) compared to values achieved after 1200 mg twice daily doses of amprenavir.

While administration of amprenavir with food results in a 25 % reduction in AUC, it had no effect on

the concentration of amprenavir 12 hours after dosing (C 12 ). Therefore, although food affects the

extent and rate of absorption, the steady-state trough concentration (C min,ss ) was not affected by food

intake.

Distribution: the apparent volume of distribution is approximately 430 litres (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. The concentration of amprenavir in the cerebrospinal fluid is

less than 1 % of plasma concentration.

In in vitro studies, the protein binding of amprenavir is approximately 90 %. Amprenavir is primarily

bound to the alpha-1-acid glycoprotein (AAG), but also to albumin. 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. While absolute free active substance concentrations

remain constant, the percent of free active substance will fluctuate directly with total active substance

concentrations at steady-state go from C max,ss to C min,ss over the course of the dosing interval. This will

result in a fluctuation in the apparent volume of distribution of total active substance, but the volume

of distribution of free active substance does not change.

Clinically significant binding displacement interactions involving medicinal products primarily bound

to AAG are generally not observed. Therefore, interactions with amprenavir due to protein binding

displacement are highly unlikely.

Metabolism: amprenavir is primarily metabolised by the liver with less than 3 % excreted unchanged

in the urine. The primary route of metabolism is via the cytochrome P450 CYP3A4 enzyme.

Amprenavir is a substrate of and inhibits CYP3A4. Therefore, medicinal products that are inducers,

inhibitors or substrates of CYP3A4 must be used with caution when administered concurrently with

Agenerase (see sections 4.3, 4.4 and 4.5).

Elimination: the plasma elimination half-life of amprenavir ranges from 7.1 to 10.6 hours. The plasma

amprenavir half-life is increased when Agenerase capsules are co-administered with ritonavir.

Following multiple oral doses of amprenavir (1200 mg twice a day), there is no significant active

substance accumulation. The primary route of elimination of amprenavir is via hepatic metabolism

with less than 3 % excreted unchanged in the urine. The metabolites and unchanged amprenavir

18

account for approximately 14 % of the administered amprenavir dose in the urine, and approximately

75 % in the faeces.

Special populations:

Paediatrics: the pharmacokinetics of amprenavir in children (4 years of age and above) are similar to

those in adults. Dosages of 20 mg/kg twice a day and 15 mg/kg three times a day with Agenerase

capsules provided similar daily amprenavir exposure to 1200 mg twice a day in adults. Amprenavir is

14 % less bioavailable from the oral solution than from the capsules; therefore, Agenerase capsules

and Agenerase oral solution are not interchangeable on a milligram per milligram basis.

Elderly: the pharmacokinetics of amprenavir have not been studied in patients over 65 years of age.

Renal impairment: patients with renal impairment have not been specifically studied. Less than 3 %

of the therapeutic dose of amprenavir is excreted unchanged in the urine. The impact of renal

impairment on amprenavir elimination should be minimal therefore, no initial dose adjustment is

considered necessary. Renal clearance of ritonavir is also negligible; therefore the impact of renal

impairment on amprenavir and ritonavir elimination should be minimal.

Hepatic impairment: the pharmacokinetics of amprenavir are significantly altered in patients with

moderate to severe hepatic impairment. The AUC increased nearly three-fold in patients with

moderate impairment and four fold in patients with severe hepatic impairment. Clearance also

decreased in a corresponding manner to the AUC. The dosage should therefore be reduced in these

patients (see section 4.2). These dosing regimens will provide plasma amprenavir levels comparable to

those achieved in healthy subjects given a 1200 mg dose twice daily without concomitant

administration of ritonavir.

5.3 Preclinical safety data

In long-term carcinogenicity studies with amprenavir in mice and rats, there were benign

hepatocellular adenomas in males at exposure levels equivalent to 2.0-fold (mice) or 3.8-fold (rats)

those in humans given 1200 mg twice daily of amprenavir alone. In male mice altered hepatocellular

foci were seen at doses that were at least 2.0 times human therapeutic exposure.

A higher incidence of hepatocellular carcinoma was seen in all amprenavir male mouse treatment

groups. However, this increase was not statistically significantly different from male control mice by

appropriate tests. The mechanism for the hepatocellular adenomas and carcinomas found in these

studies has not been elucidated and the significance of the observed effects for humans is uncertain.

