INFORMATION FOR HEALTH PROFESSIONALS
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Agenerase oral solution contains 15mg/mL of amprenavir.
Agenerase™ oral solution is a clear, pale yellow to yellow solution with grape flavouring.
Agenerase is indicated in combination with other antiretroviral agents for the treatment of Human Immunodeficiency Virus (HIV) infected patients.
Agenerase oral solution is administered orally and can be taken with or without food.
Therapy should be initiated by a physician experienced in the management of HIV infection.
Agenerase is also available as capsules. Amprenavir is 14 % less bioavailable from the Agenerase oral solution than from the capsules; therefore Agenerase capsules and Agenerase oral solution are not interchangeable on a milligram per milligram basis (see Pharmacokinetic Properties).
Patients should discontinue Agenerase oral solution as soon as they are able to take the capsule formulation (see Special Warnings and Special Precautions for Use).
Adults and adolescents (from 13 years of age) (greater than 50kg body weight) unable to swallow capsules : The recommended dose of Agenerase oral solution is 1400mg (93.3mL) twice daily in combination with other antiretroviral agents.
Children (4 to 12 years) and subjects less than 50kg body weight unable to swallow capsules : The recommended dose of Agenerase oral solution is 22.5mg (1.5mL)/kg body weight twice a day, or 17mg (1.1mL)/kg three times a day, in combination with other antiretroviral agents, without exceeding a total daily dose of 2800mg.
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.
Children less than 4 years of age: Agenerase oral solution is contra-indicated for use in children less than 4 years of age. (see Contra-indications, Preclinical Safety Data).
Elderly: The pharmacokinetics of amprenavir have not been studied in patients over 65 years of age (see Pharmacokinetic Properties).
Renal impairment: Agenerase oral solution should be used with caution in patients with renal impairment (see Special Warnings and Special Precautions for Use).
Hepatic impairment: Agenerase oral solution should be used with caution in patients with hepatic impairment (see Special Warnings and Special Precautions for Use). The dose of Agenerase should be reduced to 513mg (34mLs) twice a day for adults with moderate hepatic impairment. For adults with severe hepatic impairment the dose should be reduced to 342mg (23mLs) twice a day (see Pharmacokinetic Properties). No dosage recommendation can be made in children with hepatic impairment.
Known hypersensitivity to amprenavir or any ingredient of Agenerase oral solution.
There is a potential risk of toxicity from the excipient propylene glycol. The ability to metabolise propylene glycol may not be fully developed in children less than four years of age. Children below the age of four years should not receive Agenerase oral solution (see Special Warnings and Special Precautions for Use and Pharmacokinetic Properties).
Agenerase must not be administered concurrently with medicinal products with narrow therapeutic windows that are substrates of cytochrome P450 3A4 (CYP 3A4). 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 (for example terfenadine, astemizole, cisapride, pimozide), prolonged sedation or respiratory depression (for example trizolam, midazolam) or peripheral vasospasm or ischaemia (for example ergot derivatives) (see Interaction with Other Medicinal Products and Other Forms of Interaction).
Rifampicin must not be administered concurrently with Agenerase. Rifampicin decreases the amprenavir plasma AUC by approximately 82% (see Interaction with Other Medicinal Products and Other Forms of Interaction).
As the principal route of metabolism of amprenavir and the propylene glycol excipient is via the liver, Agenerase oral solution should be used with caution in patients with hepatic impairment. The dose of Agenerase should be reduced in patients with moderate or severe hepatic impairment (see Posology and Method of Administration).
Children (4 years and above) and adults, particularly those with renal or hepatic impairment, or those with genetically lower levels of alcohol dehydrogenase (e.g. those of Japanese or Chinese origin) should be monitored for adverse reactions potentially related to the propylene glycol content (550mg/mL) of Agenerase oral solution such as 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 dehydrogenase activity (e.g. metronidazole) or preparations that contain alcohol or additional propylene glycol should be avoided (see Interaction with Other Medicinal Products and Other Forms of Interaction).
