Fosamprenavir Calcium

Name: Fosamprenavir Calcium

Indications

LEXIVA® is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection.

The following points should be considered when initiating therapy with LEXIVA plus ritonavir in protease inhibitor-experienced patients:

  • The protease inhibitor-experienced patient trial was not large enough to reach a definitive conclusion that LEXIVA plus ritonavir and lopinavir plus ritonavir are clinically equivalent [see Clinical Studies].
  • Once-daily administration of LEXIVA plus ritonavir is not recommended for adult protease inhibitor-experienced patients or any pediatric patients [see DOSAGE AND ADMINISTRATION, Clinical Studies].
  • Dosing of LEXIVA plus ritonavir is not recommended for protease inhibitor-experienced pediatric patients younger than 6 months [see CLINICAL PHARMACOLOGY].

Clinical pharmacology

Mechanism Of Action

Fosamprenavir is an antiviral agent [see Microbiology].

Pharmacokinetics

The pharmacokinetic properties of amprenavir after administration of LEXIVA, with or without ritonavir, have been evaluated in both healthy adult volunteers and in HIV-1-infected subjects; no substantial differences in steady-state amprenavir concentrations were observed between the 2 populations.

The pharmacokinetic parameters of amprenavir after administration of LEXIVA (with and without concomitant ritonavir) are shown in Table 8.

Table 8: Geometric Mean (95% CI) Steady-state Plasma Amprenavir Pharmacokinetic Parameters in Adults

Regimen Cmax
(mcg/mL)		 Tmax
(hours)a		 AUC24
(mcg•h/mL)		 Cmin
(mcg/mL)
LEXIVA 1,400 mg b.i.d. 4.82
(4.06-5.72)		 1.3
(0.8-4.0)		 33.0
(27.6-39.2)		 0.35
(0.27-0.46)
LEXIVA 1,400 mg q.d. plus Ritonavir 200 mg q.d. 7.24
(6.32-8.28)		 2.1
(0.8-5.0)		 69.4
(59.7-80.8)		 1.45
(1.16-1.81)
LEXIVA 1,400 mg q.d. plus Ritonavir 100 mg q.d. 7.93
(7.25-8.68)		 1.5
(0.75-5.0)		 66.4
(61.1-72.1)		 0.86
(0.74-1.01)
LEXIVA 700 mg b.i.d. plus Ritonavir 100 mg b.i.d. 6.08
(5.38-6.86)		 1.5
(0.75-5.0)		 79.2
(69.0-90.6)		 2.12
(1.77-2.54)
a Data shown are median
(range).

The mean plasma amprenavir concentrations of the dosing regimens over the dosing intervals are displayed in Figure 1.

Figure 1: Mean (±SD) Steady-state Plasma Amprenavir Concentrations and Mean EC50 Values against HIV from Protease Inhibitor-naïve Subjects (in the Absence of Human Serum)

Absorption And Bioavailability

After administration of a single dose of LEXIVA to HIV-1-infected subjects, the time to peak amprenavir concentration (Tmax) occurred between 1.5 and 4 hours (median 2.5 hours). The absolute oral bioavailability of amprenavir after administration of LEXIVA in humans has not been established.

After administration of a single 1,400-mg dose in the fasted state, LEXIVA oral suspension (50 mg per mL) and LEXIVA tablets (700 mg) provided similar amprenavir exposures (AUC); however, the Cmax of amprenavir after administration of the suspension formulation was 14.5% higher compared with the tablet.

Amprenavir is both a substrate for and inducer of P-glycoprotein.

Effects Of Food On Oral Absorption

Administration of a single 1,400-mg dose of LEXIVA tablets in the fed state (standardized high-fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) compared with the fasted state was associated with no significant changes in amprenavir Cmax, Tmax, or AUC0-∞. [see DOSAGE AND ADMINISTRATION].

Administration of a single 1,400-mg dose of LEXIVA oral suspension in the fed state (standardized high-fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) compared with the fasted state was associated with a 46% reduction in Cmax, a 0.72-hour delay in Tmax, and a 28% reduction in amprenavir AUC0-∞.

Distribution

In vitro, amprenavir is approximately 90% bound to plasma proteins, primarily to alpha1-acid glycoprotein. In vitro, concentration-dependent binding was observed over the concentration range of 1 to 10 mcg per mL, with decreased binding at higher concentrations. The partitioning of amprenavir into erythrocytes is low, but increases as amprenavir concentrations increase, reflecting the higher amount of unbound drug at higher concentrations.

Metabolism

After oral administration, fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. This occurs in the gut epithelium during absorption. Amprenavir is metabolized in the liver by the CYP3A4 enzyme system. The 2 major metabolites result from oxidation of the tetrahydrofuran and aniline moieties. Glucuronide conjugates of oxidized metabolites have been identified as minor metabolites in urine and feces.

Elimination

Excretion of unchanged amprenavir in urine and feces is minimal. Unchanged amprenavir in urine accounts for approximately 1% of the dose; unchanged amprenavir was not detectable in feces. Approximately 14% and 75% of an administered single dose of 14C-amprenavir can be accounted for as metabolites in urine and feces, respectively. Two metabolites accounted for greater than 90% of the radiocarbon in fecal samples. The plasma elimination half-life of amprenavir is approximately 7.7 hours.

Special Populations

Hepatic Impairment: The pharmacokinetics of amprenavir have been studied after the administration of LEXIVA in combination with ritonavir to adult HIV-1-infected subjects with mild, moderate, and severe hepatic impairment. Following 2 weeks of dosing with LEXIVA plus ritonavir, the AUC of amprenavir was increased by approximately 22% in subjects with mild hepatic impairment, by approximately 70% in subjects with moderate hepatic impairment, and by approximately 80% in subjects with severe hepatic impairment compared with HIV-1- infected subjects with normal hepatic function. Protein binding of amprenavir was decreased in subjects with hepatic impairment. The unbound fraction at 2 hours (approximate Cmax) ranged between a decrease of -7% to an increase of 57% while the unbound fraction at the end of the dosing interval (Cmin) increased from 50% to 102% [see DOSAGE AND ADMINISTRATION].

The pharmacokinetics of amprenavir have been studied after administration of amprenavir given as AGENERASE® capsules to adult subjects with hepatic impairment. Following administration of a single 600-mg oral dose, the AUC of amprenavir was increased by approximately 2.5-fold in subjects with moderate cirrhosis and by approximately 4.5-fold in subjects with severe cirrhosis compared with healthy volunteers [see DOSAGE AND ADMINISTRATION].

Renal Impairment: The impact of renal impairment on amprenavir elimination in adults has not been studied. The renal elimination of unchanged amprenavir represents approximately 1% of the administered dose; therefore, renal impairment is not expected to significantly impact the elimination of amprenavir.

Pediatric Patients: 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.

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.

The pharmacokinetics of LEXIVA oral suspension in protease inhibitor-naive infants younger than 6 months (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. 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 was not studied.

Pharmacokinetic parameters for LEXIVA administered with food and with ritonavir in this patient population at the recommended weight-band-based dosage regimens are provided in Table 9.

Table 9: Geometric Mean (95% CI) Steady-state Plasma Amprenavir Pharmacokinetic Parameters by Weight in Pediatric and Adolescent Subjects Aged at Least 4 Weeks to 18 Years Receiving LEXIVA with Ritonavir

Weight Recommended Dosage Regimen Cmax AUC24 Cmin
n (mcg/mL) n (mcg•h/mL) n (mcg/mL)
< 11 kg LEXIVA 45 mg/kg plus Ritonavir 7 mg/kg b.i.d. 12 6.00
(3.88, 9.29)		 12 57.3
(34.1, 96.2)		 27 1.65
(1.22, 2.24)
11 kg - < 15 kg LEXIVA 30 mg/kg plus Ritonavir 3 mg/kg b.i.d. Not studieda
15 kg - < 20 kg LEXIVA 23 mg/kg plus Ritonavir 3 mg/kg b.i.d. 5 9.54
(4.63, 19.7)		 5 121
(54.2, 269)		 9 3.56
(2.33, 5.43)
20 kg - < 39 kg LEXIVA 18 mg/kg plus Ritonavir 3 mg/kg b.i.d. 13 6.24
(5.01, 7.77)		 12 97.9
(77.0, 124)		 23 2.54
(2.11, 3.06)
≥ 39 kg LEXIVA 700 mg plus Ritonavir 100 mg b.i.d. 15 5.03
(4.04, 6.26)		 15 72.3
(59.6, 87.6)		 42 1.98
(1.72, 2.29)
a Recommended dose for pediatric patients weighing 11 kg to less than 15 kg is based on population pharmacokinetic analysis.

Subjects aged 2 to younger 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.

Geriatric Patients: The pharmacokinetics of amprenavir after administration of LEXIVA to patients older than 65 years have not been studied [see Use in Specific Populations].

Gender: The pharmacokinetics of amprenavir after administration of LEXIVA do not differ between males and females.

Race: The pharmacokinetics of amprenavir after administration of LEXIVA do not differ between blacks and non-blacks.

Drug Interactions

[See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS]

Amprenavir, the active metabolite of fosamprenavir, is metabolized in the liver by the cytochrome P450 enzyme system. Amprenavir inhibits CYP3A4. 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). Amprenavir is both a substrate for and inducer of P-glycoprotein.

Drug interaction trials were performed with LEXIVA and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration on AUC, Cmax, and Cmin values are summarized in Table 10 (effect of other drugs on amprenavir) and Table 12 (effect of LEXIVA on other drugs). In addition, since LEXIVA delivers comparable amprenavir plasma concentrations as AGENERASE, drug interaction data derived from trials with AGENERASE are provided in Tables 11 and 13. For information regarding clinical recommendations, [see DRUG INTERACTIONS].

