Drug Description
Fosamprenavir is the calcium phosphate ester prodrug of amprenavir, an inhibitor of HIV protease. Fosamprenavir calcium is a single stereoisomer with the (3S)(1S,2R) configuration. [1]
References
[1] FDA Lexiva Prescribing Information, 03/05/08, p. 18. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
HIV/AIDS-Related Uses
Fosamprenavir in tablet form was approved by the FDA on October 20, 2003, for the treatment of HIV-1 infection in combination with other antiretroviral medications. Fosamprenavir in oral suspension form was approved by the FDA on June 14, 2007, for use in HIV-infected adults or children 2 to 18 years old. [1] On April 27, 2012, new dosing recommendations for the use of fosamprenavir oral suspension in pediatric patients aged at least 4 weeks to 18 years was approved. [2]
References
[1] FDA Antiretroviral Drugs Used in the Treatment of HIV Infection. Available at: http://www.fda.gov/ForConsumers/byAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm118915.htm. Accessed 01/19/09.
[2] FDA Lexiva Prescribing Information, 04/27/12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021548s028,022116s012lbl.pdf. Accessed 05/14/12.
Dosing Information
Mode of Delivery
Oral. [1]
Dosage Form
Tablets containing fosamprenavir 700 mg. [2]
Suspension containing fosamprenavir 50 mg/ml as fosamprenavir calcium, equivalent to approximately 43 mg/ml amprenavir. [3] The suspension is provided in a 225-ml bottle that should be shaken vigorously before each use. [4]
The recommended dose of fosamprenavir for treatment-naive adult patients is either 1) 1,400 mg twice daily without ritonavir, 2) 1,400 mg once daily plus ritonavir 200 mg once daily, or 3) 700 mg twice daily plus ritonavir 100 mg twice daily. The recommended dose of fosamprenavir for protease inhibitor (PI)-experienced adult patients is 700 mg twice daily plus ritonavir 100 mg twice daily. An additional 100 mg/day of ritonavir is recommended when efavirenz is administered with fosamprenavir/ritonavir once daily. [5]
Pediatric doses for patients aged at least 4 weeks to 18 years should be calculated based on body weight (kg) and should not exceed the adult dose. [6]
Twice-Daily Dosage Regimens by Weight for Protease Inhibitor-Naive Pediatric Patients (Greater Than or Equal to 4 Weeks of Age) and for Protease Inhibitor-Experienced Pediatric Patients (Greater Than or Equal to 6 Months of Age) Using Lexiva Oral Suspension With Concurrent Ritonavir
Weight: Twice-Daily Dosage Regimen
• <11 kg: LEXIVA 45 mg/kg plus ritonavir 7 mg/kga
• 11 kg - <15 kg: LEXIVA 30 mg/kg plus ritonavir 3 mg/kga
• 15 kg - <20 kg: LEXIVA 23 mg/kg plus ritonavir 3 mg/kga
• ≥20 kg: LEXIVA 18 mg/kg plus ritonavir 3 mg/kga
a When dosing with ritonavir, do not exceed the adult dose of LEXIVA 700 mg/ritonavir 100 mg twice-daily dose. [7]
Alternatively, protease inhibitor-naive children 2 years of age and older can be administered LEXIVA (without ritonavir) 30 mg per kg twice daily. [8]
LEXIVA should only be administered to infants born at 38 weeks gestation or greater and who have attained a post-natal age of 28 days. [9]
For pediatric patients, pharmacokinetic and clinical data:
• do not support once-daily dosing of LEXIVA alone or in combination with ritonavir.
• do not support administration of LEXIVA alone or in combination with ritonavir for protease inhibitor-experienced children younger than 6 months of age.
• do not support twice-daily dosing of LEXIVA without ritonavir in pediatric patients younger than 2 years of age. [10]
Other Dosing Considerations:
• When administered without ritonavir, the adult regimen of LEXIVA Tablets 1,400 mg twice daily may be used for pediatric patients weighing at least 47 kg.