Amprenavir, like other HIV protease inhibitors is an inhibitor of the cytochrome P450 CYP3A4 enzyme. Agenerase should not be administered concurrently with medications with narrow therapeutic windows which are substrates of CYP3A4. There are also other agents that may result in serious and/or life-threatening drug interactions, therefore caution is advised whenever Agenerase is co-administered with medicinal products that are inducers, inhibitors or substrates of CYP3A4 (see Contra-indications and Interactions with Other Medicinal Products and Other Forms of Interaction).
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. Use the lowest possible dose of atorvastatin with careful monitoring or consider the use of pravastatin or fluvastatin as alternative HMG-CoA reductase inhibitors in combination with Agenerase.
Although the isozyme(s) responsible for bepridil metabolism has (have) not been elucidated, the metabolic pathways primarily responsible for bepridil metabolism are mediated by the CYP450 enzyme system. Because amprenavir is an inhibitor of the CYP 3A4 isozyme, the CYP450 isozyme most commonly responsible for drug metabolism, and because increased plasma bepridil exposure may increase the risk of life-threatening arrhythmia, caution is warranted when amprenavir and bepridil are coadministered.
Serious and/or life-threatening drug interactions could occur between amprenavir and amiodarone, lidocaine (systemic), tricyclic antidepressants, quinidine and warfarin. Concentration monitoring (warfarin - monitor International Normalised Ratio) of these agents is recommended as this should minimise the risk of potential safety problems with concomitant use.
Concomitant use of amprenavir and products containing Hypericum perforatum (also known as St John's Wort) is not recommended. A pharmacokinetic study with indinavir indicates that Hypericum perforatum may reduce amprenavir serum concentrations when administered concomitantly (see Interactions with Other Medicinal Products and Other Forms of Interaction).
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 methods of contraception are recommended for women of childbearing potential (see Interaction with Other Medicinal Products and Other Forms of Interaction).
The safety and efficacy of Agenerase in children less than 4 years of age has not yet been established (see Preclinical Safety Data).
Agenerase oral solution contains vitamin E (46IU/mL), therefore additional vitamin E supplementation is not recommended.
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.
Patients should be advised that Agenerase, or any other current antiretroviral therapy does not cure HIV, 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.
Amprenavir is primarily metabolised in the liver by the cytochrome P450 CYP 3A4 enzyme. Therefore, medicines that either share this metabolic pathway or modify CYP3A4 activity may modify the pharmacokinetics of amprenavir. Similarly, amprenavir might also modify the pharmacokinetics of other medicines that share this metabolic pathway.
Terfenadine, cisapride, pimozide or astemizole are contra-indicated in patients receiving Agenerase. Co-administration may result in competitive inhibition of metabolism of these products, leading to serious life threatening cardiac arrhythmias. 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. Agenerase should also not be co-administered with ergot derivatives (see Contra-indications).
Amprenavir has a low potential for clinically significant drug-drug interactions due to binding displacement. It is primarily bound to the alpha1 acid glycoprotein and binding displacement interactions with this protein are rare.
Drug interaction studies with a range of medicines likely to be co-administered with Agenerase have been performed and the results are shown in the following table.
| Pharmacokinetics for Amprenavir | Co-administered medicine |
Pharmacokinetics for co-administered drug | ||||
|---|---|---|---|---|---|---|
| Cmax | AUC | Cmin | Cmax | AUC | Cmin | |
| ↔ | ↔ | 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% |
| ↓ 16% | ↑ 32% | N/A | Ketoconazole | ↑ 19% | ↑ 44% | N/A |
| ↓ 70% | ↓ 82% | ↓ 92% | Rifampicin | ↔ | ↔ | ↔ |
| ↓ 7% | ↓ 15% | ↓ 15% | Rifabutin | ↑ 127% | ↑ 204% | ↑ 349% |
| N/A(1) | N/A(1) | N/A(1) | R-methadone (active) | ↓ 25% | ↓ 13% | ↔ |
| N/A(1) | N/A(1) | N/A(1) | S-methadone (inactive) | ↓ 48% | ↓ 40% | ↓ 23% |
| ↔ | ↓ 22% | ↓ 20% | Ethinyl estradiol norethindrome | ↔ | ↔ | ↑ 32% |
| ↑ 15% | ↑ 18% | ↑ 39% | Clarithromycin | ↓ 10% | ↔ | ↔ |
↑ = Increase; ↓ = Decrease; ↔ = no effect, N/A = Not available (1) - see Other potential interactions, Methadone, below.
