PRODUCT INFORMATION. single enantiomer with the (3S) (1S,2R) configuration and has the following structural formula: NH 2

Transcription

1 PRODUCT INFORMATION AGENERASE CAPSULES AND ORAL SOLUTION NAME OF THE DRUG: Amprenavir DESCRIPTION: The chemical name of amprenavir is (3S)-tetrahydro-3-furyl N-[(1S,2R)-3-(4-amino-Nisobutylbenzene-sulfonamido)-1-benzyl-2-hydroxypropyl] carbamate. Amprenavir is a single enantiomer with the (3S) (1S,2R) configuration and has the following structural formula: NH 2 O O O O S N HN O C H 3 OH CH 3 The molecular formula of amprenavir is C 25 H 35 N 3 O 6.S and it has a relative molecular mass of Amprenavir is a white to cream solid. The solubility of amprenavir in water is 0.04 mg/ml at 25 C. CAS REGISTRY NUMBER: PHARMACOLOGY: Pharmacodynamics Amprenavir is an 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 non-infectious viral particles. 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 to 0.08 μm in acutely infected cells and was 0.41 μm in chronically infected cells (1 μm = 0.5 μg/ml). Amprenavir exhibited synergistic anti-hiv-1 activity in combination with abacavir, zidovudine, didanosine or saquinavir, and additive anti-hiv-1 activity in combination with indinavir, nelfinavir or ritonavir, in vitro. These combinations have not been adequately studied in humans. The relationship between in vitro anti-hiv-1 activity and the inhibition of HIV-1 replication in humans has not been defined. The resistance profile seen with amprenavir is different from that observed with other PIs in clinical practice. Amprenavir resistant isolates of HIV have been selected in vitro. The key Agenerase Issue 8

2 mutation I50V is associated with resistance to amprenavir, with at least three mutations were generally required at amino acid positions 46, 47 and 50 within the HIV protease, to produce a strain with a greater than 10 fold increase in IC 50. Little cross-resistance has been observed between amprenavir selected resistant variants and other PIs, suggesting the potential for PI salvage therapy. Other mutations associated with amprenavir resistance (I84V) have rarely been selected during amprenavir therapy. HIV-1 isolates resistant to amprenavir have also been obtained from patients treated with amprenavir. Genotypic analysis showed mutations in the HIV-1 protease gene resulting in amino acid substitutions which confer reduced susceptibility to amprenavir at either positions I50V, or I54L/M or, V32I+I47V or rarely, I84V. Each of the four genetic patterns may confer cross resistance to ritonavir, but susceptibility to indinavir, nelfinavir and saquinavir is retained. Many in vitro PI-resistant variants, and 322 of 433 (74%) clinical PI-resistant variants with multiple protease inhibitor resistance mutations were susceptible to amprenavir. The principal protease mutation associated with cross-resistance to amprenavir following treatment failure with other protease inhibitors was I84V, particularly when mutations L10I/V/F were also present. Cross-resistance should not occur between amprenavir and reverse transcriptase inhibitors, because the enzyme targets are different. Pharmacokinetics Absorption: The absolute bioavailability is unknown due to the lack of an acceptable intravenous formulation for use in man. Following oral administration, the mean time (t max ) to maximal serum concentrations of amprenavir is between 1-2 hours for the capsule and approximately 0.75 hours 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 steady state C max of amprenavir from capsules is 5.36 ( ) μg/ml and the C min is 0.28 ( ) μg/ml. The mean AUC over a dosing interval of 12 hours is ( ) μg.h/ml. The 50 mg and 150 mg capsules have been shown to be bioequivalent. The oral solution at equivalent doses is less bioavailable compared to the capsules, with an AUC and C max approximately 14% and 19% lower respectively. These presentations are not interchangeable on a milligram per milligram basis. Administration of amprenavir with food (high fat meal) has a modest effect on overall plasma concentrations (AUC), reducing the AUC of amprenavir by between 14-25% and reducing C max by approximately 33%. However, tmax is increased by 66% and plasma concentration of amprenavir after 12 hours (C 12 ) is unchanged. Distribution: The apparent volume of distribution is approximately 420 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. Amprenavir is approximately 90% protein bound in vitro. It is primarily bound to the alpha 1 acid glycoprotein (AAG), but also to albumin. Agenerase Issue 8 2

