LEXIVA (fosamprenavir calcium 700 mg) Dailymed

Therapy-Naive Adults •LEXIVA 1,400 mg twice daily (without ritonavir). •LEXIVA 1,400 mg once daily plus ritonavir 200 mg once daily. •LEXIVA 1,400 mg once daily plus ritonavir 100 mg once daily. •Dosing of LEXIVA 1,400 mg once daily plus ritonavir 100 mg once daily is supported by pharmacokinetic data [see Clinical Pharmacology (12.3)]. •LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily. •Dosing of LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily is supported by pharmacokinetic and safety data [see Clinical Pharmacology (12.3)]. Protease Inhibitor-Experienced Adults •LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily. Pregnancy •LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily. •Dosing of LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily should only be considered in pregnant patients who are already on a stable twice-daily regimen of LEXIVA/ritonavir 700 mg/100 mg prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). Lower exposures of amprenavir were observed during pregnancy; therefore, viral load should be monitored closely to ensure viral suppression is maintained [see Use in Specific Populations (8.1), Clinical Pharmacology ( 12.3 )]. Data regarding use of other regimens of LEXIVA (with or without ritonavir) in pregnancy are not available.



Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LEXIVA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Limited data are available for use of LEXIVA in pregnancy. LEXIVA 700 mg twice daily taken with ritonavir 100 mg twice daily should only be considered in pregnant patients who are already on a stable twice-daily regimen of LEXIVA/ritonavir 700 mg/100 mg prior to pregnancy, and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) (see Clinical Considerations and Data). There are insufficient human data on the use of fosamprenavir during pregnancy to adequately assess a drug-associated risk for birth defects and miscarriage. Given the limited number of pregnancies exposed to fosamprenavir-based regimens, no conclusions can be drawn on the safety of fosamprenavir in pregnancy. The background risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7% (see Data). The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. In animal reproduction studies, no evidence of major adverse developmental outcomes was observed following oral administration of fosamprenavir. Systemic exposure to amprenavir (the active ingredient) was less than (rabbits) or up to 2 times (rats) those in humans at the maximum recommended human dose (MRHD) with or without ritonavir. In contrast, oral administration of amprenavir was associated with abortions in pregnant rabbits at doses that produced approximately one-twentieth the human exposure at the MRHD. In the rat pre- and postnatal development study, toxicities to the offspring, including reduced survival and reproductive performance, were observed at maternal systemic exposures (AUC) to amprenavir that were approximately 2 times the exposure in humans at the MRHD of fosamprenavir alone or approximately the same as those seen in humans following administration of the MRHD of fosamprenavir in combination with ritonavir (see Data). Clinical Considerations Virologic Monitoring During Pregnancy and the Postpartum Period: Based on limited data on the use of LEXIVA during pregnancy, no dosage adjustments are required for pregnant patients who are already on a stable twice-daily regimen of LEXIVA 700 mg taken with ritonavir 100 mg prior to pregnancy, and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)]. In a clinical trial of 10 HIV-1–infected pregnant women treated with LEXIVA 700 mg taken with ritonavir 100 mg twice daily through postpartum, total amprenavir exposures were lower during pregnancy compared with the postpartum period. Therefore, viral load should be monitored closely to ensure viral suppression is maintained [see Data, Dosage and Administration (2.2), Clinical Pharmacology (12.3)]. Pregnancy data with other dosage regimens of LEXIVA (with or without ritonavir) are not available. Data Human Data: LEXIVA 700 mg taken with ritonavir 100 mg twice daily in combination with a background regimen was evaluated in a clinical trial of 10 HIV-1–infected pregnant women during the second and third trimesters and postpartum. Subjects initiated LEXIVA/ritonavir during pregnancy at a median of 19 weeks’ gestation; 4 had undetectable HIV-1 RNA viral load (less than 50 copies/mL) at the time of initiation. Amprenavir pharmacokinetics and placental transfer were studied during the second trimester (n = 6) or third trimester (n = 9) and postpartum (n = 9). Pregnancy outcomes were available for all 10 subjects, among which 1 twin pregnancy was included. Compared to the postpartum period, geometric mean amprenavir AUC was 35% lower in the second trimester and 25% lower in the third trimester. The amprenavir geometric mean