Agenerase Oral Solution (Amprenavir)
Amprenavir is a non-peptidic competitive inhibitor of HIV-1 protease. It blocks the ability of viral protease to process gag and gag-pol polyproteins necessary for viral replication.
Absorption and Bioavailability: Amprenavir was rapidly absorbed after oral administration in HIV-1-infected patients with a time to peak concentration (t max) typically between 1and 2hours after a single oral dose. The absolute oral bioavailability of amprenavir in humans has not been established.
Increases in the area under the plasma concentration versus time curve (AUC) after single oral doses between 150and 1200mg were slightly greater than dose-proportional. Increases in AUC were dose-proportional after 3weeks of dosing with doses from 300to 1200mg twice daily.
The relative bioavailability of amprenavir capsules and oral solution was assessed in healthy adults. Amprenavir oral solution was 14% less bioavailable compared to the capsules.
Effects of Food on Oral Absorption: The relative bioavailability of amprenavir capsules was assessed in the fasting and fed states in healthy volunteers (standardized high-fat meal: 967kcal, 67g fat, 33g protein, 58g carbohydrate). Administration of a single 1200mg dose of amprenavir in the fed state compared to the fasted state was associated with changes in C max (fed: 6.18±2.92µg/mL, fasted: 9.72±2.75µg/mL), T max (fed: 1.51±0.68h, fasted 1.05±0.63h), and AUC (fed: 22.06±11.6µg.h/mL, fasted: 28.05±10.1µg.h/mL). Amprenavir may be taken with or without food, but should not be taken with a high-fat meal (see Dosage).
Agenerase oral solution contains a large amount of propylene glycol, which is hepatically metabolized by the alcohol and aldehyde dehydrogenase enzyme pathway. Alcohol dehydrogenase (ADH) is present in the human fetal liver at 2months of gestational age, but at only 3% of adult activity. Although the data are limited, it appears that by 12to 30months of postnatal age, ADH activity is equal to or greater than that observed in adults. Additionally, certain patient groups (females, patients of Asian origin, Aboriginals) may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol (see Pharmacology, Special Populations, Gender).
Special Populations: Adults with Impaired Renal Function: Amprenavir oral solution is contraindicated in patients with renal failure.
Patients with renal impairment are at increased risk of propylene glycol-associated adverse events. Additionally, because metabolites of the excipient propylene glycol in amprenavir oral solution may alter acid-base balance, patients with renal impairment should be monitored for potential adverse events (see Warnings). Amprenavir oral solution should be used with caution in patients with renal impairment. The impact of renal impairment on amprenavir elimination has not been studied. The renal elimination of unchanged amprenavir represents <3% of the administered dose.
Adults with Impaired Hepatic Function: Amprenavir oral solution is contraindicated in patients with hepatic failure.
Patients with hepatic impairment are at increased risk of propylene glycol-associated adverse events (see Warnings). Amprenavir oral solution should be used with caution in patients with hepatic impairment. Amprenavir capsules have been studied in adult patients with impaired hepatic function using a single 600mg oral dose. The AUC 0Ã¥ was significantly greater in patients with moderate cirrhosis (25.76±14.68µg.h/mL) compared with healthy volunteers (12.00±4.38µg.h/mL). The AUC 0Ã¥ and C max were significantly greater in patients with severe cirrhosis (AUC 0Ã¥: 38.66±16.08µg.h/mL; C max: 9.43±2.61µg/mL) compared with healthy volunteers (AUC 0Ã¥: 12.00±4.38µg.h/mL; C max: 4.90±1.39µg/mL). Patients with impaired hepatic function require dosage adjustment (see Dosage).
Pediatric Patients: Agenerase oral solution is contraindicated in infants and children below 4years of age (see Contraindications and Warnings).
The pharmacokinetics of amprenavir have been studied after either single or repeat doses of amprenavir capsules or oral solution in 84pediatric patients. Twenty HIV-1-infected children ranging in age from 4to 12years received single doses from 5mg/kg to 20mg/kg using 25mg or 150mg capsules. The C max of amprenavir increased less than proportionally with dose. The AUC 0Ã¥ increased proportionally at doses between 5and 20mg/kg. Amprenavir is 14% less bioavailable from the liquid formulation than from the capsules; therefore amprenavir capsules and amprenavir oral solution are not interchangeable on a mg/mg basis.