3 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 drugs that are inducers, inhibitors or substrates of CYP3A4 must be used with caution when administered concurrently with Agenerase (see Interaction with Other Medicines). Elimination: The plasma elimination half-life of amprenavir ranges from 7.1 to 10.6 hours. Following multiple oral doses of amprenavir 1200 mg twice a day, there is no significant drug 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 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 15mg/kg three times a day of Agenerase capsules, provided similar plasma concentrations compared to those obtained with 1200 mg twice a day in adults (See Contraindications, Amprenavir Oral Solution). Elderly: The pharmacokinetics of amprenavir have not been studied in patients over 65 years of age. When treating elderly patients, consideration should be given to potential hepatic, renal or cardiac dysfunction, concomitant disease or other drug therapy. Impaired renal function: 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 (See Contraindications, Amprenavir Oral Solution). Impaired hepatic function: The pharmacokinetics of amprenavir are significantly altered in patients with moderate to severe hepatic impairment. The AUC increased nearly threefold 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 Contraindications, Amprenavir Oral Solution). Clinical Trials In a double-blind study (PROB3001) in antiretroviral naïve HIV-infected adults (n=232), at 16 weeks, amprenavir (1200 mg bd) in combination with zidovudine (300 mg bd) and lamivudine (150 mg bd)was significantly superior to zidovudine (300 mg bd) and lamivudine (150 mg bd). In an intent-to-treat analysis, the proportion of subjects with plasma HIV-1 RNA<400 copies/ml was 59% in the amprenavir/lamivudine/zidovudine group and 17% in the lamivudine/zidovudine group (p<0.001); in the per protocol analysis, these proportions were 88% and 19%, respectively (p<0.001). The proportion of subjects with plasma HIV-1 RNA<50 copies/ml was 59% in the amprenavir/lamivudine/zidovudine group and 10% in the lamivudine/zidovudine group (p<0.001). In an open label study (PROB3006) in antiretroviral experienced, protease inhibitor naïve, adults (n=504), in combination with various nucleoside analogues, the proportion of Agenerase Issue 8 3

4 subjects with plasma HIV-RNA < 400 copies/ml at week 48 was 30% in the amprenavir arm (1200 mg bd) and 46% in the indinavir arm (800 mg tds) in the intent-to-treat analysis; in the per protocol analysis, these proportions were 64% and 79%, respectively. The proportion of subjects with plasma HIV-RNA < 50 copies/ml was 23% in the amprenavir group and 37% in the indinavir group. The open-label nature of this study, with a higher proportion of early discontinuations due to adverse events in the amprenavir arm, contributed to the differences in response rates. At week 48, the median change from baseline in plasma HIV-1 RNA was 1.0 log 10 copies/ml and 1.2 log 10 copies/ml for the amprenavir and indinavir arm, respectively. The combination therapy with amprenavir and NRTIs in antiretroviral experienced subjects demonstrated lower efficacy in reduction of viral load than combination therapy with indinavir and NRTIs. In PROB3006 fifty-nine subjects discontinued randomised indinavir, and of these, 41 subjects changed to an amprenavir containing regimen. In patients with a viral load of 400 copies/ml at the time of switch the median change from baseline in viral load was 0.02 to 0.68 log 10 copies/ml over the 48 week period. Sixty-seven percent of the 6 subjects evaluable at Week 48 had a viral load of <400 copies/ml. Another 65 subjects discontinued randomised amprenavir, and of these, 55 subjects changed to an indinavir containing regimen. In patients with a viral load of 400 copies/ml at the time of switch the median change from baseline in viral load was 0.74 to 1.00 log 10 copies/ml over the 49 week period. Fifty percent of the 12 subjects evaluable at Week 48 had a viral load of <400 copies/ml. In a paediatric study (PROB3004) in 81 HIV-infected, antiretroviral experienced children (aged 3 to 17 years), at 16 weeks, in combination with nucleoside analogues, amprenavir was superior to placebo (proportion of subjects with plasma HIV-RNA < 400 copies/ml was 33% versus 0%, respectively). Protease inhibitor(pi) naïve children were more likely to achieve HIV-RNA below 400 copies/ml than those who were PI-experienced. ACTG398 is a randomised, placebo controlled study of dual protease inhibitor (PI) containing therapy versus single PI-containing therapy for HIV-1 infected patients with at least 16 weeks of prior PI exposure. All subjects received a core regimen of abacavir 300 mg bd, efavirenz 600 mg qd, adefovir dipivoxil 600 mg qd and amprenavir 1200 mg bd and were selectively randomised, based on prior PI experience to received either saquinavir soft gel capsules 1600 mg bd, indinavir 1200 mg bd, nelfinavir 1250 mg bd or placebo. The proportion of subjects with plasma HIV-1 RNA <200 copies/ml at week 24 in the intent-to-treat population was 34-36% in the dual protease inhibitor arms and 23% in the single protease inhibitor (amprenavir) arm. The proportion of subjects with viral load<200 copies/ml for non-nucleoside reverse transcriptase inhibitors (NNRTI) experienced subjects was 16% and for the NNRTI naïve subjects was 43% (p<0.001). INDICATIONS: Agenerase is indicated in combination with other antiretroviral agents for the treatment of protease inhibitor experienced HIV-1 infected adults and children aged 4 years and older. CONTRAINDICATIONS: Agenerase is contra-indicated in patients with known hypersensitivity to amprenavir or to any ingredient of the preparation. Because of potential toxicity from the large amount of the excipient propylene glycol contained in Agenerase Oral Solution, this formulation is contraindicated in infants and Agenerase Issue 8 4