• When administered in combination with ritonavir, LEXIVA Tablets may be used for pediatric patients weighing at least 39 kg; ritonavir capsules may be used for pediatric patients weighing at least 33 kg. [11]
Fosamprenavir should be used with caution in all patients with hepatic impairment, including hepatitis B or C or a marked elevation in transaminases levels prior to treatment. [12] In treatment-naive patients with mild hepatic impairment (Child-Pugh score of 5 to 6), a reduced fosamprenavir dosage of 700 mg twice daily alone or with ritonavir 100 mg once daily is recommended. PI-experienced patients with mild impairment should receive a fosamprenavir dosage of 700 mg twice daily combined with ritonavir 100 mg once daily. [13]
In treatment-naive patients with moderate hepatic impairment (Child-Pugh score of 7 to 9), a reduced fosamprenavir dosage of 700 mg twice daily without ritonavir or 450 mg twice daily combined with ritonavir 100 mg once daily is recommended. PI-experienced patients with moderate impairment should receive fosamprenavir 450 mg twice daily combined with ritonavir 100 mg once daily. [14]
In treatment-naive patients with severe hepatic impairment (Child-Pugh score of 10 to 12), a reduced fosamprenavir dosage of 350 mg twice daily without ritonavir is recommended. No data exists to support use of fosamprenavir combined with ritonavir in patients with severe hepatic impairment. [15]
Storage
Store tablets at 25 C (77 F); excursions permitted to 15 C to 30 C (59 F to 86 F). [16]
Store suspension at 5 C to 30 C (40 F to 86 F). Do not freeze; refrigeration is allowed to improve the taste. Shake vigorously before each use. [17]
References
[1] AHFS Drug Information 2008; p. 648
[2] AHFS Drug Information 2008; p. 648
[3] FDA Lexiva Prescribing Information, 03/05/08, p. 38. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[4] FDA Lexiva Prescribing Information, 03/05/08, p. 2. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[5] FDA Lexiva Prescribing Information, 03/05/08, p. 2. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[6] FDA Lexiva Prescribing Information, 04/27/12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021548s028,022116s012lbl.pdf. Accessed 05/14/12.
[7] FDA Lexiva Prescribing Information, 04/27/12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021548s028,022116s012lbl.pdf. Accessed 05/14/12.
[8] FDA Lexiva Prescribing Information, 04/27/12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021548s028,022116s012lbl.pdf. Accessed 05/14/12.
[9] FDA Lexiva Prescribing Information, 04/27/12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021548s028,022116s012lbl.pdf. Accessed 05/14/12.
[10] FDA Lexiva Prescribing Information, 04/27/12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021548s028,022116s012lbl.pdf. Accessed 05/14/12.
[11] FDA Lexiva Prescribing Information, 04/27/12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021548s028,022116s012lbl.pdf. Accessed 05/14/12.
[12] FDA Important information about Lexiva (fosamprenavir calcium) Tablets and Oral Suspension. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm192905.htm. Accessed on: 12/10/09.