Table 10: Drug Interactions: Pharmacokinetic Parameters for Amprenavir after Administration of LEXIVA in the Presence of the Coadministered Drug(s)

Coadministered Drug(s) and Dose(s) Dose of LEXIVAa n % Change in Amprenavir Pharmacokinetic Parameters (90% CI)
Cmax AUC Cmm
Antacid (MAALOX TC®) 30 mL single dose 1,400 mg single dose 30 ↓35
(↓24 to ↓42)		 ↓18
(↓9 to ↓26)		 ↑14
(↓7 to ↑39)
Atazanavir 300 mg q.d. for 10 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 10 days 22 ↔ ↔ ↔
Atorvastatin 10 mg q.d. for 4 days 1,400 mg b.i.d. for 2 weeks 16 ↓18
(↓34 to ↑1)		 ↓27
(↓41 to ↓12)		 ↓12
(↓27 to ↓6)
Atorvastatin 10 mg q.d. for 4 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 16 ↔ ↔ ↔
Efavirenz 600 mg q.d. for 2 weeks 1,400 mg q.d. plus ritonavir 200 mg q.d. for 2 weeks 16 ↔ ↓13
(↓30 to ↑7)		 ↓36
(↓8 to ↓56)
Efavirenz 600 mg q.d. plus additional ritonavir 100 mg q.d. for 2 weeks 1,400 mg q.d. plus ritonavir 200 mg q.d. for 2 weeks 16 ↑18
(↑1 to ↑38)		 ↑11
(0 to ↑24)		 ↔
Efavirenz 600 mg q.d. for 2 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 16 ↔ ↔ ↓17
(↓4 to ↓29)
Esomeprazole 20 mg q.d. for 2 weeks 1,400 mg b.i.d. for 2 weeks 25 ↔ ↔ ↔
Esomeprazole 20 mg q.d. for 2 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 23 ↔ ↔ ↔
Ethinyl estradiol/ norethindrone 0.035 mg/0.5 mg q.d. for 21 days 700 mg b.i.d. plus ritonavirb 100 mg b.i.d. for 21 days 25 ↔c ↔c ↔c
Ketoconazoled 200 mg q.d. for 4 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 4 days 15 ↔ ↔ ↔
Lopinavir/ritonavir 533 mg/133 mg b.i.d. 1,400 mg b.i.d. for 2 weeks 18 ↓13e ↓26e ↓42e
Lopinavir/ritonavir 400 mg/100 mg b.i.d. for 2 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 18 ↓58
(↓42 to ↓70)		 ↓63
(↓51 to ↓72)		 ↓65
(↓54 to ↓73)
Maraviroc 300 mg b.i.d. for 10 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 20 days 14 ↓34
(↓25 to ↓41)		 ↓35
(↓29 to ↓41)		 ↓36
(↓27 to ↓43)
Maraviroc 300 mg q.d. for 10 days 1,400 mg q.d. plus ritonavir 100 mg q.d. for 20 days 14 ↓29
(↓20 to ↓38)		 ↓30
(↓23 to ↓36)		 ↓15
(↓3 to ↓25)
Methadone 70 to 120 mg q.d. for 2 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 19 ↔c ↔c ↔c
Nevirapine 200 mg b.i.d. for 2 weeksf 1,400 mg b.i.d. for 2 weeks 17 ↓25
(↓37 to ↓10)		 ↓33
(↓45 to ↓20)		 ↓35
(↓50 to ↓15)
Nevirapine 200 mg b.i.d. for 2 weeksf 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 17 ↔ ↓11
(↓23 to ↑3)		 ↓19
(↓32 to ↓4)
Phenytoin 300 mg q.d. for 10 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 10 days 13 ↔ ↑20
(↑8 to ↑34)		 ↑19
(↑6 to ↑33)
Raltegravir 400 mg b.i.d. for 14 days 1,400 mg b.i.d. for 14 days
(fasted)		 14 ↓27
(↓46 to ↔)		 ↓36
(↓53 to ↓13)		 ↓43g
(↓59 to ↓21)
1,400 mg b.i.d. for 14 daysh 14 ↓15
(↓27 to ↓1)		 ↓17
(↓27 to ↓6)		 ↓32g
(↓53 to ↓1)
700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 14 days
(fasted)		 14 ↓14
(↓39 to ↑20)		 ↓17
(↓38 to ↑12)		 ↓20g
(↓45 to ↑17)
700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 14 daysh 12 ↓25
(↓42 to ↓2)		 ↓25
(↓44 to ↔)		 ↓33g
(↓52 to ↓7)
Raltegravir 400 mg b.i.d. for 14 days 1,400 mg q.d. plus ritonavir 100 mg q.d. for 14 days
(fasted)		 13 ↓18
(↓34 to ↔)		 ↓24
(↓41 to ↔)		 ↓50g
(↓64 to ↓31)
1,400 mg q.d. plus ritonavir 100 mg q.d. for 14 daysh 14 ↑27
(↓1 to ↑62)		 ↑13
(↓7 to ↑38)		 ↓17g
(↓45 to ↑26)
Ranitidine 300 mg single dose
(administered 1 hour before fosamprenavir)		 1,400 mg single dose 30 ↓51
(↓43 to ↓58)		 ↓30
(↓22 to ↓37)		 ↔
(↓19 to ↑21)
Rifabutin 150 mg q.o.d. for 2 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 15 ↑36c
(↑18 to ↑55)		 ↑35c (↑17 to ↑56) ↑17c
(↓1 to ↑39)
Tenofovir 300 mg q.d. for 4 to 48 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 4 to 48 weeks 45 NA NA ↔i
Tenofovir 300 mg q.d. for 4 to 48 weeks 1,400 mg q.d. plus ritonavir 200 mg q.d. for 4 to 48 weeks 60 NA NA ↔i
a Concomitant medication is also shown in this column where appropriate.
b Ritonavir Cmax, AUC, and Cmin increased by 63%, 45%, and 13%, respectively, compared with historical control.
c Compared with historical control.
d Subjects were receiving LEXIVA/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and LEXIVA/ritonavir.
e Compared with LEXIVA 700 mg/ritonavir 100 mg b.i.d. for 2 weeks.
fSubjects were receiving nevirapine for at least 12 weeks prior to trial.
g Clast (C12 h or C24 h).
h Doses of LEXIVA and raltegravir were given with food on pharmacokinetic sampling days and without regard to food all other days.
i Compared with parallel control group.
↑= Increase; ↓= Decrease; ↔ = No change (↑or ↓ less than or equal to 10%), NA = Notapplicable.

Table 11: Drug Interactions: Pharmacokinetic Parameters for Amprenavir after Administration of AGENERASE in the Presence of the Coadministered Drug(s)

Coadministered Drug(s) and Dose(s) Dose of AGENERASEa n % Change in Amprenavir Pharmacokinetic Parameters (90% CI)
Cmax AUC Cmin
Abacavir 300 mg b.i.d. for 2 to 3 weeks 900 mg b.i.d. for 2 to 3 weeks 4 ↔a ↔a ↔a
Clarithromycin 500 mg b.i.d. for 4 days 1,200 mg b.i.d. for 4 days 12 ↑15
(↑1 to ↑31)		 ↑18
(↑8 to ↑29)		 ↑39
(↑31 to ↑47)
Delavirdine 600 mg b.i.d. for 10 days 600 mg b.i.d. for 10 days 9 ↑40b ↑130b ↑125b
Ethinyl estradiol/norethindrone 0.035 mg/1 mg for 1 cycle 1,200 mg b.i.d. for 28 days 10 ↔ ↓22
(↓35 to ↓8)		 ↓20
(↓41 to ↑8)
Indinavir 800 mg t.i.d. for 2 weeks (fasted) 750 or 800 mg t.i.d. for 2 weeks
(fasted)		 9 ↑18
(↑13 to ↑58)		 ↑33
(↑2 to ↑73)		 ↑25
(↓27 to ↑116)
Ketoconazole 400 mg single dose 1,200 mg single dose 12 ↓16
(↓25 to ↓6)		 ↑31
(↑20 to ↑42)		 NA
Lamivudine 150 mg single dose 600 mg single dose 11 ↔ ↔ NA
Methadone 44 to 100 mg q.d. for > 30 days 1,200 mg b.i.d. for 10 days 16 ↓27c ↓30c ↓25c
Nelfinavir 750 mg t.i.d. for 2 weeks (fed) 750 or 800 mg t.i.d. for 2 weeks
(fed)		 6 ↓14
(↓38 to ↑20)		 ↔ ↑189
(↑52 to ↑448)
Rifabutin 300 mg q.d. for 10 days 1,200 mg b.i.d. for 10 days 5 ↔ ↓15
(↓28 to 0)		 ↓15
(↓38 to ↑17)
Rifampin 300 mg q.d. for 4 days 1,200 mg b.i.d. for 4 days 11 ↓70
(↓76 to ↓62)		 ↓82
(↓84 to ↓78)		 ↓92
(↓95 to ↓89)
Saquinavir 800 mg t.i.d. for 2 weeks (fed) 750 or 800 mg t.i.d. for 2 weeks
(fed)		 7 ↓37
(↓54 to ↓14)		 ↓32
(↓49 to ↓9)		 ↓14
(↓52 to ↑54)
Zidovudine 300 mg single dose 600 mg single dose 12 ↔ ↑13
(↓2 to ↑31)		 NA
a Compared with parallel control group.
bMedian percent change; confidence interval not reported.
c Compared with historical data.
↑ = Increase; ↓ = Decrease; ↔ = No change
(↑or ↓ less than 10%); NA = Cmin not calculated for single-dose trial.