5 children below the age of 4 years, pregnant women, patients with hepatic and renal failure, and patients treated with disulfiram and metronidazole. Agenerase should not be administered concurrently with terfenadine, astemizole, cisapride, pimozide, midazolam, triazolam, or ergot derivatives. Co-administration may result in competitive inhibition of metabolism of these products and may cause serious or life-threatening adverse events, such as cardiac arrhythmia (e.g. terfenadine, astemizole, cisapride), prolonged sedation or respiratory depression (e.g. trizolam, midazolam) or peripheral vasospasm or ischaemia (e.g. ergot derivatives). Rifampicin must not be administered concurrently with Agenerase. Rifampicin decreases the amprenavir plasma AUC by approximately 82%. PRECAUTIONS: General: Because of possible toxicity associated with the large amount of propylene glycol and the lack of information on chronic exposure to large amounts of propylene glycol, Agenerase oral solution should be used only when Agenerase capsules or other protease inhibitors are not therapeutic options. Agenerase oral solution contains vitamin E (46 IU/mL), therefore additional vitamin E supplementation is not recommended. Children (4 years and above) and adults, particularly those with renal or hepatic impairment, or those with genetically lower ability to metabolise alcohol (e.g. those of Japanese or Chinese origin) should be monitored for adverse reactions potentially related to the propylene glycol content (550 mg/ml) of Agenerase oral solution. These reactions include seizures, stupor, tachycardia, hyperosmolarity, lactic acidosis, renal toxicity, haemolysis. For the same reason, the concomitant administration of Agenerase oral solution with disulfiram or other medicinal products that reduce alcohol metabolism (e.g. metronidazole) or preparations that contain alcohol or additional propylene glycol should be avoided. Amprenavir is a sulfonamide. The potential for cross-sensitivity between the sulfonamide class and amprenavir is unknown. Patients with a known sulfonamide allergy should be treated with caution. Formulations of Agenerase provide high daily doses of vitamin E. High vitamin E doses may exacerbate the blood coagulation defect of vitamin K deficiency caused by anticoagulant therapy and malabsorption. Impaired hepatic function: The principal route of metabolism and excretion of amprenavir is via the liver. This is also the principal route of metabolism for the propylene glycol excipient in Agenerase oral solution. Agenerase oral solution should not be used by patients with impaired hepatic function and Agenerase capsules should be used with caution in patients with impaired hepatic function. The dose of Agenerase should be reduced in patients with moderate or severe hepatic impairment (See Dosage and Administration). Agenerase Issue 8 5

6 Use in children: Amprenavir has been administered to 118 patients aged 4 to 17 years in clinical studies. The pharmacokinetics and adverse event profile were similar to those in adults. Agenerase oral solution is contraindicated in children aged less than 4 years of age because of the potential risks of toxicity from the large amount of excipient propylene glycol. The safety, effectiveness and pharmacokinetics of amprenavir have not been established in children less than 4 years of age. Toxicity studies in rats initially of four days of age showed high mortalities after oral treatment with either the vehicle alone, or amprenavir plus the vehicle, which is consistent with an inability to detoxify or excrete the formulation components. In clinical studies, Agenerase has been administered to children from four years of age and has been shown to be well tolerated. The safety and efficacy of Agenerase in children less than four years of age has not yet been established. St John s Wort: Concomitant use of amprenavir and products containing Hypericum perforatum (also known as St John s Wort) is not recommended. A pharmacokinetic study with indinavir indicated that Hypericum perforatum may reduce indinavir serum concentration. Consequently, amprenavir serum levels may be reduced with concomitant administration of Hypericum perforatum. Body fat changes: Redistribution / accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, elevated serum lipid and blood glucose levels, have been observed either separately or together in some patients receiving combination antiretroviral therapy (see 4.8 Undesirable Effects). Whilst all members of the PI and NRTI classes of medicinal products have been associated with one or more of these specific adverse events, linked to a general syndrome commonly referred to as lipodystrophy, data indicate that there are differences in the risk between individual members of the respective therapeutic classes. In addition, the lipodystrophy syndrome has a multi-factorial etiology; with for example HIV disease status, older age and duration of antiretroviral treatment all playing important, possibly synergistic roles. The long-term consequences of these events are currently unknown. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate. Immune Reconstitution Syndrome: In HIV-infected patients with severe immune deficiency at the time of initiation of anti-retroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections 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 ART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci (P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Agenerase Issue 8 6

7 Hyperglycaemia: New onset of diabetes mellitus, hyperglycaemia or exacerbations of pre-existing diabetes mellitus have been reported in HIV infected patients receiving protease inhibitor therapy. In some patients, the hyperglycaemia was severe and in some cases 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 or hyperglycaemia. Haemophilia: 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. Information for patients: Patients should be advised that Agenerase, or any other current antiretroviral therapy, does not cure HIV. Patients 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. Carcinogenicity and mutagenicity In long-term carcinogenicity studies with amprenavir, there were benign hepatocellular adenomas in males at the high dose of 500 mg/kg/day in mice or 750 mg/kg/day in rats. Exposures at these dose levels were equivalent to 2.0-fold (mice) or 3.8-fold (rats) those in humans given 1200 mg twice daily of amprenavir alone. Altered hepatocellular foci were seen in male mice at doses of 275 and 500 mg/kg/day (exposure at least 2.0 times human therapeutic exposure). The significance of the observed effects for humans is uncertain, however there is no evidence from clinical trials or 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. Impairment of fertility The effects of amprenavir on fertility and general reproductive performance were investigated in male rats (treated for 28 days before mating, at doses producing up to twice the expected clinical exposure based on AUC comparisons) and female rats (treated for 15 days before mating through day 17 of gestation, at doses producing up to twice the expected clinical exposure). Amprenavir did not impair mating or fertility of male or female rats and did not affect the development and maturation of sperm from treated rats. The reproductive performance of the F 1 generation born to female rats given amprenavir was not different from control animals. Agenerase Issue 8 7

