LEXIVA (Brand for FOSAMPRENAVIR CALCIUM)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
-Tablets: May be taken with or without food.

Oral Liquid Formulations
-Oral Solution: Administer to pediatric patients with food. If emesis occurs within 30 minutes of administration, re-administer the dose. Shake vigorously before measuring a dose. Administer using a calibrated oral dosing syringe or dosing cup.

Among the most common treatment-emergent adverse events in general clinical trials of fosamprenavir was diarrhea (5%-13% adults). Additionally, diarrhea was among the most common adverse events leading to treatment discontinuation in clinical trials (<= 1% of patients discontinued treatment due to adverse events). In general, adverse events occurred with similar frequency in pediatric patients as compared to adults.

Among the most common treatment-emergent adverse events in clinical trials of fosamprenavir were nausea and vomiting. In pediatric clinical trials, the reported adverse events were similar in frequency to adult reported adverse events except for vomiting. Vomiting was reported 20% of patients 4 weeks to < 2 years and in 36% of patients 2 to 18 years old who received fosamprenavir/ritonavir as well as in in 60% of patients 2 to 5 years old who received fosamprenavir alone. Vomiting was the treatment-limiting adverse event in 4 children. Nausea was reported in 3-7% of adult patients. Additionally, nausea and vomiting were among the most common adverse events leading to treatment discontinuation in clinical trials (<= 1% of patients discontinued treatment due to adverse events).

In general, adverse events occurred with similar frequency in pediatric patients as compared to adults during fosamprenavir trials. Headache was reported in 2-4% of adult patients in clinical trials.

In general, adverse events occurred with similar frequency in pediatric patients as compared to adults during fosamprenavir trials. Among the most common treatment-emergent adverse events in clinical trials of fosamprenavir was rash (unspecified). Rash was among the most common adverse events leading to treatment discontinuation in clinical trials (<= 1% of patients discontinued treatment due to adverse events). Rash occurred, overall, in 19% of patients during clinical trials. Skin rashes usually consisted of mild to moderate maculopapular rash, sometimes associated with pruritus. Rash onset was typically 11 days after initiation and lasted approximately 13 days. Treatment was typically continued in patients with mild or moderate rash, and if treatment was interrupted, reintroduction generally did not result in rash recurrence. In clinical trials, severe and life threatening skin reactions have been reported, including 1 case of Stevens-Johnson syndrome (n = 700). Fosamprenavir should be discontinued if severe or life-threatening rashes or moderate rashes with systemic symptoms occur and should not be reinstituted.

Angioedema has been reported with fosamprenavir during post-marketing surveillance.

Myocardial infarction has been reported with fosamprenavir during postmarketing surveillance.

In general, adverse events occurred with similar frequency in pediatric patients as compared to adults during fosamprenavir trials. Abdominal pain (<= 2% adults) was among the GI related adverse event reported in clinical trials.

In general, adverse events occurred with similar frequency in pediatric patients as compared to adults during fosamprenavir trials. Central nervous system related adverse reactions were reported in adult clinical trials, including fatigue (2-4% adults). Oral paresthesias have been noted in post-marketing reports.

Grade 3 or 4 neutropenia (neutrophils < 750/mm3) was reported in 15% of pediatric patients treated with fosamprenavir with or without ritonavir. Neutropenia occurred in 10% of patients 4 weeks to < 2 years and in 16% of patients 2-18 years of age. In general, other adverse events occurred with similar frequency in pediatric patients as compared to adults during fosamprenavir trials. Lab abnormalities were reported during clinical trials. Elevated hepatic enzymes (4-8% adults), have been reported. Elevated hepatic enzymes, specifically increased AST and ALT, was among the most common adverse events leading to treatment discontinuation in clinical trials (<= 1% of patients discontinued treatment due to adverse events). Higher than recommended adult doses of fosamprenavir with ritonavir may result in increased hepatic enzymes. Patients with underlying hepatitis B or C may be at increased risk. Other lab abnormalities include serum lipase > 2xULN (5-8% adults) and hypertriglyceridemia (6-11% adults). Hypercholesterolemia has been noted in post-marketing reports. Triglyceride and cholesterol testing should be performed prior to initiation therapy and periodically throughout therapy.

Nephrolithiasis has been reported with fosamprenavir during post-marketing surveillance. Due to the nature of post-marketing reports, a true incidence or relationship to drug administration is difficult to determine; however, if signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy may be considered.