Table 12: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of LEXIVA

Coadministered Drug(s) and Dose(s) Dose of LEXIVAa n % Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI)
Cmax AUC Cmin
Atazanavir 300 mg q.d. for 10 daysb 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 10 days 21 ↓24
(↓39 to ↓6)		 ↓22
(↓34 to ↓9)		 ↔
Atorvastatin 10 mg q.d. for 4 days 1,400 mg b.i.d. for 2 weeks 16 ↑304
(↑205 to ↑437)		 ↑130
(↑100 to ↑164)		 ↓10
(↓27 to ↑12)
Atorvastatin 10 mg q.d. for 4 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 16 ↑184
(↑126 to ↑257)		 ↑153
(↑115 to ↑199)		 ↑73
(↑45 to ↑108)
Esomeprazole 20 mg q.d. for 2 weeks 1,400 mg b.i.d. for 2 weeks 25 ↔ ↑55
(↑39 to ↑73)		 ND
Esomeprazole 20 mg q.d. for 2 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 23 ↔ ↔ ND
Ethinyl estradiolc 0.035 mg q.d. for 21 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 21 days 25 ↓28
(↓21 to ↓35)		 ↓37
(↓30 to ↓42)		 ND
Dolutegravir 50 mg q.d. 700 mg b.i.d. plus ritonavir 100 mg b.i.d. 12 ↓24
(↓8 to ↓37)		 ↓35
(↓22 to ↓46)		 ↓49
(↓37 to ↓59)
Ketoconazoled 200 mg q.d. for 4 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 4 days 15 ↑25
(↑0 to ↑56)		 ↑169
(↑108 to ↑248)		 ND
Lopinavir/ritonavire 533 mg/133 mg b.i.d. for 2 weeks 1,400 mg b.i.d. for 2 weeks 18 ↔f ↔f ↔f
Lopinavir/ritonavire 400 mg/100 mg b.i.d. for 2 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 18 ↑30
(↓15 to ↑47)		 ↑37
(↓20 to ↑55)		 ↑52
(↓28 to ↑82)
Maraviroc 300 mg b.i.d. for 10 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 20 days 14 ↑52
(↑27 to ↑82)		 ↑149
(↑119 to ↑182)		 ↑374
(↑303 to ↑457)
Maraviroc 300 mg q.d. for 10 days 1,400 mg q.d. plus ritonavir 100 mg q.d. for 20 days 14 ↑45
(↑20 to ↑74)		 ↑126
(↑99 to ↑158)		 ↑80
(↑53 to ↑113)
Methadone 70 to 120 mg q.d. for 2 weeks 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 19 R-Methadone
(active)
↓21g
(↓30 to ↓12)		 ↓18g
(↓27 to ↓8)		 ↓11g
(↓21 to ↑1)
S-Methadone
(inactive)
↓43g (↓49 to ↓37) ↓43g (↓50 to ↓36) ↓41g
(↓49 to ↓31)
Nevirapine 200 mg b.i.d. for 2 weeksh 1,400 mg b.i.d. for 2 weeks 17 ↑25
(↑14 to ↑37)		 ↑29
(↑19 to ↑40)		 ↑34
(↑20 to ↑49)
Nevirapine 200 mg b.i.d. for 2 weeksh 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 17 ↑13
(↑3 to ↑24)		 ↑14
(↑5 to ↑24)		 ↑22
(↑9 to ↑35)
Norethindronec 0.5 mg q.d. for 21 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 21 days 25 ↓38
(↓32 to ↓44)		 ↓34
(↓30 to ↓37)		 ↓26
(↓20 to ↓32)
Phenytoin 300 mg q.d. for 10 days 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 10 days 14 ↓20
(↓12 to ↓27)		 ↓22
(↓17 to ↓27)		 ↓29
(↓23 to ↓34)
Rifabutin 150 mg every other day for 2 weeks i
(25-O-desacetylrifabutin metabolite) Rifabutin + 25-O-desacetylrifabutin metabolite		 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks 15 ↓14
(↓28 to ↑4)		 ↔ ↑28
(↑12 to ↑46)
↑579
(↑479 to ↑698)		 ↑1,120
(↑965 to ↑1,300)		 ↑2,510
(↑1,910 to ↑3,300)
NA ↑64
(↑46 to ↑84)		 NA
Rosuvastatin 10 mg single dose 700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 7 days (↑45) (↑8) NA
a Concomitant medication is also shown in this column where appropriate.
b Comparison arm of atazanavir 300 mg q.d. plus ritonavir 100 mg q.d. for 10 days.
c Administered as a combination oral contraceptive tablet: ethinyl estradiol 0.035 mg/norethindrone 0.5 mg.
d Subjects were receiving LEXIVA/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and LEXIVA/ritonavir.
e Data represent lopinavir concentrations.
fCompared with lopinavir 400 mg/ritonavir 100 mg b.i.d. for 2 weeks.
g Dose normalized to methadone 100 mg. The unbound concentration of the active moiety, R-methadone, was unchanged.
hSubjects were receiving nevirapine for at least 12 weeks prior to trial.
i Comparison arm of rifabutin 300 mg q.d. for 2 weeks. AUC is AUC(0-48 h).
↑ = Increase; ↓= Decrease; ↔ = No change (↑or ↓less than 10%); ND = Interaction cannot be determined as Cmin was below the lower limit of quantitation.

Table 13: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of AGENERASE

Coadministered Drug(s) and Dose(s) Dose of AGENERASE n % Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI)
Cmax AUC Cmm
Abacavir 300 mg b.i.d. for 2 to 3 weeks 900 mg b.i.d. for 2 to 3 weeks 4 ↔a ↔a ↔a
Clarithromycin 500 mg b.i.d. for 4 days 1,200 mg b.i.d. for 4 days 12 ↓10
(↓24 to ↑7)		 ↔ ↔
Delavirdine 600 mg b.i.d. for 10 days 600 mg b.i.d. for 10 days 9 ↓47b ↓61b ↓88b
Ethinyl estradiol 0.035 mg for 1 cycle 1,200 mg b.i.d. for 28 days 10 ↔ ↔ ↑32
(↓3 to ↑79)
Indinavir 800 mg t.i.d. for 2 weeks (fasted) 750 mg or 800 mg t.i.d. for 2 weeks
(fasted)		 9 ↓22a ↓38a ↓27a
Ketoconazole 400 mg single dose 1,200 mg single dose 12 ↑19
(↑8 to ↑33)		 ↑44
(↑31 to ↑59)		 NA
Lamivudine 150 mg single dose 600 mg single dose 11 ↔ ↔ NA
Methadone 44 to 100 mg q.d. for > 30 days 1,200 mg b.i.d. for 10 days 16 R-Methadone (active)
↓25
(↓32 to ↓18)		 ↓13
(↓21 to ↓5)		 ↓21
(↓32 to ↓9)
S-Methadone (inactive)
↓48
(↓55 to ↓40)		 ↓40
(↓46 to ↓32)		 ↓53
(↓60 to ↓43)
Nelfinavir 750 mg t.i.d. for 2 weeks (fed) 750 mg or 800 mg t.i.d. for 2 weeks
(fed)		 6 ↑12a ↑15a ↑14a
Norethindrone 1 mg for 1 cycle 1,200 mg b.i.d. for 28 days 10 ↔ ↑18
(↑1 to ↑38)		 ↑45
(↑13 to ↑88)
Rifabutin 300 mg q.d. for 10 days 1,200 mg b.i.d. for 10 days 5 ↑119
(↑82 to ↑164)		 ↑193
(↑156 to ↑235)		 ↑271
(↑171 to ↑409)
Rifampin 300 mg q.d. for 4 days 1,200 mg b.i.d. for 4 days 11 ↔ ↔ ND
Saquinavir 800 mg t.i.d. for 2 weeks (fed) 750 mg or 800 mg t.i.d. for 2 weeks
(fed)		 7 ↑21a ↓19a ↓48a
Zidovudine 300 mg single dose 600 mg single dose 12 ↑40
(↑14 to ↑71)		 ↑31
(↑19 to ↑45)		 NA
a Compared with historical data.
b Median percent change; confidence interval not reported.
↑ = Increase; ↓ = Decrease; ↔= No change
(↑or ↓ less than 10%); NA = Cmin not calculated forsingle-dose trial; ND = Interaction cannot be determined as Cmin was below the lower limit of quantitation.

Microbiology

Mechanism Of Action

Fosamprenavir is a prodrug that is rapidly hydrolyzed to amprenavir by cellular phosphatases in the gut epithelium as it is absorbed. Amprenavir is an inhibitor of HIV-1 protease. Amprenavir binds to the active site of HIV-1 protease and thereby prevents the processing of viral Gag and Gag-Pol polyprotein precursors, resulting in the formation of immature non-infectious viral particles.

Antiviral Activity

Fosamprenavir has little or no antiviral activity in cell culture. The antiviral activity of amprenavir was evaluated against HIV-1 IIIB in both acutely and chronically infected lymphoblastic cell lines (MT-4, CEM-CCRF, H9) and in peripheral blood lymphocytes in cell culture. The 50% effective concentration (EC50) of amprenavir ranged from 0.012 to 0.08 microM in acutely infected cells and was 0.41 microM in chronically infected cells (1 microM = 0.50 mcg per mL). The median EC50 value of amprenavir against HIV-1 isolates from clades A to G was 0.00095 microM in peripheral blood mononuclear cells (PBMCs). Similarly, the EC50 values for amprenavir against monocytes/macrophage tropic HIV-1 isolates (clade B) ranged from 0.003 to 0.075 microM in monocyte/macrophage cultures. The EC50 values of amprenavir against HIV-2 isolates grown in PBMCs were higher than those for HIV-1 isolates, and ranged from 0.003 to 0.11 microM. Amprenavir exhibited synergistic anti-HIV-1 activity in combination with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, lamivudine, stavudine, tenofovir, and zidovudine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine and efavirenz; and the protease inhibitors atazanavir and saquinavir. Amprenavir exhibited additive anti-HIV-1 activity in combination with the NNRTI nevirapine, the protease inhibitors indinavir, lopinavir, nelfinavir, and ritonavir; and the fusion inhibitor enfuvirtide. These drug combinations have not been adequately studied in humans.

Resistance

HIV-1 isolates with decreased susceptibility to amprenavir have been selected in cell culture and obtained from subjects treated with fosamprenavir. Genotypic analysis of isolates from treatment-naive subjects failing amprenavir-containing regimens showed substitutions in the HIV-1 protease gene resulting in amino acid substitutions primarily at positions V32I, M46I/L, I47V, I50V, I54L/M, and I84V, as well as substitutions in the p7/p1 and p1/p6 Gag and Gag-Pol polyprotein precursor cleavage sites. Some of these amprenavir resistance-associated substitutions have also been detected in HIV-1 isolates from antiretroviral-naive subjects treated with LEXIVA. Of the 488 antiretroviral-naive subjects treated with LEXIVA 1,400 mg twice daily or LEXIVA 1,400 mg plus ritonavir 200 mg once daily in Trials APV30001 and APV30002, respectively, 61 subjects (29 receiving LEXIVA and 32 receiving LEXIVA/ritonavir) with virologic failure (plasma HIV-1 RNA greater than 1,000 copies per mL on 2 occasions on or after Week 12) were genotyped. Five of the 29 antiretroviral-naive subjects (17%) receiving LEXIVA without ritonavir in Trial APV30001 had evidence of genotypic resistance to amprenavir: I54L/M (n = 2), I54L + L33F (n = 1), V32I + I47V (n = 1), and M46I + I47V (n = 1). No amprenavir resistance-associated substitutions were detected in antiretroviral-naive subjects treated with LEXIVA/ritonavir for 48 weeks in Trial APV30002. However, the M46I and I50V substitutions were detected in isolates from 1 virologic failure subject receiving LEXIVA/ritonavir once daily at Week 160 (HIV-1 RNA greater than 500 copies per mL). Upon retrospective analysis of stored samples using an ultrasensitive assay, these resistant substitutions were traced back to Week 84 (76 weeks prior to clinical virologic failure).