[13] FDA Lexiva Prescribing Information, 03/05/08, p. 3. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[14] FDA Lexiva Prescribing Information, 03/05/08, p. 3. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[15] FDA Lexiva Prescribing Information, 03/05/08, p. 3. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[16] FDA Lexiva Prescribing Information, 03/05/08, p. 38. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[17] FDA Lexiva Prescribing Information, 03/05/08, p. 38. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
Pharmacology
Fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate by cellular phosphatases in the gut epithelium as it is absorbed. Amprenavir binds to the active site of HIV-1 protease and prevents the processing of viral Gag and Gag-Pol polyprotein precursors, resulting in the formation of immature, noninfectious viral particles. [1]
Fosamprenavir has been studied in both healthy adult volunteers and HIV-infected patients; no substantial differences in steady-state amprenavir concentrations were observed between the two populations. The time to peak amprenavir concentration (Tmax) after administration of a single dose of fosamprenavir occurred between 1.5 and 4 hours (median, 2.5 hours). The absolute oral bioavailability of amprenavir after administration of fosamprenavir has not been established. [2]
In a fasted state, administration of single, 1,400-mg doses using the fosamprenavir 50 mg/ml suspension and of the 700 mg tablet provided similar amprenavir area under the concentration-time curve (AUC) exposures, although the maximum plasma concentration (Cmax) of amprenavir increased 14.5% with administration of the suspension compared with the tablet. [3]
When administered twice daily with ritonavir, the median Cmax was 6.08 mcg/ml, the median Tmax was 1.5 hours, and the median AUC was 79.2 mcg hour/ml. [4]
In vitro, amprenavir is approximately 90% bound to plasma proteins, with concentration-dependent binding observed over the concentration range of 1 to 10 mcg/ml. Fosamprenavir primarily binds to alpha1-acid glycoprotein. Higher amounts of unbound amprenavir present as amprenavir serum concentrations increase. The partitioning of amprenavir into erythrocytes is low but increases as amprenavir concentrations increase, reflecting the higher amount of unbound drug at higher concentrations. [5]
Amprenavir is metabolized in the liver by the cytochrome P450 (CYP) 3A4 enzyme system. The two major metabolites result from the oxidation of the tetrahydrofuran and aniline moieties. The plasma elimination half-life of amprenavir is approximately 7.7 hours. Excretion of unchanged amprenavir in the urine and feces is minimal. [6]
The pharmacokinetics of amprenavir following administration of LEXIVA Oral Suspension and LEXIVA Tablets, with or without ritonavir, have been studied in a total of 212 HIV-1–infected pediatric subjects enrolled in 3 trials. LEXIVA without ritonavir was administered as 30 or 40 mg per kg twice daily to children aged 2 to 5 years. LEXIVA with ritonavir was administered as LEXIVA 30 mg per kg plus ritonavir 6 mg per kg once daily to children aged 2 to 18 years and as LEXIVA 18 to 60 mg per kg plus ritonavir 3 to 10 mg per kg twice daily to children aged at least 4 weeks to 18 years; body weights ranged from 3 to 103 kg. [7]
Amprenavir apparent clearance decreased with increasing weight. Weight-adjusted apparent clearance was higher in children younger than 4 years, suggesting that younger children require higher mg per kg dosing of LEXIVA. [8]
The pharmacokinetics of LEXIVA Oral Suspension in protease inhibitor-naive infants younger than 6 months of age (n = 9) receiving LEXIVA 45 mg per kg plus ritonavir 10 mg per kg twice daily generally demonstrated lower AUC12 and Cmin than adults receiving twice-daily LEXIVA 700 mg plus ritonavir 100 mg, the dose recommended for protease-experienced adults. The mean steady-state amprenavir AUC12, Cmax, and Cmin were 26.6 mcg•hour per mL, 6.25 mcg per mL, and 0.86 mcg per mL, respectively. These data do not support twice-daily dosing of LEXIVA alone or in combination with ritonavir in protease inhibitor-experienced patients less than 6 months of age. Because of expected low amprenavir exposure and a requirement for large volume of drug, twice-daily dosing of LEXIVA alone (without ritonavir) in pediatric subjects younger than 2 years of age was not studied. [9]
Subjects aged 2 to less than 6 years receiving LEXIVA 30 mg per kg twice daily without ritonavir achieved geometric mean (95% CI) amprenavir Cmax (n = 9), AUC12 (n = 9), and Cmin (n = 19) of 7.15 (5.05, 10.1), 22.3 (15.3, 32.6), and 0.513 (0.384, 0.686), respectively. [10]
Fosamprenavir is in FDA Pregnancy Category C. It is not known whether amprenavir crosses the human placenta; however, it does cross the placenta in rats. [11] There are no adequate and well-controlled studies to date using the drug in pregnant women. Fosamprenavir should be used during pregnancy only when clearly needed. An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to antiretroviral agents, including fosamprenavir. Physicians may register patients by calling 1-800-258-4263 or online at: http://www.APRegistry.com. It is not known whether amprenavir is distributed into human milk; however, it is distributed into milk in rats. Because of both the potential for HIV transmission and for serious adverse reactions in nursing infants, women should be instructed not to breastfeed if they are taking fosamprenavir. [12]
HIV-1 isolates with a decreased susceptibility to amprenavir have been selected in vitro and obtained from patients treated with fosamprenavir. Amprenavir resistance-associated mutations at positions I54L/M, V32I, I47V, and M46I have been detected in HIV isolates from antiretroviral-naive patients treated with fosamprenavir. No such mutations were detected in one clinical study of antiretroviral-naive patients treated with fosamprenavir/ritonavir. [13]
References
[1] FDA Lexiva Prescribing Information, 03/05/08, p. 32. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[2] FDA Lexiva Prescribing Information, 03/05/08, pp. 19, 21. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[3] FDA Lexiva Prescribing Information, 03/05/08, p. 21. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[4] FDA Lexiva Prescribing Information, 03/05/08, p. 20. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[5] FDA Lexiva Prescribing Information, 03/05/08, p. 21. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[6] FDA Lexiva Prescribing Information, 03/05/08, p. 21. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[7] FDA Lexiva Prescribing Information, 04/27/12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021548s028,022116s012lbl.pdf. Accessed 05/14/12.