Geriatric Patients: The pharmacokinetics of amprenavir have not been studied in patients over 65years of age.
Gender: The pharmacokinetics of amprenavir do not differ in males and females. Females may have a lower amount of alcohol dehydrogenase compared with males and may be at increased risk of propylene glycol-associated adverse events; no data are available on propylene glycol metabolism in females.
Amprenavir Is A Non-peptidic Competitive Inhibitor Of HIV-1 Protease. It Blocks The Ability Of Viral Protease To Process Gag And Gag-pol Polyproteins Necessary For Viral Replication.
Absorption And Bioavailability: Amprenavir Was Rapidly Absorbed After Oral Administration In HIV-1-infected Patients With A Time To Peak Concentration (t Max) Typically Between 1and 2hours After A Single Oral Dose. The Absolute Oral Bioavailability Of Amprenavir In Humans Has Not Been Established.
Increases In The Area Under The Plasma Concentration Versus Time Curve (AUC) After Single Oral Doses Between 150and 1200mg Were Slightly Greater Than Dose-proportional. Increases In AUC Were Dose-proportional After 3weeks Of Dosing With Doses From 300to 1200mg Twice Daily.
The Relative Bioavailability Of Amprenavir Capsules And Oral Solution Was Assessed In Healthy Adults. Amprenavir Oral Solution Was 14% Less Bioavailable Compared To The Capsules.
Effects Of Food On Oral Absorption: The Relative Bioavailability Of Amprenavir Capsules Was Assessed In The Fasting And Fed States In Healthy Volunteers (standardized High-fat Meal: 967kcal, 67g Fat, 33g Protein, 58g Carbohydrate). Administration Of A Single 1200mg Dose Of Amprenavir In The Fed State Compared To The Fasted State Was Associated With Changes In C Max (fed: 6.18±2.92µg/mL, Fasted: 9.72±2.75µg/mL), T Max (fed: 1.51±0.68h, Fasted 1.05±0.63h), And AUC (fed: 22.06±11.6µg.h/mL, Fasted: 28.05±10.1µg.h/mL). Amprenavir May Be Taken With Or Without Food, But Should Not Be Taken With A High-fat Meal (see Dosage).
Agenerase Oral Solution Contains A Large Amount Of Propylene Glycol, Which Is Hepatically Metabolized By The Alcohol And Aldehyde Dehydrogenase Enzyme Pathway. Alcohol Dehydrogenase (ADH) Is Present In The Human Fetal Liver At 2months Of Gestational Age, But At Only 3% Of Adult Activity. Although The Data Are Limited, It Appears That By 12to 30months Of Postnatal Age, ADH Activity Is Equal To Or Greater Than That Observed In Adults. Additionally, Certain Patient Groups (females, Patients Of Asian Origin, Aboriginals) May Be At Increased Risk Of Propylene Glycol-associated Adverse Events Due To Diminished Ability To Metabolize Propylene Glycol (see Pharmacology, Special Populations, Gender).
Special Populations: Adults With Impaired Renal Function: Amprenavir Oral Solution Is Contraindicated In Patients With Renal Failure.
Patients With Renal Impairment Are At Increased Risk Of Propylene Glycol-associated Adverse Events. Additionally, Because Metabolites Of The Excipient Propylene Glycol In Amprenavir Oral Solution May Alter Acid-base Balance, Patients With Renal Impairment Should Be Monitored For Potential Adverse Events (see Warnings). Amprenavir Oral Solution Should Be Used With Caution In Patients With Renal Impairment. The Impact Of Renal Impairment On Amprenavir Elimination Has Not Been Studied. The Renal Elimination Of Unchanged Amprenavir Represents <3% Of The Administered Dose.
Adults With Impaired Hepatic Function: Amprenavir Oral Solution Is Contraindicated In Patients With Hepatic Failure.