However, there is little evidence from the exposure data in humans, both in clinical trials and from

marketed use, to suggest that these findings are of clinical significance.

Amprenavir was not mutagenic or genotoxic in a battery of in vivo and in vitro genetic toxicity assays,

including bacterial reverse mutation (Ames Test), mouse lymphoma, rat micronucleus, and

chromosome aberration in human peripheral lymphocytes.

In toxicological studies with mature animals, the clinically relevant findings were mostly confined to

the liver and gastrointestinal disturbances. Liver toxicity consisted of increases in liver enzymes, liver

weights and microscopic findings including hepatocyte necrosis. This liver toxicity can be monitored

for and detected in clinical use, with measurements of AST, ALT and alkaline phosphatase activity.

However, significant liver toxicity has not been observed in patients treated in clinical studies, either

during administration of Agenerase or after discontinuation.

Amprenavir did not affect fertility.

Local toxicity and sensitising potential was absent in animal studies, but slight irritating properties to

the rabbit eye were identified.

19

Toxicity studies in young animals, treated from four days of age, resulted in high mortality in both the

control animals and those receiving amprenavir. These results imply that young animals lack fully

developed metabolic pathways enabling them to excrete amprenavir or some critical components of

the formulation (e.g. propylene glycol, PEG 400). However, the possibility of anaphylactic reaction

related to PEG 400 cannot be excluded. In clinical studies, the safety and efficacy of amprenavir have

not yet been established in children below four years of age.

In pregnant mice, rabbits and rats there were no major effects on embryo-foetal development.

However, at systemic plasma exposures significantly below (rabbits) or not significantly higher (rat)

than the expected human exposures during therapeutic dosing, a number of minor changes, including

thymic elongation and minor skeletal variations were seen, indicating developmental delay. A dose-

dependent increase in placental weight was found in the rabbit and rat which may indicate effects on

placental function. It is therefore recommended that women of child-bearing potential taking

Agenerase should practice effective contraception (e.g. barrier methods).

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule shell :

gelatin,

glycerol,

d-sorbitol (E420) and sorbitans solution,

titanium dioxide,

red printing ink.

Capsule contents:

d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS),

macrogol 400 (PEG 400),

propylene glycol.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30°C.

Keep the container tightly closed.

6.5 Nature and contents of container

White High Density Polyethylene (HDPE) bottles containing 480 capsules.

6.6 Special precautions for disposal

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

20

7.

MARKETING AUTHORISATION HOLDER

Glaxo Group Ltd

Glaxo Wellcome House

Berkeley Avenue

Greenford

Middlesex UB6 0NN

United Kingdom

8.

MARKETING AUTHORISATION NUMBER

EU/1/00/148/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 October 2000

Date of last renewal: 17 November 2005

10. DATE OF THE REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines

Agency (EMEA) http://www.emea.europa.eu.

21

1.

NAME OF THE MEDICINAL PRODUCT

Agenerase 150 mg soft capsules.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 150 mg amprenavir.

Excipients:

Sorbitol (E420)

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Soft capsule.

Oblong, opaque, off-white to cream coloured, printed with ‘GX CC2’.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Agenerase, in combination with other antiretroviral agents, is indicated for the treatment of protease

inhibitor (PI) experienced HIV-1 infected adults and children above the age of 4 years. Agenerase

capsules should normally be administered with low dose ritonavir as a pharmacokinetic enhancer of

amprenavir (see sections 4.2 and 4.5). The choice of amprenavir should be based on individual viral

resistance testing and treatment history of patients (see section 5.1).

The benefit of Agenerase boosted with ritonavir has not been demonstrated in PI naïve patients (see

section 5.1)

4.2 Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

The importance of complying with the full recommended dosing regimen should be stressed to all

patients.

Agenerase is administered orally and can be taken with or without food.

Agenerase is also available as an oral solution for use in children or adults unable to swallow capsules.

Amprenavir is 14 % less bioavailable from the oral solution than from the capsules; therefore,

Agenerase capsules and Agenerase oral solution are not interchangeable on a milligram per milligram

basis (see section 5.2).

Adults and adolescents of 12 years of age and older (greater than 50 kg body weight): the

recommended dose of Agenerase capsules is 600 mg twice daily with ritonavir, 100 mg twice daily, in

combination with other antiretroviral agents.

If Agenerase capsules are used without the boosting effect of ritonavir higher doses of Agenerase

(1200 mg twice daily) should be used.

22