[8] FDA Lexiva Prescribing Information, 04/27/12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021548s028,022116s012lbl.pdf. Accessed 05/14/12.
[9] FDA Lexiva Prescribing Information, 04/27/12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021548s028,022116s012lbl.pdf. Accessed 05/14/12.
[10] FDA Lexiva Prescribing Information, 04/27/12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021548s028,022116s012lbl.pdf. Accessed 05/14/12.
[11] Wolters Kluwer Health, Inc. Fosamprenavir, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 01/19/09.
[12] FDA Lexiva Prescribing Information, 03/05/08, p. 17. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[13] FDA Lexiva Prescribing Information, 03/05/08, pp. 32-3. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
Adverse Events/Toxicity
The most common adverse effects associated with fosamprenavir use include hypertriglyceridemia, skin rash, depressive or mood disorders, hyperglycemia, nausea, abdominal pain, diarrhea, fatigue, headache, and vomiting. [1]
LEXIVA with and without ritonavir was studied in 237 HIV-1–infected pediatric subjects aged at least 4 weeks to 18 years in 3 open-label trials, APV20002, APV20003, and APV29005. Vomiting and neutropenia occurred more frequently in pediatric subjects compared to adults. Other adverse events occurred with similar frequency in pediatric patients compared with adults. [2]
Patients receiving fosamprenavir may develop new onset or exacerbations of diabetes mellitus. [3]
In clinical studies, 19% of patients treated with fosamprenavir developed skin rash. Most rashes were of mild to moderate intensity; fewer than 1% of patients receiving fosamprenavir developed a severe or life-threatening rash (Grade 3 or 4), including Stevens-Johnson syndrome. Fosamprenavir should be discontinued in patients with severe or life-threatening rash or with moderate rash accompanied by systemic reactions. [4]
There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors (PIs). In some patients additional factor VIII was required. In many of the reported cases, treatment with PIs was continued or restarted. A causal relationship between PI therapy and these episodes has not been established. [5]
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including fosamprenavir. During the initial phase of combination antiretroviral treatment, a patient whose immune system improves may develop an inflammatory response to indolent or residual opportunistic infections, such as Mycobacterium avium infection, cytomegalovirus infections, Pneumocystis jirovecii pneumonia, or tuberculosis. Symptoms of immune reconstitution syndrome necessitate further evaluation and treatment. [6]
Redistribution of body fat, peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. [7]
Treatment with amprenavir alone or in combination with ritonavir has resulted in increases in the concentration of total cholesterol and triglycerides. Reports have also indicated that patients who are receiving fosamprenavir have an increased risk of myocardial infarction and hypercholesterolemia. Cholesterol and triglyceride testing should be performed prior to initiation of amprenavir therapy and at periodic intervals during treatment. Lipid disorders should be managed as clinically appropriate. [8] Other modifiable risk factors for cardiovascular disease (e.g., hypertension, diabetes, smoking) should be monitored and managed as clinically appropriate. [9]
There have been reports of nephrolithiasis occurring in people who received fosamprenavir. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of fosamprenavir may be considered. [10]
References
[1] Pharm GKB The Pharmacogenetics and Pharmacogenomics Knowledge Base - fosamprenavir. Available at: http://www.pharmgkb.org. Accessed 01/19/09.