New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia have been reported with the use of protease inhibitors. In adult clinical trials, hyperglycemia was reported only in protease inhibitor-experienced patients treated with fosamprenavir/ritonavir at a rate of 2%. Diabetic ketoacidosis has also occurred with other protease inhibitors. Initiation or adjustment of hypoglycemic therapy is required in some patients after beginning protease inhibitor treatment. On average, 50% of patients who develop hyperglycemia discontinue their protease inhibitor therapy as a result of this adverse reaction. In some patients who have discontinued protease inhibitor therapy, hyperglycemia has persisted. Since these adverse events have been reported voluntarily as part of post-marketing surveillance, the exact incidence and actual relationship to protease inhibitor therapy cannot be established. It should also be noted that many of these patients have confounding medical conditions that require therapy with drugs that have been associated with the development of diabetes mellitus or hyperglycemia.

A lipodystrophy syndrome, consisting of redistribution/accumulation of body fat, has been reported in patients receiving protease inhibitors such as fosamprenavir. The mechanism and long-term consequences are not known. A causal relationship has not been established.

Hemolytic anemia has been reported in one patient treated with amprenavir. There have also been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. A causal relationship has not been established.

Unplanned fosamprenavir therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), or drug non-availability. If short-term treatment interruption is necessary (i.e., less than 1 to 2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable serum concentrations of efavirenz and nevirapine ranges from less than 1 week to more than 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel the patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

Fosamprenavir contains a sulfonamide moiety and therefore should be used with caution in patients with a known sulfonamide hypersensitivity. The potential for cross-sensitivity between sulfonamide agents and fosamprenavir is unknown. In clinical trials where patients received fosamprenavir, 16-20% of patients with a history of sulfonamide allergy experienced rash, while 12-33% of patients with no history of sulfonamide allergy experienced rash.

Perform hepatitis B virus (HBV) screening in any patient who presents with HIV-infection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection who require treatment for either infection should be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. The HIV guidelines recommend that coinfected pediatric patients 2 years and older receive an antiretroviral regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, another agent with anti-HBV activity should be used in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Management of HIV should be continued with the goal of maximal suppression. Additionally, patients with underlying hepatitis B or C prior to fosamprenavir treatment may be at increased risk for developing transaminase elevations.

Patients with hepatic disease may require dosage adjustment of fosamprenavir based upon the severity of the hepatic impairment. Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for developing transaminase elevations. Use of higher than recommended doses may result in transaminase elevations; do not exceed recommended dosage limits. Appropriate laboratory testing should be conducted prior to initiating therapy with fosamprenavir and patients should be monitored closely during treatment.

Consider patient specific factors, such as preexisting hyperlipidemia, when selecting an antiretroviral treatment regimen. Hyperlipidemia is a recognized side effect of protease inhibitor-based regimens. Obtain a random or fasting lipid profile at entry of care, initiation or modification of antiretroviral therapy, every 12 months, and as clinically indicated. Possible interventions for patients who develop hyperlipidemia during treatment with fosamprenavir include dietary modification, use of lipid lowering agents, or switching to a regimen with a more favorable lipid profile. Clinicians should be aware of the potential for drug interactions with certain cholesterol-lowering drugs.

Patients should be monitored closely for new onset diabetes mellitus, diabetic ketoacidosis, or hyperglycemia. Patients with diabetes mellitus or hyperglycemia may experience an exacerbation of their condition during fosamprenavir treatment. Some patients may require either initiation or dose adjustments of insulin or oral hyperglycemic agents.

Protease inhibitors, such as fosamprenavir, should be used cautiously in patients with hemophilia A or B due to reports of spontaneous bleeding episodes requiring treatment with additional factor VIII. In many cases, treatment with protease inhibitors was continued or restarted. A causal relationship has not been established.

Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test results kept in the patient's medical record until they become clinically useful. As with all other antiretroviral agents, resistance can develop when fosamprenavir is used either alone or in combination. Monotherapy with fosamprenavir is not recommended. HIV-1 isolates resistant to fosamprenavir have been shown to be cross-resistant to ritonavir and indinavir in vitro.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including those containing fosamprenavir. During the initial phase of HIV treatment, patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis carinii pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.

Acute hemolytic anemia has been reported in a patient treated with amprenavir, the active metabolite of fosamprenavir. While patients are receiving fosamprenavir it would be prudent to closely monitor for signs and symptoms of hemolytic anemia.