When either zidovudine, lamivudine, abacavir, indinavir, saquinavir or nelfinavir are used in combination with Agenerase no dosage adjustments are considered necessary. Where pharmacokinetic changes were observed, as with indinavir, saquinavir and nelfinavir, antiviral efficacy was shown in clinical studies to be maintained.
Rifampicin reduces trough plasma concentration of amprenavir by approximately 80% and must not be used concurrently with Agenerase (see Contra-indications).
Co-administration of amprenavir with rifabutin results in a 200% increase in rifabutin plasma AUC, and an increase of rifabutin related adverse events. A dosage reduction of rifabutin of at least half the recommended dose is required, if it is clinically necessary to coadminister with Agenerase.
No dosage adjustment is considered necessary when ketoconazole or clarithromycin is administered with Agenerase.
Ritonavir: Co-administration of ritonavir with amprenavir results in a significant increase in the Cmin and AUC of amprenavir. When amprenavir capsules are given in combination with ritonavir in adults, reduced doses of both medicinal products should be used (see Posology and Method of Administration). In clinical practice doses of amprenavir 600mg twice daily and ritonavir 100mg twice daily are being used: evaluation of the safety and efficacy of these regimens is ongoing. Amprenavir oral solution and ritonavir oral solution should not be co-administered (see Special Warnings and Special Precautions for Use).
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs):
Efavirenz: efavirenz has been seen to decrease the Cmax, AUC, and Cmin,ss of amprenavir by approximately 40 % in adults. No dose recommendations can be given for the co-administration of amprenavir, with or without another protease inhibitor, and efavirenz.
Nevirapine: Based on its effect on other HIV protease inhibitors, nevirapine may decrease the serum concentrations of amprenavir.
Delavirdine: delavirdine may increase the serum concentrations of amprenavir.
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. The clinical significance of these potential interactions are unknown and have not been studied. Patients should therefore be monitored for toxicities associated with such drugs when these are used in combination with Agenerase.
Alcohol and Alcohol Dehyrogenase Inhibitors: Agenerase oral solution contains propylene glycol (550mg/mL), which is primarily metabolised via alcohol dehydrogenase. Therefore, concomitant administration with disulfiram or other medicinal products that reduce alcohol dehydrogenase activity (e.g. metronidazole) or 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.
Benzodiazepines: Alprazolam, clorazepate, diazepam, and flurazepam may have their serum concentrations increased by amprenavir, which could increase their activity.
Calcium channel blockers: Diltiazem, nicardipine, nifedipine, and nimodipine may have their serum concentrations increased by amprenavir, which could increase their activity.
HMG-CoA reductase inhibitors: Lovastitin, simvastatin, atorvastatin and to a lesser extent pravastatin and fluvastatin may have their serum concentrations increased by amprenavir, which could increase their activity or toxicity (see Specail Warnings and Special Precautions for Use).
Erectile dysfunction agents: Based on data for other protease inhibitors caution should be used when prescribing sildenafil to patients receiving amprenavir. Co-administration of amprenavir with sildenafil may substantially increase sildenafil plasma concentrations and may result in sildenafil-associated adverse events.
Methadone: Co-administration of amprenavir and methadone resulted in a 30%, 27% and 25% decrease in serum amprenavir AUC, Cmax, and Cmin, respectively, as compared to a non-matched historical control group.
Steroids: Oestrogens, progestogens, and some glucocorticoids may have an interaction with amprenavir but there is insufficient information to predict the nature of the interaction. Alternative 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 Special Warnings and Special Precautions for Use).
Caution should be used when amprenavir is coadministered with drugs known to induce CYP 3A4, such as phenobarbital, phenytoin, carbamazepine and dexamethasone. Induction of amprenavir (CYP 3A4) metabolism may result in reduced serum amprenavir concentrations.