8 Use in Pregnancy: Agenerase oral solution is contraindicated in pregnancy due to the risk of toxicity to the foetus from the propylene glycol content. If Agenerase is used during pregnancy, Agenerase capsules should be used. There are no controlled clinical studies in the use of amprenavir in pregnant women. Category B3. Embryo/fetal development studies were conducted in rats and rabbits. In pregnant rabbits, amprenavir administration was associated with an increased incidence of minor skeletal variations resulting from deficient ossification of bones. Systemic exposure at the highest tested dose was approximately one-thirtieth of the exposure seen at the recommended human dose. In rat fetuses, thymic elongation and incomplete ossification of bones were attributed to amprenavir. Findings were seen at systemic exposures that were less than (incomplete ossification) or comparable (thymic elongation) to that associated with the recommended human dose. Reduced body weights were observed in the offspring of rats in a pre- and post-natal development study (see Use in lactation). Use in lactation: Some health experts recommend that HIV-infected women do not breast feed their infants in order to avoid transmission of HIV. It is recommended that mothers do not breast feed their infants while receiving treatment with Agenerase. Although it is not known if amprenavir is excreted in human milk, amprenavir is found in the milk of lactating rats. Reduced body weights (10% to 20%) were observed in the offspring of rats in a pre- and post-natal developmental study. The maternal plasma drug concentration associated with this finding was approximately twice the peak value in humans following administration of the recommended dose; mean milk concentrations were similar to maternal plasma concentrations. It is not known if reduced offspring body weights were associated with drug exposure in utero or from milk. The subsequent development of these offspring, including fertility and reproductive performance, was not affected by the maternal administration of amprenavir. Interaction with Other Medicines (See Contraindications): Amprenavir is metabolized in the liver by the cytochrome P450 enzyme system. Amprenavir is an inhibitor of cytochrome P450 CYP3A4 metabolism and therefore should not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4. Caution should be used when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4, or potentially toxic medications that are metabolized by CYP3A4. Amprenavir does not inhibit CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2E1, or uridine glucuronosyltransferase (UDPGT). Pharmacokinetic studies with other CYP 3A4 inhibitors, including other protease inhibitors, indicate that amprenavir may significantly increase lovastatin and simvastatin concentrations, which have been associated with an increased incidence of myopathy, including rhabdomyolysis. Pharmacokinetic studies with other CYP 3A4 inhibitors, including other protease inhibitors, indicate that amprenavir may increase atorvastatin concentrations therefore use the lowest possible dose of atorvastatin with careful monitoring. Drug interaction studies with a range of drugs likely to be co-administered with Agenerase have been performed and the results are shown in the following table. Agenerase Issue 8 8

9 Pharmacokinetics for Amprenavir C max AUC C min Coadministered Pharmacokinetics for co-administered drug drug C max AUC C min N/A zidovudine 40% 31% N/A N/A lamivudine 16% 9% N/A abacavir 18% 33% 25% indinavir 22% 38% 27% 37% 32% 14% saquinavir 21% 19% 48% 14% 9% 189 % nelfinavir 12% 15% 14% 39% 36% 43% efavirenz 16% 32% N/A ketoconazole 19% 44% N/A 70% 82% 92% rifampicin 7% 15% 15% rifabutin 127% 204% 349% 18% 39% clarithromycin 10% 15% 72% 12% 483% Lopinavir / ritonavir = Increase; = Decrease; = no effect, NA = Not available 38% 28% 52% Amprenavir has a low potential for clinically significant drug-drug interactions due to binding displacement. It is primarily bound to the alpha 1 acid glycoprotein and binding displacement interactions with this protein are rare. Nucleoside Reverse Transcriptase Inhibitors (NRTIs): When zidovudine, lamivudine and abacavir are used in combination with Agenerase no dosage adjustments are considered necessary. HIV Protease Inhibitors: The effect of amprenavir on total drug concentrations of other HIV protease inhibitors in subjects receiving both agents was evaluated using comparisons to historical data. Indinavir steady-state C max, AUC, and C min were decreased by 22%, 38%, and 27%, respectively, by concomitant amprenavir. Similar decreases in C max and AUC were seen after the first dose. Nelfinavir steady-state C max, AUC, and C min were increased by 12%, 15%, and 14%, respectively, by concomitant amprenavir. Co-administration of amprenavir with saquinavir results in a reduction of amprenavir AUC and Cmin of 32% and 14% respectively. The clinical significance of these reductions in amprenavir plasma concentrations in combination with saquinavir have not been fully studied, although initial clinical studies have shown that with this dual PI combination, antiviral efficacy is maintained. Caution is therefore advised when amprenavir and saquinavir are used in combination because these parameters at steady state have been correlated with antiviral response and development of resistance. Co-administration of ritonavir with amprenavir results in a significant increase in the C max and AUC of amprenavir. When given in combination in adults, reduced doses of both medicinal products should be used (see Dosage and Administration). In clinical practice, doses of amprenavir 600 mg twice daily and ritonavir 100 mg twice daily are being used; the evaluation of the safety and efficacy of these regimens is ongoing. Amprenavir oral solution and ritonavir oral solution should not be co-administered. Agenerase Issue 8 9