Patients With Hepatic Impairment Are At Increased Risk Of Propylene Glycol-associated Adverse Events (see Warnings). Amprenavir Oral Solution Should Be Used With Caution In Patients With Hepatic Impairment. Amprenavir Capsules Have Been Studied In Adult Patients With Impaired Hepatic Function Using A Single 600mg Oral Dose. The AUC 0Ã¥ Was Significantly Greater In Patients With Moderate Cirrhosis (25.76±14.68µg.h/mL) Compared With Healthy Volunteers (12.00±4.38µg.h/mL). The AUC 0Ã¥ And C Max Were Significantly Greater In Patients With Severe Cirrhosis (AUC 0Ã¥: 38.66±16.08µg.h/mL; C Max: 9.43±2.61µg/mL) Compared With Healthy Volunteers (AUC 0Ã¥: 12.00±4.38µg.h/mL; C Max: 4.90±1.39µg/mL). Patients With Impaired Hepatic Function Require Dosage Adjustment (see Dosage).
Pediatric Patients: Agenerase Oral Solution Is Contraindicated In Infants And Children Below 4years Of Age (see Contraindications And Warnings).
The Pharmacokinetics Of Amprenavir Have Been Studied After Either Single Or Repeat Doses Of Amprenavir Capsules Or Oral Solution In 84pediatric Patients. Twenty HIV-1-infected Children Ranging In Age From 4to 12years Received Single Doses From 5mg/kg To 20mg/kg Using 25mg Or 150mg Capsules. The C Max Of Amprenavir Increased Less Than Proportionally With Dose. The AUC 0Ã¥ Increased Proportionally At Doses Between 5and 20mg/kg. Amprenavir Is 14% Less Bioavailable From The Liquid Formulation Than From The Capsules; Therefore Amprenavir Capsules And Amprenavir Oral Solution Are Not Interchangeable On A Mg/mg Basis.
Geriatric Patients: The Pharmacokinetics Of Amprenavir Have Not Been Studied In Patients Over 65years Of Age.
Gender: The Pharmacokinetics Of Amprenavir Do Not Differ In Males And Females. Females May Have A Lower Amount Of Alcohol Dehydrogenase Compared With Males And May Be At Increased Risk Of Propylene Glycol-associated Adverse Events; No Data Are Available On Propylene Glycol Metabolism In Females.
Contraindications: Because of potential risk of toxicity from the large amount of the excipient propylene glycol Agenerase oral solution is contraindicated in infants and children below the age of 4years, pregnant women, patients with hepatic or renal failure, and patients treated with disulfiram or metronidazole (see Warnings and Precautions).
Amprenavir oral solution should not be administered concurrently with astemizole, cisapride, diazepam, dihydroergotamine, ergotamine, flurazepam, midazolam, pimozide, terfenadine, or triazolam. Although these drugs have not been specifically studied, coadministration may result in competitive inhibition of metabolism of these products and may cause serious or life-threatening adverse events.
Amprenavir should not be given with rifampin. Rifampin reduces trough plasma concentrations of amprenavir by approximately 92%.
Amprenavir is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the products.
Because of the 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 inhibitor formulations are not therapeutic options. Certain ethnic populations (patients of Asian origin, Aboriginals) and women may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol; no data are available on propylene glycol metabolism in these groups.
If patients require treatment with Agenerase oral solution, they should be monitored closely for propylene glycol-associated adverse events, including seizures, stupor, tachycardia, hyperosmolality, lactic acidosis, renal toxicity, and hemolysis. Patients should be switched from amprenavir oral solution to amprenavir capsules as soon as they are able to take the capsule formulation.
Use of alcoholic beverages is not recommended in patients treated with amprenavir oral solution.
Serious and/or life-threatening drug interactions could occur between amprenavir and amiodarone, lidocaine (systemic), tricyclic antidepressants, quinidine or warfarin (monitorINR). Concentration monitoring of these agents is recommended if these agents are used concomitantly with amprenavir. Phenobarbital and phenytoin may decrease amprenavir concentrations.
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between protease inhibitor therapy and these events have not been established.