Cross-resistance

Varying degrees of cross-resistance among HIV-1 protease inhibitors have been observed. An association between virologic response at 48 weeks (HIV-1 RNA level less than 400 copies per mL) and protease inhibitor-resistance substitutions detected in baseline HIV-1 isolates from protease inhibitor-experienced subjects receiving LEXIVA/ritonavir twice daily (n = 88), or lopinavir/ritonavir twice daily (n = 85) in Trial APV30003 is shown in Table 14. The majority of subjects had previously received either one (47%) or 2 protease inhibitors (36%), most commonly nelfinavir (57%) and indinavir (53%). Out of 102 subjects with baseline phenotypes receiving twice-daily LEXIVA/ritonavir, 54% (n = 55) had resistance to at least one protease inhibitor, with 98% (n = 54) of those having resistance to nelfinavir. Out of 97 subjects with baseline phenotypes in the lopinavir/ritonavir arm, 60% (n = 58) had resistance to at least one protease inhibitor, with 97% (n = 56) of those having resistance to nelfinavir.

Table 14: Responders at Trial Week 48 by Presence of Baseline Protease Inhibitor Resistance-associated Substitutionsa

Protease Inhibitor Resistance-associated Substitutionsb LEXIVA/Ritonavir b.i.d.
(n = 88)		 Lopinavir/Ritonavir b.i.d.
(n = 85)
D30N 21/22 95% 17/19 89%
N88D/S 20/22 91% 12/12 100%
L90M 16/31 52% 17/29 59%
M46I/L 11/22 50% 12/24 50%
V82A/F/T/S 2/9 22% 6/17 35%
I54V 2/11 18% 6/11 55%
I84V 1/6 17% 2/5 40%
a Results should be interpreted with caution because the subgroups were small.
bMost subjects had greater than 1 protease inhibitor resistance-associated substitution at baseline.

The virologic response based upon baseline phenotype was assessed. Baseline isolates from protease inhibitor-experienced subjects responding to LEXIVA/ritonavir twice daily had a median shift in susceptibility to amprenavir relative to a standard wild-type reference strain of 0.7 (range: 0.1 to 5.4, n = 62), and baseline isolates from individuals failing therapy had a median shift in susceptibility of 1.9 (range: 0.2 to 14, n = 29). Because this was a select patient population, these data do not constitute definitive clinical susceptibility break points. Additional data are needed to determine clinically relevant break points for LEXIVA.

Isolates from 15 of the 20 subjects receiving twice-daily LEXIVA/ritonavir up to Week 48 and experiencing virologic failure/ongoing replication were subjected to genotypic analysis. The following amprenavir resistance-associated substitutions were found either alone or in combination: V32I, M46I/L, I47V, I50V, I54L/M, and I84V. Isolates from 4 of the 16 subjects continuing to receive twice-daily LEXIVA/ritonavir up to Week 96 who experienced virologic failure underwent genotypic analysis. Isolates from 2 subjects contained amprenavir resistance-associated substitutions: V32I, M46I, and I47V in 1 isolate and I84V in the other.

Clinical Studies

Therapy-naive Adult Trials

APV30001

A randomized, open-label trial evaluated treatment with LEXIVA tablets (1,400 mg twice daily) versus nelfinavir (1,250 mg twice daily) in 249 antiretroviral treatment-naive subjects. Both groups of subjects also received abacavir (300 mg twice daily) and lamivudine (150 mg twice daily).

The mean age of the subjects in this trial was 37 years (range: 17 to 70 years); 69% of the subjects were male, 20% were CDC Class C (AIDS), 24% were white, 32% were black, and 44% were Hispanic. At baseline, the median CD4+ cell count was 212 cells per mm³ (range: 2 to 1,136 cells per mm³ ; 18% of subjects had a CD4+ cell count of less than 50 cells per mm³ and 30% were in the range of 50 to less than 200 cells per mm³). Baseline median HIV-1 RNA was 4.83 log10 copies per mL (range: 1.69 to 7.41 log10 copies per mL; 45% of subjects had greater than 100,000 copies per mL).

The outcomes of randomized treatment are provided in Table 15.

Table 15: Outcomes of Randomized Treatment through Week 48 (APV30001)

Outcome (Rebound or discontinuation = failure) LEXIVA 1,400 mg b.i.d.
(n = 166)		 Nelfinavir 1,250 mg b.i.d.
(n = 83)
Respondera 66% (57%) 52% (42%)
Virologic failure 19% 32%
  Rebound 16% 19%
  Never suppressed through Week 48 3% 13%
Clinical progression 1% 1%
Death 0% 1%
Discontinued due to adverse reactions 4% 2%
Discontinued due to other reasonsb 10% 10%
a Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL (less than 50 copies per mL) through Week 48 (Roche AMPLICOR HIV-1 MONITOR Assay Version 1.5).
b Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, and other reasons.

Treatment response by viral load strata is shown in Table 16.

Table 16: Proportions of Responders through Week 48 by Screening Viral Load (APV30001)

Screening Viral Load HIV-1 RNA (copies/mL) LEXIVA 1,400 mg b.i.d. Nelfinavir 1,250 mg b.i.d.
< 400 copies/mL n < 400 copies/mL n
≤ 100,000 65% 93 65% 46
> 100,000 67% 73 36% 37

Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 201 cells per mm³ in the group receiving LEXIVA and 216 cells per mm³ in the nelfinavir group.

APV30002

A randomized, open-label trial evaluated treatment with LEXIVA tablets (1,400 mg once daily) plus ritonavir (200 mg once daily) versus nelfinavir (1,250 mg twice daily) in 649 treatment-naive subjects. Both treatment groups also received abacavir (300 mg twice daily) and lamivudine (150 mg twice daily).

The mean age of the subjects in this trial was 37 years (range: 18 to 69 years); 73% of the subjects were male, 22% were CDC Class C, 53% were white, 36% were black, and 8% were 3 Hispanic. At baseline, the median CD4+ cell count was 170 cells per mm (range: 1 to 1,055 cells per mm³ ; 20% of subjects had a CD4+ cell 3count of less than 50 cells per mm and 3 35% were in the range of 50 to less than 200 cells per mm ). Baseline median HIV-1 RNA was 4.81 log10 copies per mL (range: 2.65 to 7.29 log10 copies per mL; 43% of subjects had greater than 100,000 copies per mL).

The outcomes of randomized treatment are provided in Table 17.

Table 17: Outcomes of Randomized Treatment through Week 48 (APV30002)

Outcome (Rebound or discontinuation = failure) LEXIVA 1,400 mg q.d./ Ritonavir 200 mg q.d.
(n = 322)		 Nelfinavir 1,250 mg b.i.d.
(n = 327)
Respondera 69% (58%) 68% (55%)
Virologic failure 6% 16%
  Rebound 5% 8%
  Never suppressed through Week 48 1% 8%
Death 1% 0%
Discontinued due to adverse reactions 9% 6%
Discontinued due to other reasonsb 15% 10%
a Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL (less than 50 copies per mL) through Week 48 (Roche AMPLICOR HIV-1 MONITOR Assay Version 1.5).
b Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, and other reasons.

Treatment response by viral load strata is shown in Table 18.

Table 18: Proportions of Responders through Week 48 by Screening Viral Load (APV30002)

Screening Viral Load HIV-1 RNA (copies/mL) LEXIVA 1,400 mg q.d./ Ritonavir 200 mg q.d. Nelfinavir 1,250 mg b.i.d.
< 400 copies/mL n < 400 copies/mL n
&e;100,000 72% 197 73% 194
> 100,000 66% 125 64% 133

Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 203 cells per mm³ in the group receiving LEXIVA and 207 cells per mm³ in the nelfinavir group.

Protease Inhibitor-experienced Adult Trials

APV30003

A randomized, open-label, multicenter trial evaluated 2 different regimens of LEXIVA plus ritonavir (LEXIVA tablets 700 mg twice daily plus ritonavir 100 mg twice daily or LEXIVA tablets 1,400 mg once daily plus ritonavir 200 mg once daily) versus lopinavir/ritonavir (400 mg/100 mg twice daily) in 315 subjects who had experienced virologic failure to 1 or 2 prior protease inhibitor-containing regimens.

The mean age of the subjects in this trial was 42 years (range: 24 to 72 years); 85% were male, 33% were CDC Class C, 67% were white, 24% were black, and 9% were Hispanic. The median CD4+ cell count at baseline was 263 cells per mm³ (range: 2 to 1,171 cells per mm³ ). Baseline median plasma HIV-1 RNA level was 4.14 log10 copies per mL (range: 1.69 to 6.41 log10 copies per mL).

The median durations of prior exposure to NRTIs were 257 weeks for subjects receiving LEXIVA/ritonavir twice daily (79% had greater than or equal to 3 prior NRTIs) and 210 weeks for subjects receiving lopinavir/ritonavir (64% had greater than or equal to 3 prior NRTIs). The median durations of prior exposure to protease inhibitors were 149 weeks for subjects receiving LEXIVA/ritonavir twice daily (49% received greater than or equal to 2 prior protease inhibitors) and 130 weeks for subjects receiving lopinavir/ritonavir (40% received greater than or equal to 2 prior protease inhibitors).

The time-averaged changes in plasma HIV-1 RNA from baseline (AAUCMB) at 48 weeks (the endpoint on which the trial was powered) were -1.4 log10 copies per mL for twice-daily LEXIVA/ritonavir and -1.67 log10 copies per mL for the lopinavir/ritonavir group. The proportions of subjects who achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL (secondary efficacy endpoint) were 58% with twice-daily LEXIVA/ritonavir and 61% with lopinavir/ritonavir (95% CI for the difference: -16.6, 10.1). The proportions of subjects with HIV-1 RNA less than 50 copies per mL with twice-daily LEXIVA/ritonavir and with lopinavir/ritonavir were 46% and 50%, respectively (95% CI for the difference: -18.3, 8.9).

The proportions of subjects who were virologic failures were 29% with twice-daily LEXIVA/ritonavir and 27% with lopinavir/ritonavir.

The frequency of discontinuations due to adverse events and other reasons, and deaths were similar between treatment arms.

Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 81 cells per mm³ with twice-daily LEXIVA/ritonavir and 91 cells per mm³ with lopinavir/ritonavir.

This trial was not large enough to reach a definitive conclusion that LEXIVA/ritonavir and lopinavir/ritonavir are clinically equivalent.