10 The amprenavir plasma Cmin values achieved with the combination of amprenavir (600 mg twice daily) in combination with 400 mg lopinavir 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 lopinavir/ritonavir regimen increases lopinavir Cmin values, but not amprenavir Cmin values Delavirdine: 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 subtherapeutic plasma concentrations. Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Efavirenz has been seen to decrease the C max, AUC and C min,ss of amprenavir by approximately 40% in adults. If efavirenz is given to adults in combination with amprenavir and ritonavir, the reduced doses of both ritonavir and amprenavir should be used (see ritonavir above). 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 and patients with renal impairment. Such combinations should be avoided in patients with hepatic impairment. Nevirapine may decrease amprenavir serum concentrations. Delavirdine may increase serum concentrations of amprenavir There are other agents that may result in serious and/or life-threatening drug interactions: Table 1: Drug Interactions with AGENERASE Should Not Be Coadministered Drug Class Drug Within Class Not To Be Coadministered Antihistamines Astemizole, terfenadine Antimycobacterials Rifampin* Benzodiazepines Midazolam, triazolam Ergot derivatives Dihydroergotamine, ergotamine GI motility agents Cisapride Antipsychotic Pimozide *Decreases plasma concentrations of amprenavir and should not be coadministered as it is likely to reduce antiviral activity. Coadministration Requires Concentration Monitoring Drug Class Drug Within Class to Monitor Antiarrhythmics Amiodarone, lidocaine (systemic), quinidine Anticoagulants Warfarin* Antidepressants Tricyclic antidepressants *Monitor INR (International Normalized Ratio). Agenerase Issue 8 10

11 Dosage Adjustment Required Drug Class Drug Within Class Requiring a Dosage Adjustment Antimycobacterials Rifabutin (reduce dose to at least half that recommended)* *A complete blood count should be performed weekly and as clinically indicated in order to monitor for neutropenia in patients receiving amprenavir and rifabutin. Anticonvulsants: phenobarbital, phenytoin, carbamazepine. Cholesterol-lowering agents: atorvastatin, cerivastatin, pravastatin, lovastatin, fluvastatin, and simvastatin Erectile dysfunction agents: sildenafil Corticosteroids: dexamethasone Agenerase Issue 8 11 Other Potentially Significant Drug Interactions Induce CYP3A4 and may decrease amprenavir concentrations. May have their serum concentrations increased by AGENERASE, which could increase their activity or toxicity. Expected to substantially increase sildenafil concentrations (consult sildenafil prescribing information for dose reduction of sildenafil in patients receiving ritonavir) Induce CYP3A4 and may decrease amprenavir concentrations. Antimycobacterials: Rifampicin: Rifampicin should not be used in combination with amprenavir since it reduces plasma concentrations and AUC of amprenavir by about 90%. Rifabutin: Coadministration of amprenavir with rifabutin results in a 15% decrease in amprenavir plasma AUC and a 193% increase in rifabutin plasma AUC. Hence, concomitant use of these drugs should be avoided if possible. If it is clinically necessary to coadminister rifabutin with amprenavir, a dosage reduction of rifabutin of at least half the recommended dose is required. Other potential interactions: Other medications listed below are examples of substrates, inhibitors, or inducers of CYP3A4 that could have potential interactions, when used concomitantly with Agenerase or with other HIV protease inhibitors. The clinical significance of these potential interactions is unknown and has not been studied in conjunction with Agenerase. Patients should therefore be monitored for toxicities associated with such drugs when these are used in combination with Agenerase. Alcohol and Alcohol Dehydrogenase Inhibitors: Agenerase oral solution contains propylene glycol (550 mg/ml), which is primarily metabolised via alcohol dehydrogenase. Therefore, concomitant administration with disulfiram, other medicinal products that reduce alcohol metabolism (e.g. metronidazole), alcoholic beverages, preparations that contain alcohol or propylene glycol should be avoided. Antibiotics: Dapsone and erythromycin may have their plasma concentrations increased by amprenavir. Erythromycin may also increase amprenavir serum concentrations. Antifungals: Itraconazole may have its plasma concentrations increased by amprenavir. Itraconazole may increase serum concentrations of amprenavir. Amprenavir produced increased accumulation and decreased clearance of ketoconazole. This interaction should be monitored carefully for possible liver toxicity during co-administration of both drugs. Benzodiazepines: Alprazolam, clorazepate, diazepam, and flurazepam may have their serum concentrations increased by amprenavir, which could increase their activity. Although specific studies have not been performed, co-administration with potent sedatives metabolised by CYP3A4 (e.g. triazolam, midazolam) should be avoided due to the potential for prolonged sedation.