Fosamprenavir is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome) to any of the components of this product or to amprenavir. In clinical trials, severe and life threatening skin reactions have been reported, including 1 case of Stevens Johnson syndrome, in patients who received fosamprenavir (n = 700). Discontinue fosamprenavir in the case of life threatening or serious rash or for moderate rash accompanied by systemic symptoms.

Perform hepatitis C virus (HCV) screening in any child whose mother is known to have HCV infection and all HIV-infected adolescents. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older and adolescents with hepatitis C and HIV coinfection who have no contraindications to treatment. For antiretroviral-naive adolescent patients with CD4 counts more than 500 cells/mm3, consideration may be given to deferring ARV therapy until the hepatitis C treatment regimen has been completed. Conversely, for adolescent patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. Patients with underlying hepatitis C prior to fosamprenavir treatment may be at increased risk for developing transaminase elevations. All HIV-infected children and adolescents, regardless of HIV and HCV status, should receive standard vaccination with hepatitis A and B vaccines. Additionally, counsel HIV/HCV-coinfected adolescents to avoid alcohol.

Description: Fosamprenavir is a prodrug of amprenavir, a protease inhibitor used to treat infection with the human immunodeficiency virus (HIV-1). It has improved solubility over the parent drug, amprenavir, and provides the opportunity for reduced pill burden for current dosing regimens. In pediatric patients, a twice-daily administration regimen boosted with ritonavir is required to assure viral suppression and maintain appropriate concentrations even though unboosted regimens are FDA-approved in treatment-naive patients >= 2 years. Fosamprenavir is FDA-approved for use in infants as young as 4 weeks, including protease inhibitor-naive infants >= 4 weeks and in protease inhibitor-experienced infants >= 6 months; however, guidelines do not recommend for use in infants < 6 months.

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV
-Fosamprenavir is NOT recommended as part of an initial protease inhibitor (PI)-based treatment regimen for treatment-naive pediatric patients due to reduced exposure observed in children and medication burden. For a PI-based regimen in infants and children, preferred PIs are lopinavir/ritonavir, darunavir/ritonavir, or atazanavir/ritonavir. For adolescents, the preferred PI is darunavir/ritonavir.
-Unboosted fosamprenavir or once-daily fosamprenavir is not recommended in pediatric patients due to low drug exposures.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents:
-for the treatment of HIV in protease inhibitor-experienced patients:
Oral dosage:
Infants and Children 6 months and older weighing less than 11 kg: 45 mg/kg/dose PO twice daily plus ritonavir 7 mg/kg/dose PO twice daily.
Infants and Children 6 months and older weighing 11 to 14 kg: 30 mg/kg/dose PO twice daily plus ritonavir 3 mg/kg/dose PO twice daily.
Children weighing 15 to 19 kg: 23 mg/kg/dose PO twice daily plus ritonavir 3 mg/kg/dose PO twice daily.
Children and Adolescents weighing 20 kg or more: 18 mg/kg/dose (Max: 700 mg/dose) PO twice daily plus ritonavir 3 mg/kg/dose (Max: 100 mg/dose) PO twice daily. Patients weighing at least 39 kg may receive tablets.
-for the treatment of HIV in protease inhibitor-naive patients:
Oral dosage:
Infants 4 weeks to 5 months : The HIV guidelines do not recommend fosamprenavir with ritonavir in infants younger than 6 months due to low drug exposures in this population. Fosamprenavir should only be administered to infants born at 38 weeks gestation or greater and who have attained a post-natal age of 28 days. The FDA-approved dosage is 45 mg/kg/dose PO twice daily plus ritonavir 7 mg/kg/dose PO twice daily for infants less than 11 kg and 30 mg/kg/dose PO twice daily plus ritonavir 3 mg/kg/dose PO twice daily for infants 11 to 14 kg.
Infants and Children 6 months and older weighing less than 11 kg: 45 mg/kg/dose PO twice daily plus ritonavir 7 mg/kg/dose PO twice daily. The HIV guidelines do not recommend unboosted fosamprenavir in pediatric patients due to low drug exposures; however, the FDA-approved labeling includes a dose of 30 mg/kg/dose PO twice daily without ritonavir as an alternative in children 2 years and older.
Infants and Children 6 months and older weighing 11 to 14 kg: 30 mg/kg/dose PO twice daily plus ritonavir 3 mg/kg/dose PO twice daily. The HIV guidelines do not recommend unboosted fosamprenavir in pediatric patients due to low drug exposures; however, the FDA-approved labeling includes a dose of 30 mg/kg/dose PO twice daily without ritonavir as an alternative in children 2 years and older.
Children weighing 15 to 19 kg: 23 mg/kg/dose PO twice daily plus ritonavir 3 mg/kg/dose PO twice daily. The HIV guidelines do not recommend unboosted fosamprenavir in pediatric patients due to low drug exposures; however, the FDA-approved labeling includes a dose of 30 mg/kg/dose PO twice daily without ritonavir as an alternative in children 2 years and older.
Children and Adolescents weighing 20 kg or more: 18 mg/kg/dose (Max: 700 mg/dose) PO twice daily plus ritonavir 3 mg/kg/dose (Max: 100 mg/dose) PO twice daily. Patients weighing at least 39 kg may receive tablets. The HIV guidelines do not recommend unboosted fosamprenavir in pediatric patients due to low drug exposures; however, the FDA-approved labeling includes a dose of 30 mg/kg/dose (Max: 1400 mg/dose) PO twice daily without ritonavir as an alternative in children 2 years and older.