Other agents: There are other agents that may have their plasma concentrations increased by amprenavir, and include but are not limited to: clozapine, cimetidine and loratadine. Cimetidine 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.
Pregnancy: Agenerase oral solution should not be used during pregnancy due to the potential risk of toxicity to the foetus from the propylene glycol content. If Agenerase is used during pregnancy, Agenerase capsules should be used. Placental transfer of amprenavir and/or its related metabolites has been shown to occur in animals.
In pregnant rats and rabbits there were no major effects on embryo-foetal development. A number of minor changes, including thymic elongation and minor skeletal variations were seen, indicating developmental delay. Systemic plasma exposure (AUC) to amprenavir in pregnant rabbits was significantly lower at all doses compared to plasma exposure found in patients in clinical studies.
Because animal reproduction studies are not always predictive of human response, this medicine should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Lactation: Amprenavir-related material was found in rat milk, but it is not known whether amprenavir is excreted in human milk. A reproduction study in pregnant rats dosed from the time of uterine implantation through lactation, showed reduced body weights in the offspring. The systemic exposure to the dams associated with this finding, was approximately twice the exposure in humans, following administration of the recommended dose. The subsequent development of these offspring, including fertility and reproductive performance, were not affected by the maternal administration of amprenavir (see Preclinical Safety Data).
It is therefore recommended that mothers being treated with Agenerase do not breast-feed their infants. Additionally, it is recommended by health experts that where possible, HIV infected women do not breast-feed their infants in order to avoid transmission of HIV.
No studies on the effects on ability to drive and use machines have been performed.
Adverse events have been reported during treatment with Agenerase. For many of these events it is unclear whether they are related to Agenerase, to concomitant treatment with the wide range of medicines 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. In children the emerging safety profile is similar in nature to that seen in adults.
From clinical studies, gastrointestinal events (nausea, diarrhoea, flatulence and vomiting) were the most commonly reported undesirable effects. There were also reports of oral/perioral paraesthesia, rash, headache and fatigue, which were considered to be related to treatment with Agenerase.
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 and cases of Stevens Johnson syndrome have been reported rarely. Only 3% of patients discontinued Agenerase due to a rash.
In clinical studies, reports of symptoms of abnormal fat redistribution were infrequent with amprenavir (less than 1% of antiretroviral naïve patients and less than 4% of NRTI-experienced patients).
Laboratory abnormalities occurred infrequently, and primarily in patients with abnormal values at baseline. Overall, the most frequently reported clinically significant laboratory abnormalities considered related to treatment with Agenerase were elevated transaminases and triglycerides.
There are limited reports of overdosage with Agenerase. If overdosage occurs the patient should be monitored for evidence of toxicity (see Undesirable Effects), and standard supportive treatment provided as necessary. Since amprenavir is highly protein bound, dialysis is unlikely to be helpful in reducing blood levels.
Pharmacotherapeutic group - protease inhibitor
Amprenavir is a non-peptidic competitive inhibitor of the HIV protease. It blocks the ability of the viral protease to cleave the precursor polyproteins necessary for viral replication. Protease inhibitors have exhibited greater potency against HIV in vitro, than the currently available nucleoside analogues that target HIV reverse transcriptase.
Amprenavir is a highly potent and selective inhibitor of HIV-1 and HIV-2 replication. It shows synergy in vitro in combination with nucleoside analogues including didanosine, zidovudine, abacavir and the protease inhibitor, saquinavir. It has been shown to be additive in combination with indinavir, ritonavir and nelfinavir.
Amprenavir resistant isolates of HIV have been selected in vitro. Under such conditions, at least three mutations were 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 IC50. The key mutation I50V, associated with resistance to amprenavir has not been observed as a natural variant, or in protease inhibitor therapy experienced patients. Little cross resistance has been observed between amprenavir selected resistant variants and other protease inhibitors, suggesting the potential for protease inhibitor salvage therapy. Other mutations associated with amprenavir resistance (I54V and I84V) have rarely been selected during amprenavir therapy.