12 Calcium channel blockers: Diltiazem, nicardipine, nifedipine, and nimodipine may have their serum concentrations increased by amprenavir, which could increase their activity. Cholesterol lowering agents: Atorvastatin, fluvastatin, cerivastatin, pravastatin, and simvastatin may have their serum concentrations increased by amprenavir, which could increase their activity or toxicity. The risk of myopathy, including rhabdomyolysis may be increased. Erectile Dysfunction Agents: Particular caution should be used when prescribing sildenafil in patients receiving amprenavir. Because amprenavir is a cytochrome P4503A4 inhibitor, coadministration of Agenerase with sildenafil is likely to result in an increase of sildenafil concentrations by competitive inhibition of metabolism. The magnitude of this interaction has not been determined. Results from drug interaction studies in healthy volunteers indicate that coadministration of saquinavir soft gelatin capsules (1200 mg t.i.d.) increases sildenafil (100 mg single dose) AUC by 210% (3.1-fold) and coadministration of ritonavir (500 mg b.i.d.) increases sildenafil (100 mg single dose) AUC by 1000% (11-fold). Providers should consult the sildenafil prescribing information for dose reductions of sildenafil in patients receiving ritonavir. Patients receiving amprenavir and sildenafil should be advised that they may be at an increased risk for sildenafil-associated adverse events, including hypotension, visual changes, and priapism, and should report these symptoms promptly to their doctor. Steroids (Hormonal contraceptives): Estrogens, progestogens, and some glucocorticoids may have an interaction with amprenavir but there is insufficient information to predict the nature of the interaction. Because of this potential for metabolic interactions with amprenavir, the efficacy of hormonal contraceptives may be reduced. Alternate or additional reliable barrier methods of contraception are recommended for women of childbearing potential. St John s Wort: Co-administration of Hypericum perforatum (St John s Wort) may lead to decreased serum levels of amprenavir (See Precautions). Other agents: There are other agents that may have their plasma concentrations increased by amprenavir, and include but are not limited to: clozapine, carbamazepine, cimetidine, loratadine, pimozide, and warfarin. Cimetidine and ritonavir may increase amprenavir plasma concentrations. Antacids (and didanosine because of its antacid content) have not been specifically studied. Based upon data with other protease inhibitors, it is advisable that antacids not be taken at the same time as Agenerase because of potential interference with absorption. It is recommended that their administration be separated by at least an hour. Terfenadine, cisapride, pimozide or astemizole should not be administered concurrently with Agenerase. Co-administration may result in competitive inhibition of metabolism of these products, leading to serious life threatening cardiac arrhythmias. Agenerase should also not be co-administered with ergot derivatives. Concomitant use of amprenavir with ritonavir and fluticasone propionate 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. 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 interaction is also expected with other corticosteroids metabolised via the P450 3A pathway. Agenerase Issue 8 12

13 Methadone: Agenerase may be less effective due to decreased amprenavir plasma concentrations in patients taking these medicinal products concomitantly. No recommendations can currently be made regarding adjustment of amprenavir dose when co-administered with methadone. Co-administration of methadone and amprenavir also resulted in a decrease in methadone plasma concentrations and patients should be monitored for opiate abstinence syndrome, in particular if low-dose ritonavir is also given." Effects on the Ability to Drive and Operate Machinery: No studies on the effects on ability to drive and use machinery have been performed. ADVERSE REACTIONS: The adverse events reported during Agenerase therapy in HIV disease were similar in adults and children. For many of these events, it is unclear whether the reported adverse events are related to Agenerase, or to the wide range of drugs used in the management of HIV disease or as a result of the disease process. Agenerase was generally well tolerated. Most undesirable effects associated with Agenerase therapy were mild to moderate in severity, early in onset, and rarely treatment limiting. From clinical studies, gastrointestinal events (nausea, diarrhoea, flatulence and vomiting) were the most commonly reported undesirable effects. There were also reports of oral/perioral paresthesia, rash, headache and fatigue, which were considered to be related to treatment with Agenerase. 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, including Stevens-Johnson syndrome, have rarely (< 1 %) occurred in patients treated with amprenavir. Laboratory abnormalities occurred infrequently, and primarily in patients with abnormal values at baseline. Agenerase Issue 8 13