[2] FDA Lexiva Prescribing Information, 04/27/12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021548s028,022116s012lbl.pdf. Accessed 05/14/12.
[3] FDA Important information about Lexiva (fosamprenavir calcium) Tablets and Oral Suspension. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm192905.htm. Accessed on: 12/10/09.
[4] FDA Lexiva Prescribing Information, 03/05/08, pp. 5, 8. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[5] FDA Lexiva Prescribing Information, 03/05/08, p. 6. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[6] FDA Lexiva Prescribing Information, 03/05/08, pp. 5-6. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[7] FDA Lexiva Prescribing Information, 03/05/08, p. 6. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[8] FDA Lexiva Prescribing Information, 03/05/08, p. 6. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[9] FDA Important information about Lexiva (fosamprenavir calcium) Tablets and Oral Suspension. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm192905.htm. Accessed on: 12/10/09.
[10] FDA Important information about Lexiva (fosamprenavir calcium) Tablets and Oral Suspension. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm192905.htm. Accessed on: 12/10/09.
Drug and Food Interactions
Fosamprenavir tablets may be taken with or without food. [1] Administration of a single, 1,400 mg dose of fosamprenavir oral suspension with a high-fat meal decreased the Cmax by 46% and decreased the amprenavir AUC by 28%. [2] Fosamprenavir oral suspension should be taken without food by adults but with food by children 2 to 18 years old. [3]
Concomitant use of fosamprenavir with certain drugs that are highly dependent on CYP3A4 for clearance may raise the plasma levels of these drugs, potentially resulting in serious or life-threatening events. Drugs that are contraindicated with amprenavir include bepridil, cisapride, dihydroergotamine, ergonovine, ergotamine, methylergonovine, midazolam, pimozide, and triazolam. Rifampin is a potent inducer of CYP3A4 and can markedly reduce plasma concentrations of fosamprenavir. If fosamprenavir is coadministered with ritonavir, flecainide and propafenone are also contraindicated. [4]
Fosamprenavir should not be coadministered with delavirdine, because it may lead to loss of virologic response and possible resistance to delavirdine. Concurrent use of efavirenz or nevirapine with fosamprenavir may decrease amprenavir concentration. [5] Decreased concentrations of fosamprenavir were observed when fosamprenavir and saquinavir were taken concurrently; the effect of fosamprenavir on saquinavir has not yet been established. [6]
Concurrent use of phenytoin with fosamprenavir may increase amprenavir concentration and decrease phenytoin concentration. Plasma phenytoin concentrations should be monitored and dose should be increased as is appropriate. No change in fosamprenavir dose is recommended. [7]
Concurrent use of paroxetine with fosamprenavir may decrease paroxetine concentration. Paroxetine dose adjustment should be guided by tolerability and efficacy. [8]
Concomitant use of products containing St. John's wort (Hypericum perforatum) with fosamprenavir or other PIs is not recommended. St. John's wort is expected to substantially decrease drug plasma levels and may lead to loss of virologic response and possible resistance to fosamprenavir or other PIs. [9]
Serious or life-threatening events can occur if amprenavir is taken with amiodarone, bepredil, lidocaine, tricyclic antidepressants, and quinidine. Patients receiving amprenavir concomitantly with any of these drugs should be carefully monitored. [10]
Alfuzosin and salmeterol should not be coadministered with any PIs, including fosamprenavir. [11]
Caution should be used when prescribing sildenafil or vardenafil in patients receiving PIs, including fosamprenavir. Coadministration of a PI with sildenafil, tadalafil, or vardenafil is expected to substantially increase sildenafil, tadalafil and vardenafil plasma concentrations and, possibly, sildenafil-associated adverse effects, including hypotension, visual changes, and priapism. [12] People taking PIs should also not be prescribed sildenafil to treat pulmonary arterial hypertension nor colchicines if they have liver or kidney impairment. [13]