Therapeutic Drug Monitoring:
Suggested target trough concentration: 2,100 ng/mL
-Routine monitoring of plasma concentrations of antiretroviral (ARV) drugs is generally not recommended in HIV-infected pediatric patients. However, therapeutic drug monitoring may be considered in the following situations :-use of drugs with limited pharmacokinetic data and/or therapeutic experience in pediatric patients
-use of drugs with significant food and/or drug interactions
-suboptimal treatment response
-suspected suboptimal absorption, distribution, metabolism, or elimination of the drug
-suspected concentration-dependent drug-associated toxicity
-use of alternative dosing regimens and ARV combinations for which safety and efficacy have not been established in clinical trials
-heavily pretreated patients experiencing virologic failure and who may have viral isolates with reduced susceptibility to ARVs


Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
< 11 kg: 90 mg/kg/day PO with ritonavir. HIV guidelines do not recommend when < 6 months.
11 kg to < 15 kg: 60 mg/kg/day PO with ritonavir. HIV guidelines do not recommend when < 6 months.
15 kg to < 20 kg: 46 mg/kg/day PO with ritonavir. HIV guidelines do not recommend when < 6 months.
-Children
< 2 years and < 11 kg: 90 mg/kg/day PO with ritonavir.
< 2 years and 11 kg to < 15 kg: 60 mg/kg/day PO with ritonavir.
< 2 years and 15 kg to < 20 kg: 46 mg/kg/day PO with ritonavir.
>= 2 years and < 11 kg: 90 mg/kg/day PO with ritonavir; 60 mg/kg/day PO without ritonavir (not recommended by HIV guidelines).
>= 2 years and 11 kg to < 15 kg: 60 mg/kg/day PO with ritonavir; 60 mg/kg/day PO without ritonavir (not recommended by HIV guidelines).
>= 2 years and 15 kg to < 20 kg: 46 mg/kg/day PO with ritonavir; 60 mg/kg/day PO without ritonavir (but not recommended by HIV guidelines).
>= 2 years and >= 20 kg: 36 mg/kg/day (Max: 1400 mg) PO with ritonavir; 60 mg/kg/day (Max: 2800 mg) PO without ritonavir (not recommended by HIV guidelines).
-Adolescents
>= 20 kg: 36 mg/kg/day (Max: 1400 mg) PO with ritonavir; 60 mg/kg/day (Max: 2800 mg) PO without ritonavir (not recommended by HIV guidelines).

Patients with Hepatic Impairment Dosing
Dosage reduction is recommended in all mild to severe hepatic impairment in adult patients; however, there are no dosage adjustment recommendations in pediatric patients.

Patients with Renal Impairment Dosing
Dosing in patients with renal impairment has not been studied. Less than 2% is excreted unchanged in the urine, therefore, the effect of renal impairment on elimination should be minimal.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Fosamprenavir is a prodrug of amprenavir. It is rapidly converted to amprenavir by cellular phosphatases following oral administration. Fosamprenavir has little or no antiviral activity in vitro; the in vitro antiviral activity observed with fosamprenavir is not measurable. Amprenavir inhibits the human immunodeficiency virus (HIV) type 1 aspartic protease enzyme. This enzyme plays a key role in the post-translational processing of the gag and gag-pol polyprotein precursors, key structural proteins and replication enzymes of HIV-1. Thus, by inhibiting HIV-1 protease, amprenavir impairs HIV viral replication and proliferation, resulting in the formation of immature non-infectious viral particles. When fosamprenavir is combined with the protease inhibitor ritonavir an additive inhibitory effect on HIV-1 is observed.