Once-daily administration of LEXIVA plus ritonavir is not recommended for protease inhibitor-experienced patients. Through Week 48, 50% and 37% of subjects receiving LEXIVA 1,400 mg plus ritonavir 200 mg once daily had plasma HIV-1 RNA less than 400 copies per mL and less than 50 copies per mL, respectively.

Pediatric Trials

Three open-label trials in pediatric subjects aged at least 4 weeks to 18 years were conducted. In one trial (APV29005), twice-daily dosing regimens (LEXIVA with or without ritonavir) were evaluated in combination with other antiretroviral agents in pediatric subjects aged 2 to 18 years. In a second trial (APV20002), twice-daily dosing regimens (LEXIVA with ritonavir) were evaluated in combination with other antiretroviral agents in pediatric subjects aged at least 4 weeks to younger than 2 years. A third trial (APV20003) evaluated once-daily dosing of LEXIVA with ritonavir; the pharmacokinetic data from this trial did not support a once-daily dosing regimen in any pediatric patient population.

APV29005

LEXIVA: Twenty (18 therapy-naive and 2 therapy-experienced) pediatric subjects received LEXIVA oral suspension without ritonavir twice daily. At Week 24, 65% (13 of 20) achieved HIV-1 RNA less than 400 copies per mL, and the median increase from baseline in CD4+ cell count was 350 cells per mm³.

LEXIVA plus Ritonavir: Forty-nine protease inhibitor-naive and 40 protease inhibitor-experienced pediatric subjects received LEXIVA oral suspension or tablets with ritonavir twice daily. At Week 24, 71% of protease inhibitor-naive (35 of 49) and 55% of protease inhibitor-experienced (22 of 40) subjects achieved HIV-1 RNA less than 400 copies per mL; median increases from baseline in CD4+ cell counts were 184 cells per mm³ and 150 cells per mm³ in protease inhibitor-naive and experienced subjects, respectively.

APV20002

Fifty-four pediatric subjects (49 protease inhibitor-naive and 5 protease inhibitor-experienced) received LEXIVA oral suspension with ritonavir twice daily. At Week 24, 72% of subjects achieved HIV-1 RNA less than 400 copies per mL. The median increases from baseline in CD4+ 3 cell counts were 400 cells per mm³ in subjects aged at least 4 weeks to  ounger than 6 months 3 and 278 cells per mm³ in subjects aged 6 months to 2 years.

What should i discuss with my healthcare provider before taking fosamprenavir (lexiva)?

You should not take this medication if you are allergic to fosamprenavir or a similar drug called amprenavir (Agenerase).

Life-threatening side effects may occur if you take fosamprenavir with: alfuzosin (Uroxatral), cisapride (Propulsid), delavirdine (Rescriptor), pimozide (Orap), rifampin (Rifadin, Rimactane, Rifater), lovastatin (Mevacor, Altoprev, Advicor), simvastatin (Zocor, Simcor, Vytorin, Juvisync), midazolam (Versed), triazolam (Halcion), sildenafil (Revatio, for treating pulmonary arterial hypertension), St. John's wort, or an ergot medicine such as Ergomar, Cafergot, Wigraine, D.H.E. 45, Migranal, Methergine.

Fosamprenavir should not be taken together with ritonavir (Norvir) if you are also using a heart rhythm medication called flecainide (Tambocor) or propafenone (Rythmol). Ask your doctor about taking a different medication for your heart rhythm disorder.

To make sure you can safely take fosamprenavir, tell your doctor if you have any of these other conditions:

  • liver disease;
  • kidney disease;
  • diabetes;
  • a bleeding disorder such as hemophilia;
  • heart disease, history of heart attack;
  • an allergy to sulfa drugs;
  • high cholesterol or triglycerides; or
  • if you have ever used a protease inhibitor in the past.

FDA pregnancy category C. It is not known whether fosamprenavir will harm an unborn baby. Tell your doctor if you are pregnant. HIV can be passed to your baby if you are not properly treated during pregnancy. Take all of your HIV medicines as directed to control your infection.

Your name may need to be listed on an antiviral pregnancy registry when you start using this medication.

Taking fosamprenavir together with another HIV medicine called ritonavir (Norvir) and also using birth control pills can increase your risk of liver problems. Ask your doctor about using a non-hormone method of birth control (such as a condom, diaphragm, spermicide) to prevent pregnancy while taking fosamprenavir and ritonavir.

Women with HIV or AIDS should not breast-feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

Fosamprenavir should not be given to an infant younger than 4 weeks (28 days) old.

Interactions for Fosamprenavir Calcium

Amprenavir (active metabolite of fosamprenavir) is metabolized by CYP3A4.1

Amprenavir inhibits CYP3A4 and also may induce CYP3A4.1

Amprenavir does not inhibit CYP2D6, 1A2, 2C9, 2C19, or P2E11 or uridine glucuronosyltransferase (UDPGT).1

Some interaction studies have been performed using fosamprenavir.1 These studies may not predict magnitude of interaction with ritonavir-boosted fosamprenavir.1

Since fosamprenavir is metabolized to amprenavir, interactions reported with amprenavir (no longer commercially available in the US) also apply to fosamprenavir.1

When fosamprenavir is used with low-dose ritonavir, consider interactions reported with low-dose ritonavir.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors or substrates of CYP3A4 with possible alteration in metabolism of amprenavir and/or the other drug.1

Drugs Affecting or Affected by P-glycoprotein Transport

Amprenavir is a substrate of and an inducer of P-glycoprotein (P-gp) transport system.1

Specific Drugs

Drug

Interaction

Comments

Abacavir

Studies using amprenavir indicate pharmacokinetic interaction unlikely1

In vitro evidence of synergistic antiretroviral effects1

Alfuzosin

Potential for increased alfuzosin concentrations that could result in hypotension1

Concomitant use with fosamprenavir (with or without low-dose ritonavir) is contraindicated1

Antacids

Decreased amprenavir concentrations and AUC1

Manufacturer of fosamprenavir states interaction not considered clinically important and makes no restrictions for concomitant use with antacids2

Some experts recommend fosamprenavir be given simultaneously with or at least 2 hours before or 1 hour after antacids200

Antiarrhythmic agents (amiodarone, dronedarone, flecainide, systemic lidocaine, propafenone, quinidine)

Possible increased antiarrhythmic agent concentrations1

Potential for serious or life-threatening effects (e.g., cardiac arrhythmias) if ritonavir-boosted fosamprenavir used in patients receiving flecainide or propafenone1

Potential for serious or life-threatening effects (e.g., cardiac arrhythmias) if fosamprenavir used in conjunction with amiodarone, systemic lidocaine, or quinidine1

In patients receiving ritonavir-boosted fosamprenavir, concomitant use with flecainide or propafenone contraindicated1

Caution if fosamprenavir used concomitantly with amiodarone, systemic lidocaine, or quinidine; antiarrhythmic concentration monitoring recommended1

Amiodarone or dronedarone: Some experts state do not use concomitantly with fosamprenavir (with or without low-dose ritonavir)200

Anticoagulants, oral

Apixaban, edoxaban, rivaroxaban: Increased anticoagulant concentrations200

Dabigatran: Possible increased dabigatran concentrations200

Warfarin: Possible altered warfarin concentrations1

Apixaban, edoxaban, rivaroxaban: Avoid concomitant use200

Dabigatran: Dosage adjustments not needed in patients with Clcr >50 mL/minute;200 avoid concomitant use in those with Clcr <50 mL/minute200

Warfarin: Monitor INR,1 especially when initiating or discontinuing fosamprenavir;200 adjust warfarin dosage as needed200

Anticonvulsants (carbamazepine, ethosuximide, lamotrigine, phenobarbital, phenytoin)

Carbamazepine, phenobarbital, phenytoin: Possible decreased amprenavir concentrations and decreased virologic response when used with unboosted fosamprenavir1 200

Carbamazepine, phenobarbital: Possible increased carbamazepine concentrations and decreased amprenavir concentrations when used with ritonavir-boosted fosamprenavir200

Ethosuximide: Possible increased ethosuximide concentrations200

Lamotrigine: Possible decreased lamotrigine concentrations if used concomitantly with ritonavir-boosted fosamprenavir200

Phenytoin: Increased amprenavir concentrations and decreased phenytoin concentrations when used with ritonavir-boosted fosamprenavir1 200

Carbamazepine, phenobarbital, phenytoin: Use concomitantly with unboosted fosamprenavir with caution;1 some experts state do not use concomitantly with unboosted fosamprenavir200

Carbamazepine, phenobarbital: If using ritonavir-boosted fosamprenavir, consider alternative anticonvulsant or monitor concentrations of the anticonvulsant and amprenavir and assess antiretroviral response200

Ethosuximide: Monitor for ethosuximide toxicity200

Lamotrigine: If used with ritonavir-boosted fosamprenavir, consider increasing lamotrigine dosage and monitoring lamotrigine concentrations;200 alternatively, consider alternative anticonvulsant200

Phenytoin: Usual dosages of ritonavir-boosted fosamprenavir may be used, but monitor phenytoin concentrations and increase phenytoin dosage as needed1 200

Antifungals, azoles (itraconazole, isavuconazonium, ketoconazole, posaconazole, voriconazole)

Itraconazole: Possible increased antifungal and amprenavir concentrations1 200

Isavuconazonium (prodrug of isavuconazole): Possible increased isavuconazole concentrations and altered fosamprenavir concentrations if used concomitantly with fosamprenavir (without low-dose ritonavir)200

Ketoconazole: Possible increased ketoconazole concentrations with fosamprenavir (with or without low-dose ritonavir)1

Posaconazole: Decreased posaconazole AUC and increased amprenavir concentrations when used concomitantly with fosamprenavir (without low-dose ritonavir);200 increased posaconazole and amprenavir concentrations when used with ritonavir-boosted fosamprenavir200

Voriconazole: Although specific data not available on interaction with ritonavir-boosted fosamprenavir, studies using low-dose ritonavir and voriconazole indicate decreased voriconazole concentrations;9 200 in addition, fosamprenavir (without low-dose ritonavir) possibly may result in increased concentrations of both drugs200

Itraconazole: In patients receiving fosamprenavir (with or without low-dose ritonavir), consider monitoring itraconazole concentrations to guide dosage adjustments; in those receiving fosamprenavir (without low-dose ritonavir), may need to reduce antifungal dosage in those receiving >400 mg of itraconazole daily;1 200 in those receiving ritonavir-boosted fosamprenavir, itraconazole dosage >200 mg daily not recommended unless plasma concentrations are monitored1 200