HMG-CoA reductase inhibitors (statins) may interact with protease inhibitors and increase the risk of myopathy including rhabdomyolysis. Concomitant use of protease inhibitors with lovastatin or simvastatin is not recommended. Other HMG-CoA reductase inhibitors (statins) may also interact with protease inhibitors. This warning is based on clinical reports, and on indirect evidence from studies on the cytochrome P450CYP3A4 metabolism pathway.
Particular caution should be used when prescribing sildenafil in patients receiving protease inhibitors, including amprenavir. Coadministration of protease inhibitors with sildenafil is expected to substantially increase sildenafil concentrations and may result in an increase in sildenafil-associated adverse events, including hypotension, visual changes, and priapism (see Precautions, Information to Be Provided to the Patient, Drug Interactions and the complete prescribing information for sildenafil).
Concomitant use of St.John's wort (Hypericum perforatum) or St.John's wort-containing products and amprenavir is not recommended. Coadministration of St.John's wort with protease inhibitors, including amprenavir, is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of amprenavir and lead to loss of virologic response and possible resistance to amprenavir or the class of protease inhibitors.
Patients taking the oral solution of Agenerase, particularly those with renal impairment or those with decreased ability to metabolize propylene glycol (e.g., patients of Asian origin), should be monitored for adverse reactions potentially related to the high propylene glycol content (550mg/mL), such as seizures, stupor, tachycardia, hyperosmolarity, lactic acidosis, renal toxicity, hemolysis. For patients with renal or hepatic failure, children and pregnant women see Contraindications. 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 (e.g., ritonavir oral solution) or additional propylene glycol should be avoided (see Precautions, Drug Interactions, Other Possible Interactions).
Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, have occurred in patients treated with amprenavir (see Adverse Effects).
Acute hemolytic anemia has been reported in a patient treated with amprenavir.
General: Formulations of Agenerase provide high daily doses of vitaminE. The effects of long-term, high-dose vitaminE administration in humans is not well characterized and has not been specifically studied in HIV-infected individuals. High vitaminE doses may exacerbate the blood coagulation defect of vitaminK deficiency caused by anticoagulant therapy or malabsorption. Each mL of Agenerase oral solution contains 46IU vitaminE. The maximum daily dose of Agenerase oral solution corresponds to vitaminE intake of approximately 8600IU/day.
Amprenavir capsules and oral solution are not interchangeable on a mg/mg basis.
Amprenavir is a sulfonamide. The potential for cross-sensitivity between drugs in the sulfonamide class and amprenavir is unknown. Patients with a known sulfonamide allergy should be treated with caution.
Amprenavir is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment.
Preliminary data from long-term carcinogenicity studies with amprenavir has revealed histopathological evidence for hepatocellular adenomas in both male mice and rats, and hepatocellular carcinomas have been seen in male mice only. The clinical relevance of these findings is unknown.
Patients with Hemophilia: There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthroses, in hemophiliac patients typeA andB treated with protease inhibitors. In some patients additional factorVIII 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. Hemophiliac patients should therefore be made aware of the possibility of increased bleeding.
Fat Redistribution: Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and “cushingoid appearance”, have been observed in patients receiving antiretroviral therapies. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Contraceptives: Because of the potential for metabolic interactions with amprenavir, the efficacy of hormonal contraceptives may be reduced. Therefore, additional reliable barrier methods of contraception are recommended for women of childbearing potential.
Resistance/Cross-resistance: Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored, it is unknown what effect amprenavir therapy will have on the activity of subsequently administered protease inhibitors.
Information to Be Provided to the Patient: Amprenavir oral solution is contraindicated in infants and children below the age of 4years, pregnant women, patients with hepatic or renal failure, and patients treated with disulfiram or metronidazole.
Agenerase oral solution should be used only when Agenerase capsules or other protease inhibitor formulations are not therapeutic options.
Patients treated with Agenerase capsules should be cautioned against switching to Agenerase oral solution because of the increased risk of adverse events from the large amount of propylene glycol in Agenerase oral solution.
Women, patients of Asian origin, Aboriginals, as well as patients who have hepatic or renal insufficiency, should be informed that they may be at increased risk of adverse events from the large amount of propylene glycol in Agenerase oral solution.