14 Percentage of Patients with clinically significant (Grade 3/4) laboratory abnormalities PROAB3001* Therapy-Naïve Patients PROAB3006** NRTI-Experienced Patients Laboratory Abnormality AGENERASE/ Lamivudine/ Zidovudine (n=113) Lamivudine/ Zidovudine (n=109) AGENERASE/ ART* (n=245) Indinavir/ART* (n=241) Haematology Haemoglobin 1 (<1%) 1 (<1%) Neutrophil count 3 (3%) 5 (5%) 5 (2%) 4 (2%) Platelets (<2%) 2 (1%) Total WBC 1 (<1%) 1 (<1%) -- 1 (<1%) Clinical Chemistry ALT 2 (2%) 2 (2%) 13 (5%) 17 (7%) AST 2 (2%) 2 (2%) 12 (5%) 15 (6%) Alkaline phosphatase (4%) 0 Amylase 1 (<1%) 2 (2%) 9 (4%) 5 (2%) Bilirubin 1 (<1%) 2 (<1%) 36 (15%) Hyperglycemia 1 (<1%) 1 (<1%) 2 (<1%) 9 (4%) Hypertriglyceridaemia 0 1 (<1%) 16 (7%) 14 (6%) *Based on Week 16 data **Based on week 48 data The most frequent clinical adverse events related to study drugs, of at least moderate intensity (Grade 2 or more), reported in two large clinical studies in adults are summarised below. All events reported in at least 1 % of subjects treated with amprenavir are included. Adverse Events by body system Digestive Nausea Vomiting Gaseous symptoms Diarrhoea Abdominal discomfort Abdominal pain Dyspeptic symptoms Loose stools PROAB3001* Antiretroviral Naïve Patients Agenerase / Lamivudine / Zidovudine (n = 113) 30% 10% 9% 7% 5% 4% 3% Lamivudine / Zidovudine (n = 109) 17% 4% 13% 6% PROAB3006** NRTI-Experienced Patients Agenerase/ NRTIs (n = 245) 10% 3% 3% 19% 4% 1% Indinavir / NRTIs (n = 241) 5% 4% 2% 5% 1% 5% 1% Skin Rash 18% 9% Neurological Headache Sleep disorders Tremors Oral/perioral paraesthesia 11% 2% <1% 12% 2% 0% 0% 4% - 2% 2% - 0% Psychiatry Mood disorders Depressive disorders 4% 2% 0% 0% - <1% - 0% Agenerase Issue 8 14

15 Non site specific Fatigue Anorexia 10% 2% 7% 3% 2% 2% 0% *Based on Week 16 data **Based on week 48 data Symptoms of abnormal fat redistribution were infrequent 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). In children, the adverse event profile was comparable to that observed in adults. The following table summarises all adverse events reported in a Phase III clinical trial in children aged 3 to 17 years. Percentage of Paediatric Patients with 2% Treatment-Emergent Drug-Related Adverse Events: PROAB3004 Adverse Event Placebo + NRTIs (n=12) AGENERASE + NRTIs (n=62) Digestive Nausea 3 (25%) 7 (11%) Vomiting 4 (33%) 8 (13%) Diarrhoea 1 (8%) 5 (8%) Loose Stools 0 4 (6%) Abdominal pain 0 3 (5%) Abdominal discomfort 0 1 (2%) Nervous Headaches 2 (17%) 1 (2%) Dizziness 1 (8%) 0 Skin Rash 1 (8%) 0 Haematology Thrombocytopenia 0 1 (2%) Urinary Tract Urinary tract haemorrhage 0 1 (2%) Non-site specific Fever 0 2 (3%) Anaemia 0 1 (2%) Increased hair growth 0 1 (2%) Malaise 1 (8%) 0 Post- marketing experience: No significant safety issues have been identified during postmarketing experience with amprenavir and no additional adverse events potentially related to amprenavir have been recognised that were not observed during the clinical trials (See Adverse Reactions detailed above). 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 Agenerase Issue 8 15

16 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 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, *abnormal fat distribution (see 4.4 Special Warnings and Special Precautions for Use) Uncommon: *Hyperglycaemia, *hypercholesterolaemia *Elevated triglycerides and hyperglycaemia (grade 3-4) were reported primarily in patients with abnormal values at baseline. *Elevations in cholesterol were of grade 3-4 intensity. *In clinical studies involving antiretroviral naïve patients, abnormal fat distribution was uncommon, after a median duration of 36 weeks exposure. Nervous system disorders Very common: *Headache Common *Oral/perioral paraesthesia Gastrointestinal disorders: Very Common: *Diarrhoea, *nausea, *flatulence, *vomiting Hepatobiliary Disorders Common: *Elevated transaminases *Elevated transaminases (grade 3-4) were reported primarily in patients with abnormal values at baseline. Skin and subcutaneous tissue disorders Very common: *Rash Rare: *Stevens Johnson syndrome Rash generally occurred during the second week of treatment and usually resolved spontaneously within two weeks, without stopping Agenerase. *However, occasionally the rash may be severe. Only 3% of patients discontinued Agenerase due to a rash. General disorders and administration site conditions Very common: *Fatigue DOSAGE AND ADMINISTRATION: Plasma concentrations of amprenavir are reduced when taken with food (high fat meal reduces AUC and Cmax by 14-25% and 40% respectively). Agenerase may be taken with or without food (see Pharmacokinetic, Absorption). Agenerase is available as 50 mg and 150 mg capsule formulations or as an oral solution for use in children or adults unable to swallow capsules. The oral solution at equivalent doses is less bioavailable compared to the capsules (AUC and Cmax 14% and 18% lower respectively). Therefore, Agenerase capsules and Agenerase oral solution are not interchangeable on a milligram per milligram basis. Agenerase Issue 8 16