For patients who have already taken a protease inhibitor for at least 10 days, initial dosage of bosentan should begin at 62.5 mg taken daily or every other day, based on individual tolerability. For patients beginning treatment with a PI who are already taking bosentan, bosentan should be discontinued at least 36 hours prior to initiation of PI treatment. Bosentan should be resumed at least 10 days after PI initiation at a dosage of 62.5 mg taken daily or every other day, based on individual tolerability. [14]
For patients who have already been on a PI for at least 1 week, tadalafil dosage should begin at 20 mg daily and increase to 40 mg daily, based on individual tolerability. For patients beginning treatment with a PI who are already taking tadalafil, tadalafil should be discontinued at least 24 hours prior to initiation of PI treatment. Tadalafil should be resumed at least 1 week later at a dosage of 20 mg daily. This should be increased to 40 mg daily, based on individual tolerability. [15]
Patients receiving colchicine for the treatment of gout flares should take 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. The dose should be repeated no earlier than 3 days later. Patients taking a PI without ritonavir should take 1.2 mg (2 tablets) x 1 dose. The dose should be repeated no earlier than 3 days later. [16]
For the prevention of gout-flares, if the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. In patients taking a PI without ritonavir, if the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. [17]
For the treatment of familial Mediterranean fever (FMF), the maximum daily dose of colchicine should be 0.6 mg (may be given as 0.3 mg twice a day). In patients taking a PI without ritonavir, the maximum daily dose should be 1.2 mg (may be given as 0.6 mg twice a day). [18]
Concomitant use of fosamprenavir with certain other drugs may significantly increase or decrease plasma concentrations of amprenavir or of the coadministered drug. Adjustment in dosage or regimen should be considered when amprenavir is coadministered with antacids, ketoconazole, itraconazole, and rifabutin. [19]
Concomitant use of fosamprenavir and oral or other contraceptives containing ethinyl estradiol/norethindrone may lead to loss of virologic response. [20] Concomitant use of fosamprenavir plus ritonavir and oral contraceptives may result in clinically significant hepatic transaminase elevations. [21] Alternative methods of nonhormonal contraception are recommended. [22]
Fosamprenavir is a sulfonamide. The potential for cross-sensitivity between other sulfonamides and amprenavir is unknown. Amprenavir should be used with caution in patients with a known sulfonamide allergy. [23]
Fosamprenavir may increase serum concentrations of warfarin when these two drugs are taken together. [24]
Concurrent use of fosamprenavir with lovastatin or simvastatin may lead to potentially serious reactions, such as a risk of myopathy, including rhabdomyolysis. The use of lovastatin or simvastatin with fosamprenavir is contraindicated. Due to drug interactions between atorvastatin and fosamprenavir, it is recommended that the atorvastatin dose be titrated carefully and the lowest necessary dose be used. Do not exceed atorvastatin 20 mg/day when used concurrently with fosamprenavir. [25] [26]
References
[1] FDA Lexiva Prescribing Information, 03/05/08, p. 2. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[2] FDA Lexiva Prescribing Information, 03/05/08, p. 21. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[3] FDA Lexiva Prescribing Information, 03/05/08, p. 2. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[4] Wolters Kluwer Health, Inc. Fosamprenavir, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 01/19/09.
[5] Wolters Kluwer Health, Inc. Fosamprenavir, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 01/19/09.
[6] Wolters Kluwer Health, Inc. Fosamprenavir, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 01/19/09.
[7] FDA Lexiva Prescribing Information, 03/05/08, p. 13. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[8] FDA Lexiva Prescribing Information, 03/05/08, p. 13. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[9] Wolters Kluwer Health, Inc. Fosamprenavir, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 01/19/09.
[10] Wolters Kluwer Health, Inc. Fosamprenavir, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 01/19/09.