Patients should inform their doctor if they have a sulfa allergy. The potential for cross-sensitivity between drugs in the sulfonamide class and amprenavir is unknown.
Patients should be advised of the importance of taking amprenavir exactly as prescribed. Amprenavir must always be used in combination with other antiretroviral drugs. Amprenavir is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including opportunistic infections. Patients should be advised that the use of amprenavir has not been shown to reduce the risk of transmission of HIV. Patients should remain under the care of a physician when using amprenavir. The long-term effects of amprenavir are unknown at this time.
Amprenavir oral solution is for oral ingestion only.
Amprenavir may interact with some drugs, therefore, patients should be advised to report to their doctor the use of any other prescription or non-prescription medication.
Patients taking antacids (or didanosine) should take amprenavir at least 1hour before or after antacid (or didanosine) use.
Patients should be advised that drinking alcoholic beverages is not recommended while taking amprenavir oral solution.
Patients receiving sildenafil should be advised that they may be at an increased risk of sildenafil-associated adverse events, including hypotension, visual changes, and priapism, and should promptly report any symptoms to their doctor.
Patients receiving hormonal contraceptives should be instructed that alternate contraceptive measures should be used during therapy with amprenavir.
High-fat meals may decrease the absorption of amprenavir and should be avoided. Amprenavir may be taken with meals of normal fat content.
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time.
Agenerase oral solution contains vitaminE (46IU/mL), therefore additional vitaminE supplementation is not recommended.
Geriatrics: Clinical studies of amprenavir did not include sufficient numbers of patients aged65 and over to determine whether they respond differently from younger adults. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Children: Agenerase oral solution is contraindicated in infants and children below the age of 4years due to the potential risk of toxicity from the excipient propylene glycol (see Contraindications and Warnings). Alcohol dehydrogenase (ADH), which metabolizes propylene glycol, is present in the human fetal liver at 2months of gestational age, but at only 3% of adult activity. Although the data are limited, it appears that by 12to 30months of postnatal age, ADH activity is equal to or greater than that observed in adults.
One hundred and eighteen patients 4to 17years of age have received amprenavir as single or multiple doses in PhaseI toIII studies. An adverse event profile similar to that seen in adults was seen in pediatric patients.
The safety, effectiveness, and pharmacokinetics of amprenavir have not been evaluated in pediatric patients below the age of 4years.
Pregnancy and Reproduction: Agenerase oral solution is contraindicated during pregnancy due to the potential risk of toxicity to the fetus from the high propylene glycol content. Therefore, if Agenerase is used in pregnant women, the Agenerase capsule formulation should be used (see Product Monograph for Agenerase capsules).
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to amprenavir, an antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling GlaxoSmithKline's Drug Surveillance Department (1-800-387-7374).
Lactation: Although it is not known if amprenavir is excreted in human milk, amprenavir is secreted into the milk of lactating rats. Because of both the potential for HIV transmission and possible adverse effects of amprenavir, mothers should be instructed not to breast-feed if they are receiving amprenavir.
Drug Interactions : Amprenavir is metabolized in the liver by the cytochromeP450 enzyme system. Amprenavir inhibitsCYP3A4. Caution should be used when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4. Amprenavir 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.
Amprenavir oral solution and ritonavir oral solution should not be coadministered.
Nucleoside analogue reverse transcriptase inhibitors (NRTIs): Didanosine: No pharmacokinetic study has been performed with amprenavir in combination with didanosine, however, due to its antacid component, it is recommended that didanosine and amprenavir should be administered at least 1hour apart.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs): NNRTIs have the potential to increase (delavirdine) or decrease (efavirenz, nevirapine) serum concentrations of amprenavir.
Antibiotics/Antifungals: Dapsone and Erythromycin: Dapsone and erythromycin may have their plasma concentrations increased by amprenavir. Erythromycin may also increase amprenavir serum concentrations.
Itraconazole: Itraconazole may have its plasma concentrations increased by amprenavir. Itraconazole may increase serum concentrations of amprenavir.
Rifampin: Rifampin should not be used in combination with amprenavir since it reduces plasma concentrations and AUC of amprenavir by approximately 92% (see Contraindications).