17 Patients should discontinue Agenerase oral solution as soon as they are able to take the capsule formulation. (See Precautions). Adults and adolescents (from 13 years or over)(greater than 50 kg body weight): - Agenerase capsules: The recommended dose of Agenerase is 1200 mg twice daily in combination with other antiretroviral agents. If Agenerase capsules are used in combination with ritonavir in adults, reduced doses of amprenavir (600 twice daily) and ritonavir (100 mg twice daily or 200 mg twice daily if efavirenz is included in the treatment regimen) are recommended (see Interactions with other Medicines). - Agenerase oral solution : For patients unable to swallow capsules the recommended dose is 1400 mg (93.3 ml) twice a day in combination with other antiretroviral agents. Children (4 years to 12 years) and subjects less than 50 kg body weight: - Agenerase capsules : the recommended dose is 20 mg/kg body weight twice a day, or 15 mg/kg three times a day, without exceeding a total daily dose of 2400 mg. - Agenerase oral solution : For patients unable to swallow capsules the recommended dose is 22.5 mg (1.5mL)/kg body weight twice a day, or 17 mg (1.1mL)/kg three times a day, in combination with other antiretroviral agents, without exceeding a total daily dose of 2800 mg. Children less than 4 years of age: Agenerase is not recommended for use in children less than 4 years of age (see Contraindications and Preclinical safety data). The pharmacokinetic interactions between Agenerase and low doses of ritonavir or other protease inhibitors have not yet been evaluated in children. Therefore, such combinations should be avoided in children. Elderly: The pharmacokinetics of amprenavir have not been studied in patients over 65 years of age (see Pharmacokinetics). Therapy should be initiated by a physician experienced in the management of HIV infection. Renal impairment: Agenerase oral solution is contraindicated in patients with renal failure (see Contraindications). Agenerase oral solution should be used with caution in patients with renal impairment (see Precautions). Hepatic impairment: Agenerase oral solution is contraindicated in patients with hepatic failure (see Contraindications). The principal route of metabolism and excretion of amprenavir is via the liver. Agenerase should be used with caution in patients with hepatic impairment. The dose of Agenerase capsules should be reduced to 450 mg twice a day for patients with moderate hepatic impairment and to 300 mg twice a day for patients with severe hepatic impairment (see Pharmacokinetics). The dose of Agenerase oral solution should be reduced to 513 mg (34mLs) twice a day for patients with moderate hepatic impairment and to 342 mg (23 mls) twice a day for patients with severe hepatic impairment. No dosage recommendation can be made in children with hepatic impairment. Agenerase Issue 8 17

18 OVERDOSAGE: There are limited reports of overdosage with Agenerase. If overdosage occurs the patient should be monitored for evidence of toxicity (see Adverse Reactions), and standard supportive treatment provided as necessary. Since amprenavir is highly protein bound, dialysis is unlikely to be helpful in reducing blood levels. In the event of overdosage with Agenerase oral solution monitoring and management of acid-base abnormalities is recommended because of the large amounts of propylene glycol in the formulation. Haemodialysis may be useful for removal of propylene glycol. PRESENTATION: Capsules: Agenerase capsules are supplied in white HDPE bottles containing 480 x 50 mg capsules or 240 x 150 mg capsules. Store below 30 C. Keep the container tightly closed. Agenerase capsules are oblong, opaque, and off-white to cream coloured. The 50 mg capsules are printed with GX CC1 and the 150 mg capsules with GX CC2. Agenerase capsules also contain gelatin, glycerol, d-sorbitol and sorbitans solution, titanium dioxide, red printing ink, d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), macrogol 400, propylene glycol Oral Solution: Agenerase oral solution is supplied in HDPE bottles containing 240 ml of oral solution. A 20 ml measuring cup is also included in the pack for measurement of the prescribed dose. Store below 25 C. The oral solution is a clear, pale yellow to yellow solution with grape flavouring. Each 1mL of solution contains 15 mg of amprenavir. Agenerase oral solution also contains propylene glycol (550mg/mL), macrogol 400, d-alpha tocopheryl polyethylene glycol 1000 succinate, acesulfame potassium, saccharin sodium, sodium chloride, artificial grape bubblegum flavour, natural peppermint flavour, menthol, citric acid, anhydrous, sodium citrate dihydrate, and purified water. NAME AND ADDRESS OF SPONSOR: GlaxoSmithKline Australia Pty Ltd 1061 Mountain Highway Boronia Victoria 3155 Agenerase is a trademark owned by the GlaxoSmithKline Group of Companies. Licensed from Vertex Pharmaceuticals Inc. Cambridge. MA Agenerase Issue 8 18