Isavuconazonium: If used with fosamprenavir (with or without low-dose ritonavir), consider monitoring isavuconazole concentrations and monitor for fosamprenavir-associated adverse effects and virologic response200

Ketoconazole: In patients receiving fosamprenavir (without low-dose ritonavir), may need to reduce antifungal dosage in those receiving >400 mg of ketoconazole daily;1 in those receiving ritonavir-boosted fosamprenavir, use caution and ketoconazole dosage >200 mg daily not recommended1

Posaconazole: If used with fosamprenavir (without low-dose ritonavir), monitor posaconazole concentrations;200 if used with ritonavir-boosted fosamprenavir, consider monitoring posaconazole concentrations and monitor for fosamprenavir-associated adverse effects200

Voriconazole: Monitor for toxicities if used with fosamprenavir (without low-dose ritonavir);9 200 do not use with ritonavir-boosted fosamprenavir unless potential benefits outweigh risks;9 200 if used with ritonavir-boosted fosamprenavir, consider monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly9 200

Antimycobacterials (bedaquiline, rifabutin, rifampin, rifapentine)

Bedaquiline: Possible increased bedaquiline concentrations;200 clinical importance unknown200

Rifabutin: 150 mg every other day with ritonavir-boosted fosamprenavir results in increased amprenavir concentrations and increased rifabutin metabolite concentrations compared with rifabutin 300 mg daily alone1

Rifampin: Studies using amprenavir indicate decreased amprenavir concentrations;1 possible decreased antiretroviral efficacy and increased risk of antiretroviral resistance1

Rifapentine: Possible decreased fosamprenavir concentrations200

Bedaquiline: Use concomitantly with ritonavir-boosted fosamprenavir with caution and only if potential benefits outweigh risks;200 monitor for QTc interval prolongation and liver dysfunction200

Rifabutin: If fosamprenavir (without low-dose ritonavir) used with rifabutin, reduce rifabutin dosage by at least 50%1 (150 mg once daily or 300 mg 3 times weekly has been suggested);200 if ritonavir-boosted fosamprenavir used with rifabutin, reduce rifabutin dosage by at least 75% (maximum dosage of 150 mg once every other day or 3 times weekly);1 200 monitor for neutropenia by performing CBCs weekly and as clinically indicated;1 monitor for antimycobacterial response and consider therapeutic drug monitoring200

Rifampin: Concomitant use contraindicated1

Rifapentine: Concomitant use not recommended200

Antiplatelet agents (ticagrelor, vorapaxar)

Ticagrelor, vorapaxar: Increased antiplatelet agent concentrations expected200

Ticagrelor, vorapaxar: Avoid concomitant use200

Antipsychotics (lurasidone, perphenazine, pimozide, quetiapine, risperidone, thioridazine)

Lurasidone: Potential for serious and/or life-threatening adverse effects if used concomitantly with ritonavir-boosted fosamprenavir1

Perphenazine, risperidone, thioridazine: Possible increased antipsychotic concentrations if used concomitantly with ritonavir-boosted fosamprenavir200

Pimozide: Possible increased pimozide concentrations;1 potential for serious and/or life-threatening effects (e.g., cardiac arrhythmias)1

Quetiapine: Increased quetiapine concentrations expected1 200

Lurasidone: Concomitant use with ritonavir-boosted fosamprenavir contraindicated;1 if concomitant use with unboosted fosamprenavir necessary, reduce lurasidone dosage1

Perphenazine, risperidone, thioridazine: If used with ritonavir-boosted fosamprenavir, initiate antipsychotic at lowest dosage and adjust maintenance dosage;200 monitor for toxicities associated with the antipsychotic200

Pimozide: Concomitant use contraindicated1

Quetiapine: Initiate quetiapine at lowest dosage and titrate as needed; if initiating fosamprenavir (with or without low-dose ritonavir) in patient receiving quetiapine, reduce quetiapine to one-sixth of original dosage; monitor for efficacy and adverse effects of quetiapine1 200

Atazanavir

Ritonavir-boosted fosamprenavir: Decreased atazanavir concentrations and AUC; no change in amprenavir concentrations and AUC 1

Fosamprenavir (without low-dose ritonavir): No data1

In vitro evidence of synergistic antiretroviral effects1

Fosamprenavir (with or without low-dose ritonavir): Appropriate dosages for concomitant use with respect to safety and efficacy not established1 200

Avanafil

Possible increased avanafil concentrations and AUC if used concomitantly with fosamprenavir (with or without low-dose ritonavir)188 200

If avanafil used for treatment of erectile dysfunction, do not exceed avanafil dosage of 50 mg once every 24 hours;188 200 concomitant use with ritonavir-boosted fosamprenavir not recommended200

β-adrenergic blocking agents (atenolol, labetalol, metoprolol, nadolol, sotalol, timolol)

Metoprolol, timolol: Possible increased concentrations of the β-blocker200

Metoprolol, timolol: Decrease in β-blocker dosage may be needed based on clinical response;200 consider using certain β-blockers not metabolized by CYP isoenzymes (e.g., atenolol, labetalol, nadolol, sotalol)200

Benzodiazepines (alprazolam, clonazepam, clorazepate, diazepam, flurazepam, midazolam, triazolam)

Midazolam or triazolam: Possible increased concentrations of midazolam or triazolam; potential for serious and/or life-threatening effects (e.g., prolonged or increased sedation or respiratory depression)1

Other benzodiazepines: Possible increased concentrations of alprazolam, clonazepam, clorazepate, diazepam, flurazepam1 200

Midazolam or triazolam: Manufacturer of fosamprenavir states that concomitant use is contraindicated;1 some experts state a single parenteral dose of midazolam can be used with caution in a monitored situation for procedural sedation;200 consider an alternative benzodiazepine metabolized by non-CYP pathways (e.g., lorazepam, oxazepam, temazepam)200

Other benzodiazepines: Clinical importance of pharmacokinetic interaction unknown; a decrease in benzodiazepine dosage may be needed1

Bosentan

Increased bosentan concentrations1

In patients already receiving fosamprenavir (with or without low-dose ritonavir) for ≥10 days, initiate bosentan using a dosage of 62.5 mg once daily or every other day based on individual tolerability1 200

In patients already receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating fosamprenavir (with or without low-dose ritonavir); after ≥10 days of fosamprenavir, resume bosentan using a dosage of 62.5 mg once daily or every other day based on individual tolerability1 200

Buprenorphine

No clinically important pharmacokinetic interactions200

Ritonavir-boosted fosamprenavir: Dosage adjustments not necessary;200 clinical monitoring recommended;200 if route of buprenorphine administration changed from transmucosal to subdermal implantation, monitor patient to ensure effect of buprenorphine is adequate and not excessive200

Buspirone

Increased buspirone concentrations expected200

Use low dosage of buspirone with caution and titrate based on clinical response200

Calcium-channel blocking agents (diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine)

Possible increased concentrations of calcium-channel blocking agent1

Use concomitantly with caution; clinical monitoring recommended1

Cisapride

Possible increased cisapride concentrations; potential for serious and/or life-threatening effects (e.g., cardiac arrhythmias)1

Concomitant use contraindicated1

Clarithromycin

Ritonavir-boosted fosamprenavir: Possible increased clarithromycin concentrations200

Studies using amprenavir indicate increased amprenavir concentrations and AUC and slightly decreased clarithromycin concentrations1

Fosamprenavir (without low-dose ritonavir): Dosage adjustment not needed200

Ritonavir-boosted fosamprenavir: Consider alternative macrolide (e.g., azithromycin);200 if used concomitantly, monitor for clarithromycin-related toxicities200

Ritonavir-boosted fosamprenavir: Some experts recommend reduce clarithromycin dosage by 50% if Clcr 30–60 mL/minute and reduce by 75% if Clcr <30 mL/minute 1

Colchicine

Increased colchicine concentrations1

Patients with renal or hepatic impairment: Concomitant use of colchicine and ritonavir-boosted fosamprenavir not recommended1

Colchicine for treatment of gout flares: In those receiving ritonavir-boosted fosamprenavir, use initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later and repeat dose no earlier than 3 days later; in those receiving fosamprenavir (without low-dose ritonavir), use initial colchicine dose of 1.2 mg and repeat dose no earlier than 3 days later1

Colchicine for prophylaxis of gout flares: In those receiving ritonavir-boosted fosamprenavir, decrease colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once every other day in those originally receiving 0.6 once daily;1 in those receiving fosamprenavir (without low-dose ritonavir), decrease colchicine dosage to 0.3 mg twice daily or 0.6 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once daily in those originally receiving 0.6 mg once daily1

Colchicine for treatment of familial Mediterranean fever (FMF): In those receiving ritonavir-boosted fosamprenavir, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily);1 in those receiving fosamprenavir (without low-dose ritonavir), use maximum colchicine dosage of 1.2 mg daily (may be given as 0.6 mg twice daily)1

Corticosteroids (beclomethasone, budesonide, dexamethasone, fluticasone, methylprednisolone, prednisolone, prednisone, triamcinolone)

Beclomethasone (orally inhaled, intranasal): Clinically important pharmacokinetic interactions not expected200

Budesonide or fluticasone (orally inhaled, intranasal): Increased corticosteroid concentrations;1 200 may result in adrenal insufficiency, including Cushing's syndrome200

Methylprednisolone, prednisolone, triamcinolone (intra-articular or other local injections): Increased corticosteroid concentrations;200 may result in adrenal insufficiency, including Cushing's syndrome200

Budesonide or prednisone (systemic): Increased corticosteroid concentrations;200 may result in adrenal insufficiency, including Cushing's syndrome200

Dexamethasone (systemic): Possible decreased amprenavir concentrations and decreased antiretroviral efficacy1 200

Budesonide or fluticasone (orally inhaled, intranasal): Do not use concomitantly unless potential benefits of inhaled corticosteroid outweigh risks of systemic corticosteroid adverse effects;200 consider alternative (e.g., beclomethasone),1 200 especially when long-term corticosteroid use anticipated1

Methylprednisolone, prednisolone, triamcinolone (intra-articular or other local injections): Do not use concomitantly; consider alternative nonsteroidal therapies; if intra-articular corticosteroid required, use alternative antiretroviral that does not alter CYP3A4 activity (e.g., dolutegravir, raltegravir)200

Budesonide or prednisone (systemic): Do not use concomitantly unless potential benefits outweigh risks of systemic corticosteroid adverse effects200