Rifabutin: Coadministration of amprenavir with rifabutin results in a 15% decrease in amprenavir plasma AUC and a 193% increase in rifabutin plasma AUC. A dosage reduction of rifabutin to at least half the recommended dose is required when amprenavir and rifabutin are coadministered. A complete blood count should be performed weekly and as clinically indicated in order to monitor for neutropenia in patients receiving amprenavir and rifabutin.
Other Possible Interactions : Other medications listed below are examples of substrates, inhibitors, or inducers of CYP3A4 that could have potential interactions, when used concomitantly with amprenavir. 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 amprenavir.
Alcohol and inhibitors of alcohol metabolism: Agenerase oral solution contains propylene glycol (550mg/mL), which is primarily metabolized via alcohol dehydrogenase. Therefore, concomitant administration with disulfiram or other medicinal products that reduce alcohol metabolism (e.g., metronidazole) or preparations that contain alcohol (e.g., ritonavir oral solution) or propylene glycol should not be coadministered with Agenerase oral solution (see Contraindications and Warnings).
Use of alcoholic beverages is not recommended in patients treated with Agenerase oral solution.
Antacids: Antacids (and didanosine secondary to the 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 amprenavir because of potential interference with absorption. It is recommended that their administration be separated by at least 1hour.
Benzodiazepines: Alprazolam, clorazepate, diazepam, and flurazepam, midazolam and triazolam 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.
Cholesterol-lowering Agents: HMG-CoA reductase inhibitors (statins) may interact with protease inhibitors and increase the risk of myopathy including rhabdomyolysis. Concomitant use of protease inhibitors with lovastatin or simvastatin is not recommended. Other HMGCoA reductase inhibitors (statins), may also interact with protease inhibitors. This warning is based on clinical reports, and on indirect evidence from studies on the cytochrome P450CYP3A4 metabolism pathway.
Erectile Dysfunction Agents: Based on data for other protease inhibitors caution should be used when prescribing sildenafil to patients receiving amprenavir. Coadministration of amprenavir with sildenafil may substantially increase sildenafil plasma concentrations and may result in sildenafil-associated adverse events.
Methadone and Opiate Derivatives: Patients treated with methadone and opiate derivatives should be monitored carefully as the concurrent administration of amprenavir and opiate derivatives may result in a significant interaction.
Steroids: 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: Patients on amprenavir should not use products containing St.John's Wort (Hypericum perforatum) since it may result in reduced plasma concentrations of amprenavir (see Warnings).
Other Agents: There are other agents that may have their plasma concentrations increased by amprenavir, and include but are not limited to: clozapine, carbamazepine, loratadine, pimozide, and warfarin. Cimetidine may increase amprenavir plasma concentrations.
Rates of discontinuation of randomized therapy due to adverse events were 15% in amprenavir vs 3% in placebo recipients from Study3001, and 16% in amprenavir vs 8% in indinavir recipients from Study3006. In these studies, adverse events leading to amprenavir discontinuation included gastrointestinal events (11%), rash (3%), and paresthesias (<1%).
Most gastrointestinal events (nausea, vomiting, diarrhea, and abdominal pain) that led to amprenavir discontinuation were graded as mild or moderate in severity.
In all multidose studies in HIV-infected patients, skin rash occurred in 28% of patients treated with amprenavir. Rashes were usually maculopapular and of mild or moderate intensity, some with pruritus. Rashes had onsets ranging from 7to 73days (median: 10days) after amprenavir initiation. With mild or moderate rash, amprenavir dosing was often continued without interruption; if interrupted, reintroduction of amprenavir generally did not result in rash recurrence (PhaseIII studies).
Severe or life-threatening rash, including Stevens-Johnson syndrome, occurred in 1% of recipients of amprenavir (4% of recipients who developed rash) (see Warnings). Amprenavir therapy should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms.
The most frequent clinical adverse events related to study drugs, of at least moderate intensity (Grade2 or more), reported in 2large clinical studies in adults are summarized in TableII. All events reported in at least 1% of subjects treated with amprenavir are included.