[11] FDA. “New label information affecting all approved protease inhibitors for treatment of HIV” April 27, 2010. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm209920.htm. Accessed: 04/30/2010.
[12] Wolters Kluwer Health, Inc. Fosamprenavir, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 01/19/09.
[13] FDA. “New label information affecting all approved protease inhibitors for treatment of HIV” April 27, 2010. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm209920.htm. Accessed: 04/30/2010.
[14] FDA. “New label information affecting all approved protease inhibitors for treatment of HIV” April 27, 2010. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm209920.htm. Accessed: 04/30/2010.
[15] FDA. “New label information affecting all approved protease inhibitors for treatment of HIV” April 27, 2010. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm209920.htm. Accessed: 04/30/2010.
[16] FDA. “New label information affecting all approved protease inhibitors for treatment of HIV” April 27, 2010. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm209920.htm. Accessed: 04/30/2010.
[17] FDA. “New label information affecting all approved protease inhibitors for treatment of HIV” April 27, 2010. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm209920.htm. Accessed: 04/30/2010.
[18] FDA. “New label information affecting all approved protease inhibitors for treatment of HIV” April 27, 2010. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm209920.htm. Accessed: 04/30/2010.
[19] Wolters Kluwer Health, Inc. Fosamprenavir, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 01/19/09.
[20] Wolters Kluwer Health, Inc. Fosamprenavir, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 01/19/09.
[21] FDA Important information about Lexiva (fosamprenavir calcium) Tablets and Oral Suspension. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm192905.htm. Accessed on: 12/10/09.
[22] Wolters Kluwer Health, Inc. Fosamprenavir, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 01/19/09.
[23] Wolters Kluwer Health, Inc. Fosamprenavir, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 01/19/09.
[24] Wolters Kluwer Health, Inc. Fosamprenavir, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 01/19/09.
[25] FDA Important information about Lexiva (fosamprenavir calcium) Tablets and Oral Suspension. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm192905.htm. Accessed on: 12/10/09.
[26] FDA Lexiva Prescribing Information, February 2012. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021548s029,022116s013lbl.pdf. Accessed 03/04/12.
Contraindications
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.
Fosamprenavir is contraindicated when coadministered with drugs that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events.
Drugs Contraindicated With LEXIVA (Information in the table applies to LEXIVA with or without ritonavir, unless otherwise indicated.)
- Alpha 1-adrenoreceptor antagonist: Alfuzosin. Potentially increased alfuzosin concentrations can result in hypotension.
- Antiarrhythmics: Flecainide, propafenone. POTENTIAL for serious and/or life-threatening reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics if LEXIVA is co-prescribed with ritonavir.
- Antimycobacterials: Rifampin. May lead to loss of virologic response and possible resistance to LEXIVA or to the class of protease inhibitors.
- Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine. POTENTIAL for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
- GI motility agents: Cisapride. POTENTIAL for serious and/or life-threatening reactions such as cardiac arrhythmias.
- Herbal products: St. John’s wort (Hypericum perforatum). May lead to loss of virologic response and possible resistance to LEXIVA or to the class of protease inhibitors.
- HMG co-reductase inhibitors: Lovastatin, simvastatin. POTENTIAL for serious reactions such as risk of myopathy including rhabdomyolysis.
- Neuroleptic: Pimozide. POTENTIAL for serious and/or life-threatening reactions such as cardiac arrhythmias.
- Non-nucleoside reverse transcriptase inhibitor: Delavirdine. May lead to loss of virologic response and possible resistance to delavirdine.
- PDE5 inhibitor: Sildenafil (REVATIO®) (for treatment of pulmonary arterial hypertension). A safe and effective dose has not been established when used with LEXIVA. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope).
- Sedative/hypnotics: Midazolam, triazolam. POTENTIAL for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
Fosamprenavir is contraindicated when coadministered with ritonavir in patients receiving the antiarrhythmic agents flecainide and propafenone. If LEXIVA is coadministered with ritonavir, reference should be made to the full prescribing information for ritonavir for additional contraindications. [1]
References
[1] FDA Lexiva Prescribing Information, February 2012. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021548s029,022116s013lbl.pdf. Accessed 03/04/12.