Dexamethasone (systemic): Use concomitantly with caution;1 200 consider alternative corticosteroid for long-term use200

Daclatasvir

No effect on daclatasvir concentrations if used concomitantly with fosamprenavir (with or without low-dose ritonavir)200

Dosage adjustments not needed178 200

Darunavir

Data not available regarding concomitant use of darunavir and fosamprenavir (with or without low-dose ritonavir)200

Delavirdine

Studies using amprenavir indicate possible increased amprenavir concentrations and AUC and possible decreased delavirdine plasma concentrations and AUC;1 possible decreased antiretroviral efficacy and increased risk of antiretroviral resistance1

In vitro evidence of synergistic antiretroviral effects1

Concomitant use contraindicated1

Didanosine

In vitro evidence of synergistic antiretroviral effects1

Dolutegravir

Ritonavir-boosted fosamprenavir: Decreased dolutegravir concentrations and AUC;1 200 236 effect on fosamprenavir pharmacokinetics unlikely236

No in vitro evidence of antagonistic antiretroviral effects with amprenavir236

Ritonavir-boosted fosamprenavir: In integrase strand transfer inhibitor-naive (INSTI-naive) patients, use dolutegravir 50 mg twice daily;1 200 236 in INSTI-experienced patients with documented or suspected INSTI resistance, consider alternative to ritonavir-boosted fosamprenavir whenever possible1 200 236

Efavirenz

Substantially decreased amprenavir concentrations if used with fosamprenavir (without low-dose ritonavir);1 additional pharmacokinetic interactions if used with ritonavir-boosted fosamprenavir1

In vitro evidence of synergistic antiretroviral effects1

Fosamprenavir (without low-dose ritonavir): Appropriate dosages for concomitant use with respect to safety and efficacy not established1

Ritonavir-boosted fosamprenavir: Use usual efavirenz dosage with fosamprenavir 1.4 g once daily and ritonavir 300 mg once daily or, alternatively, fosamprenavir 700 mg twice daily and ritonavir 100 mg twice daily1 200

Elbasvir and grazoprevir

Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): No data200

Elvitegravir

Cobicistat-boosted elvitegravir: Altered concentrations of elvitegravir, cobicistat, and/or fosamprenavir if used with fosamprenavir (with or without low-dose ritonavir)200

Cobicistat-boosted elvitegravir: Do not used concomitantly with fosamprenavir (with or without low-dose ritonavir)200

Eplerenone

Increased eplerenone concentrations expected200

Experts state concomitant use contraindicated200

Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)

Possible increased concentrations of ergot alkaloids and potential for serious and/or life-threatening effects such as ergot toxicity (peripheral vasospasm and ischemia of the extremities and other tissues)1

Concomitant use contraindicated1

If treatment of uterine atony and excessive postpartum bleeding is indicated in a woman receiving fosamprenavir, use methylergonovine maleate (Methergine) only if alternative treatments cannot be used and if potential benefits outweigh risks; use methylergonovine at lowest dosage and shortest duration possible202

Estrogens/progestins

Hormonal contraceptive containing ethinyl estradiol 35 mcg with norethindrone 0.5 mg per tablet: Decreased ethinyl estradiol and norethindrone concentrations with ritonavir-boosted fosamprenavir; clinically important increase in serum transaminase concentrations1

Hormonal contraceptives: Possible loss of virologic response if used with fosamprenavir (without low-dose ritonavir)1

Subdermal implants containing etonogestrel, transdermal systems containing ethinyl estradiol and norelgestromin: No data200

Hormonal contraceptives: Consider alternative or additional contraception methods or consider alternative antiretroviral regimen1 200

Subdermal implants containing etonogestrel, transdermal systems containing ethinyl estradiol and norelgestromin: Consider alternative or additional methods of contraception or consider alternative antiretroviral regimen200

Etravirine

Fosamprenavir (with or without low-dose ritonavir): Substantially increased amprenavir concentrations214

Fosamprenavir (with or without low-dose ritonavir): Do not administer concomitantly200

Flibanserin

Increased flibanserin concentrations expected200

Experts state concomitant use contraindicated200

Fluvoxamine

Possible altered fosamprenavir concentrations200

Consider alternative antidepressant or alternative antiretroviral therapy200

Histamine H2-receptor antagonists (cimetidine, famotidine, nizatidine, ranitidine)

Decreased amprenavir plasma concentrations and AUC;1 possible decreased antiretroviral efficacy1

Use concomitantly with caution;1 administer fosamprenavir (without low-dose ritonavir) at least 2 hours before the H2-receptor antagonist;200 consider using ritonavir-boosted fosamprenavir200

HMG-CoA reductase inhibitors (statins)

Atorvastatin, lovastatin, rosuvastatin, simvastatin: Increased concentrations and AUCs of the statin; increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis1 186 200

Atorvastatin: Do not exceed atorvastatin dosage of 20 mg daily in patients receiving fosamprenavir (with or without low-dose ritonavir);1 186 200 carefully titrate atorvastatin dosage; use lowest necessary dosage with close monitoring for adverse effects1 200

Lovastatin: Concomitant use with fosamprenavir (with or without low-dose ritonavir) contraindicated1 186 200

Pitavastatin: Dosage adjustments not necessary200

Rosuvastatin: Dosage adjustments not necessary200

Simvastatin: Concomitant use with fosamprenavir (with or without low-dose ritonavir) contraindicated1 186 200

Immunosuppressive agents (cyclosporine, everolimus, sirolimus, tacrolimus)

Increased concentrations of immunosuppressive agent expected1 200

Monitor immunosuppressive agent concentrations;1 200 some experts state initiate immunosuppressive agent with adjusted dosage to account for potential increased concentrations,200 monitor for toxicities,200 consult a specialist if needed200

Indinavir

Fosamprenavir: Possible increased amprenavir concentrations and AUC; effect on indinavir concentrations not well established1

Ritonavir-boosted fosamprenavir: Concomitant use not evaluated1

In vitro evidence of additive antiretroviral effects1

Fosamprenavir (with or without low-dose ritonavir): Appropriate dosages for concomitant use with respect to safety and efficacy not established1

Ivabradine

Increased ivabradine concentrations expected200

Experts state concomitant use contraindicated200

Lamivudine

Studies using amprenavir indicate no evidence of pharmacokinetic interaction1

In vitro evidence of synergistic antiretroviral effects1

Ledipasvir and sofosbuvir

Fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir): Pharmacokinetic interactions not expected if used concomitantly with fosamprenavir (with or without low-dose ritonavir)200

Concomitant use of ledipasvir/sofosbuvir and HIV antiretroviral regimen that includes ritonavir-boosted fosamprenavir and tenofovir DF: Possible increased tenofovir concentrations;181 200 safety of increased tenofovir concentrations not established181 200

Ledipasvir/sofosbuvir: Dosage adjustments not needed if used concomitantly with fosamprenavir (with or without low-dose ritonavir)200

Concomitant use of ledipasvir/sofosbuvir and HIV antiretroviral regimen that includes ritonavir-boosted fosamprenavir and tenofovir DF: Consider alternative HCV treatment or an alternative antiretroviral regimen;181 200 if concomitant use necessary, monitor patient for tenofovir-associated adverse effects181 200

Lopinavir/ritonavir

Fosamprenavir: Decreased amprenavir concentrations and AUC; no change in lopinavir concentrations or AUC1

Ritonavir-boosted fosamprenavir: Decreased amprenavir concentrations and AUC; altered lopinavir concentrations and AUC (decreased or increased)1

Increased incidence of adverse effects reported1

In vitro evidence of additive antiretroviral effects1

Fosamprenavir (with or without low-dose ritonavir): Concomitant use not recommended;200 appropriate dosages for concomitant use with respect to safety and efficacy not established1 200

Maraviroc

Increased maraviroc concentrations and AUC; decreased amprenavir concentrations and AUC1 200 224

No in vitro evidence of antagonistic antiretroviral effects224

Recommended maraviroc dosage is 150 mg twice daily with usual dosage of ritonavir-boosted fosamprenavir;1 200 224 do not use unboosted fosamprenavir1 224

Methadone

Decreased methadone concentrations;1 opiate withdrawal unlikely but may occur200

Methadone dosage may need to be adjusted;1 monitor for opiate withdrawal and increase methadone dosage as clinically indicated1 200

Nelfinavir

Studies using amprenavir indicate concomitant use may affect pharmacokinetics of both drugs;1 concomitant use of ritonavir-boosted fosamprenavir and nelfinavir not evaluated1

In vitro evidence of additive antiretroviral effects1

Appropriate dosages for concomitant use with respect to safety and efficacy not established1

Nevirapine

Fosamprenavir (without low-dose ritonavir): Decreased amprenavir AUC and increased nevirapine AUC1

Ritonavir-boosted fosamprenavir (twice-daily regimen): Decreased amprenavir AUC and increased nevirapine AUC1

Ritonavir-boosted fosamprenavir (once-daily regimen): Concomitant use with nevirapine not studied

In vitro evidence of additive antiretroviral effects1

Fosamprenavir (without low-dose ritonavir): Concomitant use not recommended1

RItonavir-boosted fosamprenavir (twice-daily regimen): Use usual nevirapine dosage with fosamprenavir 700 mg twice daily and ritonavir 100 mg twice daily1

Ombitasvir, paritaprevir, ritonavir, and dasabuvir

Fosamprenavir (without low-dose ritonavir): Concomitant use with fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) with dasabuvir may result in increased paritaprevir and amprenavir concentrations1

Ritonavir-boosted fosamprenavir: Increased paritaprevir concentrations expected if used concomitantly with ombitasvir/paritaprevir/ritonavir with dasabuvir;1 possible increased amprenavir concentrations1

Fosamprenavir (without low-dose ritonavir): If used concomitantly with ombitasvir/paritaprevir/ritonavir with dasabuvir, dosage adjustments not established but fosamprenavir manufacturer states consider fosamprenavir 1.4 g once daily1

Ritonavir-boosted fosamprenavir: Concomitant use with ombitasvir/paritaprevir/ritonavir with dasabuvir not recommended1

Proton-pump inhibitors (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)

Esomeprazole: When used with fosamprenavir (without low-dose ritonavir), no change in amprenavir concentrations or AUC, and increased esomeprazole AUC;1 when used with ritonavir-boosted fosamprenavir, clinically important pharmacokinetic interaction unlikely1

Can be administered at the same time as proton-pump inhibitors with no change in plasma amprenavir concentrations1