The resistance profile seen with amprenavir is different from that observed with other protease inhibitors in clinical practice. In vitro, amprenavir-resistant isolates are highly susceptible to indinavir, saquinavir, and nelfinavir, but show reduced susceptibility to ritonavir. From 55 clinical isolates with mutations conferring resistance to the protease inhibitors in vivo, 55% were sensitive to amprenavir.
Cross resistance should not occur between amprenavir and reverse transcriptase inhibitors, because the enzyme targets are different.
Clinical experience
Agenerase in combination with other antiretroviral agents including nucleoside analogues, non-nucleoside analogues and protease inhibitors, has been shown to be effective in the treatment of HIV infection in adults. In clinical studies in naïve patients, the efficacy of Agenerase in combination with zidovudine and lamivudine was superior to this combination alone. Antiviral effects comparable to those seen in adults have been observed in children. The efficacy of Agenerase has been demonstrated across the whole spectrum of HIV infection including early and late stage disease, in both antiretroviral naïve and experienced patients.
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 faeces, primarily as amprenavir metabolites. Following oral administration, the mean time (tmax) 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 (1200mg twice daily), the mean steady state Cmax of amprenavir from capsules is 5.36 (0.92-9.81)mcg/mL and the Cmin is 0.28 (0.12-0.51)mcg/mL. The mean AUC over a dosing interval of 12 hours is 18.46 (3.02-32.95)mcg.h/mL. The 50mg and 150mg capsules have been shown to be bioequivalent. The oral solution at equivalent doses is less bioavailable compared to the capsules, with an AUC and Cmax approximately 14% and 19% lower respectively. The clinical significance of this difference is likely to be minimal.
Administration of amprenavir with food has a modest effect on overall plasma concentrations (AUC), reducing the AUC of amprenavir by between 14-25% and reducing Cmax by approximately 33%. This finding is not considered to be clinically significant therefore Agenerase can be taken with or without food.
Distribution: The apparent volume of distribution is approximately 430 litres (6L/kg assuming a 70kg 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. It is primarily bound to the alpha1 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 drug concentration in the plasma, however the amount of unbound amprenavir, which is the active moiety, is likely to be unchanged.
Clinically significant binding displacement interactions involving medicines primarily bound to AAG are generally not observed. Therefore, drug-drug 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 medicines that are inducers, inhibitors or substrates of CYP3A4 must be used with caution when administered concurrently with Agenerase (see Contra-indications and Interaction with Other Medicinal Products and Other Forms of Interaction).
Elimination: The plasma elimination half-life of amprenavir ranges from 7.1 to 10.6 hours. Following multiple oral doses of amprenavir 1200mg 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 20mg/kg twice a day and 15mg/kg three times a day of Agenerase capsules, provided similar plasma concentrations compared to those obtained with 1200mg twice a day in adults.
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, concomittant disease or other medicine therapy.
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.
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 Posology and Method of Administration).
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.
In mature animals, amprenavir was generally well tolerated. The clinically relevant findings were restricted to the liver. 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 measurement 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.
Toxicity studies in young animals treated from four days old resulted in high mortality in both the control animals and those receiving amprenavir. These results show that young animals lack fully developed metabolic pathways, and could not metabolise or excrete amprenavir, or some components of the formulation. 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.
Propylene glycol
Macrogol 400
d-alpha Tocopheryl polyethylene glycol 1000 succinate
Acesulfame potassium
Saccharin sodium
Sodium chloride
Artificial grape bubblegum flavour
Natural peppermint flavour
Menthol
Anhydrous citric acid
Sodium citrate dihydrate
Purified water.
Not applicable.
24 months.
Do not store above 25°C.
White HDPE bottles containing 240mL of oral solution. A 20mL measuring cup is provided in the pack.
No special requirements.
Prescription Only Medicine
Provisional consent, under section 23 of the New Zealand Medicines Act 1981, has been granted for the distribution of Agenerase oral solution.
GlaxoSmithKline New Zealand Limiited
Quay Tower
Cnr Albert and Customs Streets
Downtown Auckland
NEW ZEALAND
Phone (09) 367 2900
Fax (09) 367 2506
Issue number: 05
Issue date: 4 December 2002
Agenerase™ is a trade mark of GlaxoSmithKline Group of Companies.