ratio (95% CI) of fetal cord to maternal peripheral plasma concentration (n = 7) was 0.27 (0.24 to 0.30) [see Clinical Pharmacology (12.3)]. At delivery, 9 subjects had HIV-1 viral load less than 50 copies/mL, and 1 subject had a viral load of 111 copies/mL. All 11 infants born had test results that were negative for HIV-1 at the time of delivery and through 12 months postpartum. There were no new safety findings compared with the known safety profile of LEXIVA/ritonavir in HIV-1–infected adults. Based on prospective reports to the APR of approximately 146 live births following exposure to fosamprenavir-containing regimens, there were 2 birth defects reported in 109 first trimester exposures and 2 birth defects reported in 36 second and third trimester exposures. The background rate for major birth defects is 2.7% in a U.S. reference population of the MACDP. Prospective reports from the APR of overall major birth defects in pregnancies exposed to fosamprenavir are compared with the U.S. background major birth defect rate. Methodological limitations of the APR include the use of the MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations as well as confounding due to the underlying disease. Animal Data: Fosamprenavir was administered orally to pregnant rats (300, 820, or 2,240 mg per kg per day) and rabbits (74.8, 224.3, or 672.8 mg per kg per day) on Gestation Days 6 to 17 and Days 7 to 20, respectively. No major adverse effects on embryo-fetal development were observed at these dose levels, resulting in exposures (AUC0-24 h) approximately 2 times (rats) and 0.8 times (rabbits) human exposures at the MRHD of fosamprenavir alone or 0.7 times (rats) and 0.3 times (rabbits) human exposures at the MRHD of fosamprenavir in combination with ritonavir. However, increased incidence of abortion was observed in rabbits administered a maternally toxic dose of fosamprenavir (672.8 mg per kg per day). In a study where amprenavir was administered orally to pregnant rabbits (25, 50, or 100 mg per kg per day) on Gestation Days 8 to 20, increased abortions and an increased incidence of minor skeletal variations (deficient ossification of the femur, humerus, and trochlea) were observed at doses that produced approximately one-twentieth the exposure seen at the MRHD. In the rat pre- and postnatal development study, fosamprenavir was administered orally (300, 820, or 2,240 mg per kg per day) on Gestation Day 6 to Lactation/Postpartum Day 20. Fosamprenavir caused a reduction in pup survival and body weights. In surviving female offspring from the high-dose group, an increased time to successful mating, an increased length of gestation, a reduced number of uterine implantation sites per litter, and reduced gestational body weights were observed. Systemic exposure (AUC0-24 h) to amprenavir in rats was approximately 2 times the exposures in humans at the MRHD of fosamprenavir alone or approximately the same as those seen in humans at the MRHD of fosamprenavir in combination with ritonavir.

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 7. Table 7. Geometric Mean (95% CI) Steady-State Plasma Amprenavir Pharmacokinetic Parameters in Adults a Data shown are median (range). b Ctau is the concentration at the end of the dose interval. c HIV-infected adults. d AUC24 was calculated from AUC12 summary data x 2. e Healthy adults. Regimen Cmax (mcg/mL) Tmax (hours)a AUC24 (mcg•h/mL) Ctau b (mcg/mL) LEXIVA 1,400 mg Twice Daily (n = 22)c 4.82 (4.06-5.72) 1.3 (0.8-4.0) 33.0d (27.6-39.2) 0.35 (0.27-0.46) LEXIVA 1,400 mg Once Daily plus Ritonavir 200 mg Once Daily (n = 22)e 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 Once Daily plus Ritonavir 100 mg Once Daily (n = 36)e 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 Twice Daily plus Ritonavir 100 mg Twice Daily (n = 24)e 6.08 (5.38-6.86) 1.5 (0.75-5.0) 79.2d (69.0-90.6) 2.12 (1.77-2.54) 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-Naive Subjects (in the Absence of Human Serum) Absorption 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 (2)]. 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. Specific Populations Patients with 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 (2.4)]. 