Dosage adjustments of fosamprenavir (with or without low-dose ritonavir) not needed200

Raltegravir

Fosamprenavir (with or without low-dose ritonavir): Decreased concentrations and AUCs of raltegravir and amprenavir1

Fosamprenavir (with or without low-dose ritonavir): Appropriate dosage for concomitant use with respect to safety and efficacy not established;1 some experts state dosage adjustments not necessary200

Rilpivirine

Possible increased rilpivirine concentrations; not expected to affect amprenavir concentrations226

Some experts state dosage adjustments not necessary200

Ritonavir

Increased plasma concentrations and AUC of amprenavir1 200

Concomitant low-dose ritonavir used for therapeutic advantage (ritonavir-boosted fosamprenavir);1 increased potential for drug interactions since ritonavir is a potent inhibitor of CYP3A4 and also inhibits CYP2D61

In vitro evidence of additive antiretroviral effects1

When ritonavir-boosted fosamprenavir is used in a once-daily regimen, recommended dosage is fosamprenavir 1.4 g once daily with ritonavir 100 or 200 mg once daily; when used in a twice-daily regimen, recommended dosage is fosamprenavir 700 mg twice with ritonavir 100 mg twice daily1 200

Once-daily regimen of ritonavir-boosted fosamprenavir not recommended in PI-experienced patients1

St. John’s wort (Hypericum perforatum)

Possible decreased amprenavir concentrations;1 possible decreased antiretroviral efficacy and increased risk of antiretroviral resistance1

Concomitant use contraindicated1

Salmeterol

Possible increased salmeterol concentrations and increased risk of salmeterol-associated adverse cardiovascular effects, including QT interval prolongation, palpitations, and sinus tachycardia1

Concomitant use not recommended1

Saquinavir

Decreased amprenavir concentrations1

In vitro evidence of synergistic antiretroviral effects1

Appropriate dosages for concomitant use with respect to safety and efficacy not established1 200

Selective serotonin-reuptake inhibitors (SSRIs)

Paroxetine: Decreased SSRI concentrations with ritonavir-boosted fosamprenavir1

Paroxetine: Titrate dosage of the SSRI based on clinical response and tolerability1 200

Sildenafil

Possible increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)1

Sildenafil (Revatio) for treatment of pulmonary arterial hypertension (PAH): Concomitant use with fosamprenavir (with or without low-dose ritonavir) is contraindicated;1 200 fosamprenavir manufacturer states that a safe and effective dose for concomitant use not established1

Sildenafil for treatment of erectile dysfunction: If used concomitantly with fosamprenavir (with or without low-dose ritonavir), do not exceed sildenafil dosage of 25 mg once every 48 hours and closely monitor for sildenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)1 200

Simeprevir

Fosamprenavir (without low-dose ritonavir): Possible altered simeprevir concentrations;1 187 altered amprenavir concentrations not expected1

Ritonavir-boosted fosamprenavir: Increased simeprevir concentrations expected;1 altered amprenavir concentrations not expected1

Concomitant use with fosamprenavir (with or without low-dose ritonavir) not recommended1 187 200

Stavudine

In vitro evidence of synergistic antiretroviral effects1

Suvorexant

Increased suvorexant concentrations expected200

Experts state concomitant use not recommended200

Tadalafil

Possible increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)1 200

If tadalafil (Adcirca) is initiated for treatment of PAH in patients who have been receiving fosamprenavir (with or without low-dose ritonavir) for ≥1 week, use initial tadalafil dosage of 20 mg once daily and, if tolerated, increase dosage to 40 mg once daily1

If fosamprenavir (with or without low-dose ritonavir) is indicated in patient already receiving tadalafil (Adcirca) for treatment of PAH, discontinue tadalafil for at least 24 hours prior to initiating fosamprenavir; after ≥1 week of the antiretroviral agent, resume tadalafil at dosage of 20 mg once daily and, if tolerated, increase dosage to 40 mg once daily1

If tadalafil is used for treatment of erectile dysfunction in patients already receiving fosamprenavir (with or without low-dose ritonavir), do not exceed tadalafil dosage of 10 mg once every 72 hours and closely monitor for tadalafil-related adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection, syncope)1

If tadalafil is used for treatment of benign prostatic hyperplasia, do not exceed tadalafil dosage of 2.5 mg once daily200

Tenofovir

No change in amprenavir concentrations with ritonavir-boosted fosamprenavir1

In vitro evidence of synergistic antiretroviral effects1

Tipranavir

Possible decreased amprenavir concentrations if used concomitantly with ritonavir-boosted tipranavir211

Concomitant use with ritonavir-boosted tipranavir not recommended211

Trazodone

Possible increased trazodone concentrations with fosamprenavir (with or without low-dose ritonavir)1

Increased risk of trazodone-associated adverse effects1

Use concomitantly with caution; consider reduced trazodone dosage;1 use lowest possible trazodone dosage and monitor for adverse CNS and cardiovascular effects200

Tricyclic antidepressants (amitriptyline, desipramine, imipramine, nortriptyline)

Amitriptyline, desipramine, imipramine, nortriptyline: Possible increased concentrations of the tricyclic antidepressant1 200

Amitriptyline, desipramine, imipramine, nortriptyline: Use lowest possible antidepressant dosage; titrate antidepressant dosage based on clinical assessment and/or antidepressant concentrations200

Vardenafil

Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)1 200

If fosamprenavir (with or without low-dose ritonavir) is used in patients receiving vardenafil for treatment of erectile dysfunction, do not exceed vardenafil dosage of 2.5 mg once every 72 hours and closely monitor for vardenafil-related adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)1

Zidovudine

Studies using amprenavir indicate possible increased amprenavir AUC;1 possible increased zidovudine plasma concentrations and AUC1

In vitro evidence of synergistic antiretroviral effects1

Zolpidem

Ritonavir-boosted fosamprenavir: Possible increased zolpidem concentrations200

Ritonavir-boosted fosamprenavir: Experts state initiate using low dosage of zolpidem;200 dosage reduction may be needed200

Fosamprenavir Calcium Pharmacokinetics

Absorption

Bioavailability

Fosamprenavir calcium is a prodrug of amprenavir (no longer commercially available in the US).1

Absolute oral bioavailability of amprenavir after administration of fosamprenavir calcium has not been established;1 peak amprenavir concentrations attained 1.5–4 hours after administration of the prodrug.1

When a single 1.4-g dose is administered on an empty stomach as tablets or the oral suspension, amprenavir exposure (AUC) is similar, but peak amprenavir concentrations are 14.5% higher with the suspension compared with the tablet.1

Food

Tablets: Administration of fosamprenavir calcium tablets with food has no effect on bioavailability of amprenavir.1

Suspension: Administration of fosamprenavir calcium suspension with food (i.e., standardized high-fat meal) reduces peak plasma concentrations of amprenavir by 46%, delays time to peak plasma concentration by 0.72 hours, and reduces AUC by 28% compared with administration in the fasting state.1

Distribution

Extent

Amprenavir crosses the placenta and is distributed into milk in animals.1 Not known whether drug crosses human placenta or is distributed into human milk.1

Plasma Protein Binding

90% bound to plasma proteins, primarily to α1-acid glycoprotein.1

Elimination

Metabolism

Following oral administration, fosamprenavir calcium is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate in the intestinal epithelium during absorption.1

Amprenavir is metabolized in liver principally by CYP3A4.1

Elimination Route

About 14% of an oral dose excreted in urine and 75% eliminated in feces as metabolites.1 Only minimal amounts eliminated unchanged in urine or feces.1

Half-life

Amprenavir elimination half-life approximately 7.7 hours.1

Special Populations

Following administration of ritonavir-boosted fosamprenavir, AUC of amprenavir increased 22, 70, or 80% in those with mild, moderate, or severe hepatic impairment, respectively.1 Plasma protein binding decreased in these individuals.1

Pharmacokinetics not studied to date in patients with impaired renal function,1 but renal impairment not expected to have a clinically important effect on pharmacokinetics.1

Pharmacokinetics studied in pediatric patients 2–5 years of age receiving fosamprenavir 30 mg/kg twice daily, patients 6–11 years of age receiving fosamprenavir 18 mg/kg and ritonavir 3 mg/kg twice daily, and in those 12–18 years of age receiving fosamprenavir 700 mg and ritonavir 100 mg twice daily.1

Actions and Spectrum

  • Fosamprenavir calcium is a prodrug of amprenavir (no longer commercially available in the US) and has little or no antiretroviral activity until hydrolyzed in vivo to amprenavir.1

  • Amprenavir, a PI, inhibits replication of HIV-1 by interfering with HIV protease.1

  • HIV-1 with reduced susceptibility to amprenavir were selected in vitro and have emerged during therapy with fosamprenavir.1

  • Varying degrees of cross-resistance occur among PIs; only limited data available to date regarding cross-resistance between amprenavir and other PIs.1

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1

  • Importance of using in conjunction with other antiretrovirals–not for monotherapy.1

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1 Sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.1

  • Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 200

  • Importance of reading patient information provided by the manufacturer.1

  • If a dose is missed, take the dose as soon as it is remembered and take next dose at regularly scheduled time.1 If a dose is skipped, do not take a double dose to make up for the missed dose.1

  • When the oral suspension is used, advise adults to take the preparation on an empty stomach.1 Advise children to take the oral suspension with food.1 Refrigeration of the suspension may improve the taste.1

  • When the oral suspension is used, repeat dose if vomiting occurs within 30 minutes of ingestion.1

  • Importance of patients informing their clinician if they are allergic to sulfonamides.1

  • Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products (e.g., St. John’s wort), as well as any concomitant illnesses.1

  • Advise patients receiving selective phosphodiesterase type 5 (PDE5) inhibitors (e.g., avanafil, sildenafil, tadalafil, vardenafil) that they may be at increased risk of PDE5 inhibitor-associated adverse effects (e.g., hypotension, syncope, visual disturbances, priapism) and that any symptoms should be promptly reported to their clinician.1 Fosamprenavir should not be used concomitantly with sildenafil used for treatment of pulmonary arterial hypertension (PAH).1

  • Importance of women using a reliable nonhormonal (e.g., barrier) method of contraception because of the potential interaction with hormonal contraceptives.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise HIV-infected women not to breast-feed.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Fosamprenavir Calcium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Suspension

50 mg (of fosamprenavir) per mL

Lexiva

ViiV

Tablets, film-coated

700 mg (of fosamprenavir)

Fosamprenavir Calcium Tablets

Lexiva

ViiV
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