Symptoms of abnormal fat redistribution were infrequent with amprenavir. In study PROAB3001 only 1case (a buffalo hump) was reported in 113 (<1%) antiretroviral naïve subjects treated with amprenavir in combination with lamivudine/zidovudine for a median duration of 36weeks. In study PROAB3006, 7cases (3%) were reported in 245 NRTI-experienced subjects treated with amprenavir and in 27 (11%) of 241subjects treated with indinavir, in combination with various NRTIs for a median duration of 56weeks (p<0.001).
In phaseIII trials, in combination with various NRTIs, the most frequent treatment-emergent laboratory abnormalities (Grade2 or more) were elevated transaminases (5%), hypertriglyceridemia (4%), elevated amylase (2.5%), hyperbilirubinemia (<1%) and hyperglycemia (<1%); almost all subjects with abnormal liver function tests were coinfected with HepatitisB orC virus.
Increased CPK, myalgia, myositis and infrequently rhabdomyolysis have been reported with protease inhibitors particularly in combination with nucleoside analogues.
Symptoms and Treatment: There is no known antidote for amprenavir. It is not known whether amprenavir can be removed by peritoneal dialysis or hemodialysis. If overdosage occurs, the patient should be monitored for evidence of toxicity and standard supportive treatment applied as necessary.
Agenerase oral solution contains large amounts of propylene glycol. In the event of overdosage, monitoring and management of acid-base abnormalities is recommended. Propylene glycol can be removed by hemodialysis.
Amprenavir can be taken with or without food; however, a high-fat meal decreases the absorption of amprenavir and should be avoided.
Each mL of Agenerase oral solution contains 46IU vitaminE. The maximum daily dose of Agenerase oral solution corresponds to vitaminE intake of approximately 8600IU/day.
Propylene glycol is included in the oral solution formulation to achieve adequate solubility of amprenavir. The recommended daily dose of Agenerase oral solution of 22.5mg/kg twice daily corresponds to a propylene glycol intake of 1650mg/kg/day. Acceptable intake of propylene glycol for pharmaceuticals has not been established.
Patients unable to swallow amprenavir capsules: The recommended dose of amprenavir oral solution is 22.5mg (1.5mL)/kg twice a day or 17mg (1.1mL)/kg 3 times a day, in combination with other antiretroviral agents, without exceeding a total daily dose of 2800mg.
The pharmacokinetic interactions between amprenavir and low doses of ritonavir or other protease inhibitors, have not been evaluated in children. Therefore, such combinations should be avoided in children.
Children <4years: Amprenavir is not recommended in children <4years of age.
Patients with Hepatic Impairment: Amprenavir oral solution is contraindicated in patients with hepatic failure.
Patients with hepatic impairment are at increased risk of propylene glycol-associated adverse events (see Warnings). Amprenavir oral solution should be used with caution in patients with hepatic impairment. Based on a study with amprenavir capsules, adult patients with a Child-Pugh score ranging from 5 to 8 should receive a reduced dose of amprenavir oral solution of 513mg (34mL) twice daily, and adult patients with a Child-Pugh score ranging from 9 to 12 should receive a reduced dose of amprenavir oral solution of 342mg (23mL) twice daily.
Amprenavir oral solution has not been studied in children with hepatic impairment.
Patients with Renal Impairment: Amprenavir oral solution is contraindicated in patients with renal failure (see Contraindications).
Patients with renal impairment are at increased risk of propylene glycol-associated adverse events. Amprenavir oral solution should be used with caution in patients with renal impairment (see Warnings).
Amprenavir capsules and oral solution are not interchangeable on a mg/mg basis.
Information for the Patient: See Blue Section--Information for the Patient “Agenerase Oral Solution”.
Each mL of clear, pale yellow to yellow, grape/bubblegum flavored solution contains: amprenavir 15mg. Nonmedicinal ingredients: acesulfame potassium, artificial grape/bubblegum flavor, citric acid (anhydrous), d-alpha tocopheryl polyethylene glycol1000 succinate (TPGS), menthol, natural peppermint flavor, polyethylene glycol400 (PEG400), propylene glycol, saccharin sodium, sodium chloride and sodium citrate (dihydrate). Bottles of 240mL. Store between 5 and 25°C.
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