Clinical Trials
Click here to search ClinicalTrials.gov for trials that use Fosamprenavir.
Chemistry
CAS Name
Carbamic acid, [(1S,2R)-3-[[(4- aminophenyl)sulfonyl](2-methylpropyl)amino]-1- (phenylmethyl)-2-(phosphonooxy)propyl]-, C-[(3S)-tetrahydro-3-furanyl] ester, calcium salt [1]
CAS Number
226700-81-8 [2]
Molecular Formula
C25-H34-Ca-N3-O9-P-S
Elemental Composition
C48.2%, H5.5%, N6.7%, O23.1%, P5.0%, S5.1%, Ca6.4%
Molecular Weight
623.64
Melting Point
282 to 284 C
Physical Description
Tablets: pink, film-coated, capsule-shaped, biconvex tablets with "GX LL7" debossed on one face. [3]
Suspension: white to off-white suspension. [4]
Solubility
0.31 mg/ml in water at 25 C. [5]
References
[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 01/19/09.
[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 01/19/09.
[3] FDA Lexiva Prescribing Information, 03/05/08, p. 3. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[4] FDA Lexiva Prescribing Information, 03/05/08, p. 3. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021548s017,022116s001lbl.pdf. Accessed 01/19/09.
[5] Merck Index 2006; p. 729
Further Reading
Lexiva Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Arvieux C, Tribut O. Amprenavir or fosamprenavir plus ritonavir in HIV infection: pharmacology, efficacy and tolerability profile. Drugs. 2005;65(5):633-59. Review.
Vierling P, Greiner J. Prodrugs of HIV protease inhibitors. Curr Pharm Des 2003;9(22):1755-70.
Gathe JC Jr, Wood R, Sanne I, DeJesus E, Schürmann D, Gladysz A, Garris C, Givens N, Elston R, Yeo J. Long-term (120-Week) antiviral efficacy and tolerability of fosamprenavir/ritonavir once daily in therapy-naive patients with HIV-1 infection: an uncontrolled, open-label, single-arm follow-on study. Clin Ther. 2006 May;28(5):745-54.
Calza L, Manfredi R, Pocaterra D, Chiodo F. Efficacy and tolerability of a fosamprenavir-ritonavir-based versus a lopinavir-ritonavir-based antiretroviral treatment in 82 therapy-naïve patients with HIV-1 infection. Int J STD AIDS. 2008 Aug;19(8):541-4.
Gatti F, Nasta P, Loregian A, Puoti M, Matti A, Pagni S, Gonzalez de Requena D, Prestini K, Parisi SG, Bonora S, Palù G, Carosi G. Unboosted fosamprenavir is associated with low drug exposure in HIV-infected patients with mild-moderate liver impairment resulting from HCV-related cirrhosis. J Antimicrob Chemother. 2009 Jan 16. [Epub ahead of print].
Marcelin AG, Flandre P, Molina JM, Katlama C, Yeni P, Raffi F, Antoun Z, Ait-Khaled M, Calvez V.Genotypic resistance analysis of the virological response to fosamprenavir-ritonavir in protease inhibitor-experienced patients in CONTEXT and TRIAD clinical trials. Antimicrob Agents Chemother. 2008 Dec;52(12):4251-7. Epub 2008 Oct 13.
Manufacturer Information
Fosamprenavir
GlaxoSmithKline
5 Moore Drive
Research Triangle Park, NC 27709
Phone: 888-825-5249
Fosamprenavir
Vertex Pharmaceuticals Inc
130 Waverly Street
Cambridge, MA 02139-4242
Phone: 617-577-6000
Fax: 617-577-6680
Lexiva
GlaxoSmithKline
5 Moore Drive
Research Triangle Park, NC 27709
Phone: 888-825-5249
All Content Last Reviewed: April 29, 2010
Last Updated: May 15, 2012