Pharmacokinetics: Fosamprenavir, a phosphate ester prodrug of the antiretroviral protease inhibitor amprenavir, is administered orally as a tablet or suspension. Amprenavir is approximately 90% protein bound with a concentration-dependent binding that suggests a decreased binding with higher concentrations.

After oral administration, fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate prior to reaching circulation in the gut epithelium during absorption. Amprenavir is extensively metabolized in the liver by the cytochrome P450 3A4 (CYP3A4) enzyme system. Amprenavir is also a substrate of p-glycoprotein (P-gp). Twenty-four metabolites have been identified; the majority of these metabolites are excreted in the feces. Excretion of unchanged amprenavir in urine and feces is minimal. Unchanged amprenavir in urine accounts for approximately 1% of the fosamprenavir dose; unchanged amprenavir was not detectable in feces. Since renal elimination of unchanged amprenavir represents approximately 1% of the administered dose, renal impairment is not expected to significantly impact the elimination of amprenavir. Following a single dose of 14C-amprenavir, approximately 14% and 75% can be accounted for as metabolites in urine and feces, respectively. The plasma elimination half-life of amprenavir is approximately 7.7 hours.

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C9, CYP2D6, P-gp
Fosamprenavir is metabolized to the active drug amprenavir. Amprenavir is a strong inhibitor and a substrate of CYP3A4, an inducer and substrate of P-glycoprotein (P-gp), and a substrate of CYP2C9 and CYP2D6. Data also suggest that amprenavir induces 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).


-Route-Specific Pharmacokinetics
Oral Route
In general, the Tmax for amprenavir is reached at a median of 2.5 hours. Exposure (AUC) is similar after the administration of the tablets and suspension when administered at a fasted state; however, the Cmax of amprenavir was 14.5% higher compared to the tablet. No significant changes in pharmacokinetic parameters are seen when the tablets are administered in a fed (standardized high-fat meal) versus fasted state. Administration of the oral suspension (1400 mg single dose) with food (standardized high-fat meal) results in a decreased Cmax (by 46%), a prolonged Tmax (by 0.72 hours), and a decreased AUC (by 28%), compared to administration in a fasted state.


-Special Populations
Pediatrics
Infants, Children, and Adolescents
Pharmacokinetics of fosamprenavir in the pediatric population were evaluated using the following fosamprenavir dosing regimens: (1) 30-40 mg/kg twice daily in children 2-5 years; (2) 30 mg/kg plus ritonavir 6 mg/kg once daily in children 2-18 years; (3) 18-60 mg/kg plus ritonavir 3-10 mg/kg twice daily in children 4 weeks to 18 years. Amprenavir clearance decreased with increasing weight and weight-adjusted apparent clearance was higher in children < 4 years of age, suggesting younger children require larger mg/kg dosing. Due to the potential for reduced amprenavir exposure, fosamprenavir must be used in combination with ritonavir when treating children < 2 years of age. Additionally, lower amprenavir exposures preclude the use of fosamprenavir (alone or with ritonavir) in protease inhibitor-experienced infants < 6 months of age. HIV guidelines suggest that the lower fosamprenavir concentrations noted with infants < 6 months may not be sufficient for treatment of any infant < 6 months, regardless of exposure to previous protease inhibitors.

Hepatic Impairment
In adults with mild to moderate hepatic impairment, after administration of fosamprenavir plus ritonavir for 2 weeks, the amprenavir AUC was increased by approximately 22%, 70%, and 80% in patients with mild, moderate, and severe hepatic dysfunction, respectively. Additionally, protein binding is decreased in patients with hepatic impairment with the unbound fraction of amprenavir ranged at 2 hours (approximate Cmax) by -7% to 57% and at the end of the dosing interval (Cmin) by 50 to 102%. No data are available on the use of fosamprenavir plus ritonavir in pediatric patients with any degree of hepatic impairment. Dosing adjustments are required in adults with hepatic impairment; dosage adjustments have not been determined for pediatric patients.

Renal Impairment
The renal elimination of unchanged amprenavir, the active metabolite of fosamprenavir, is minimal; therefore, renal impairment is not expected to significantly impact elimination.