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 (2.4)]. Patients with 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. Pregnant Women: Amprenavir pharmacokinetics were studied in pregnant women receiving LEXIVA (700 mg) plus ritonavir (100 mg) twice daily during the second trimester (n = 6) or third trimester (n = 9) and postpartum (n = 9). Compared to postpartum, geometric mean amprenavir AUC was 35% lower in the second trimester and 25% lower in the third trimester (Table 8). This decrease results in amprenavir concentrations that are within the range observed across regimens of LEXIVA in non-pregnant adults and lower concentrations compared with LEXIVA (700 mg) plus ritonavir (100 mg) twice daily in non-pregnant adults (Table 7, Table 8). This decrease is not expected to be considered clinically relevant in patients who are virologically suppressed; however, viral load should be monitored closely to ensure viral suppression is maintained [see Dosage and Administration (2.2), Use in Specific Populations (8.1)]. The amprenavir geometric mean ratio (95% CI) of fetal cord to maternal peripheral plasma concentration (n = 7) was 0.27 (0.24 to 0.30). Table 8. Geometric Mean (95% CI) Steady-State Plasma Amprenavir Pharmacokinetic Parameters in Pregnant Women Receiving LEXIVA with Ritonavir a AUC24 was calculated from AUC12 summary data x 2. b Ctau represents the concentration at the end of the dose interval. Pharmacokinetic Parameter LEXIVA 700 mg Twice Daily plus Ritonavir 100 mg Twice Daily Second Trimester (n = 6) Third Trimester (n = 9) Postpartum (n = 9) AUC12 (mcg•h/mL) 26.0 (19.5, 34.6) 30.1 (21.6, 41.9) 39.9 (31.9, 50.1) AUC24 (mcg•h/mL)a 52.0 (39.0, 69.2) 60.2 (43.2, 83.8) 79.8 (63.8, 100.2) Cmax (mcg/mL) 4.19 (3.19, 5.51) 5.36 (3.98, 7.22) 6.65 (5.24, 8.44) Ctau (mcg/mL)b 1.31 (0.97, 1.77) 1.34 (0.95, 1.89) 2.03 (1.46, 2.83) 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 a Recommended dose for pediatric patients weighing 11 kg to less than 15 kg is based on population pharmacokinetic analysis. 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 twice daily 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 twice daily Not studieda 15 kg - <20 kg LEXIVA 23 mg/kg plus Ritonavir 3 mg/kg twice daily 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 twice daily 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 twice daily 15 5.03 (4.04, 6.26) 15 72.3 (59.6, 87.6) 42 1.98 (1.72, 2.29) 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 (8.5)]. Male and Female Patients: The pharmacokinetics of amprenavir after administration of LEXIVA do not differ between males and females. Racial Groups: The pharmacokinetics of amprenavir after administration of LEXIVA do not differ between blacks and non-blacks. Drug Interaction Studies [See Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7).] 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 (7)]. Table 10. Drug Interactions: Pharmacokinetic Parameters for Amprenavir after Administration of LEXIVA in the Presence of the Coadministered Drug(s) 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 twice daily for 2 weeks. f Subjects 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 = Not applicable. Coadministered Drug(s) and Dose(s) Dose of LEXIVAa n % Change in Amprenavir Pharmacokinetic Parameters (90% CI) Cmax AUC Cmin 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 once daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily for 10 days 22 ↔ ↔ ↔ Atorvastatin     10 mg once daily for 4 days 1,400 mg twice daily for 2 weeks 16 ↓18 (↓34 to ↑1) ↓27 (↓41 to ↓12) ↓12 (↓27 to ↓6) Atorvastatin     10 mg once daily for 4 days 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 16 ↔ ↔ ↔ Efavirenz     600 mg once daily for 2 weeks 1,400 mg once daily plus ritonavir 200 mg once daily for 2 weeks 16 ↔ ↓13 (↓30 to ↑7) ↓36 (↓8 to ↓56) Efavirenz     600 mg once daily plus additional     ritonavir 100 mg once daily for 2 weeks 1,400 mg once daily plus ritonavir 200 mg once daily for 2 weeks 16 ↑18 (↑1 to ↑38) ↑11 (0 to ↑24) ↔ Efavirenz     600 mg once daily for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 16 ↔ ↔ ↓17 (↓4 to ↓29) Esomeprazole     20 mg once daily for 2 weeks 1,400 mg twice daily for 2 weeks 25 ↔ ↔ ↔ Esomeprazole     20 mg once daily for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 23 ↔ ↔ ↔ Ethinyl estradiol/norethindrone     0.035 mg/0.5 mg once daily for 21 days 700 mg twice daily plus ritonavirb 100 mg twice daily for 21 days 25 ↔c ↔c ↔c Ketoconazoled     200 mg once daily for 4 days 700 mg twice daily plus ritonavir 100 mg twice daily for 4 days 15 ↔ ↔ ↔ Lopinavir/ritonavir     533 mg/133 mg twice daily 1,400 mg twice daily for 2 weeks 18 ↓13e ↓26e ↓42e Lopinavir/ritonavir     400 mg/100 mg twice daily for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 18 ↓58 (↓42 to ↓70) ↓63 (↓51 to ↓72) ↓65 (↓54 to ↓73) Maraviroc     300 mg twice daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily for 20 days 14 ↓34 (↓25 to ↓41) ↓35 (↓29 to ↓41) ↓36 (↓27 to ↓43) Maraviroc     300 mg once daily for 10 days 1,400 mg once daily plus ritonavir 100 mg once daily for 20 days 14 ↓29 (↓20 to ↓38) ↓30 (↓23 to ↓36) ↓15 (↓3 to ↓25) Methadone     70 to 120 mg once daily for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 19 ↔c ↔c ↔c Nevirapine     200 mg twice daily for 2 weeksf 1,400 mg twice daily for 2 weeks 17 ↓25 (↓37 to ↓10) ↓33 (↓45 to ↓20) ↓35 (↓50 to ↓15) Nevirapine     200 mg twice daily for 2 weeksf 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 17 ↔ ↓11 (↓23 to ↑3) ↓19 (↓32 to ↓4) Phenytoin     300 mg once daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily for 10 days 13 ↔ ↑20 (↑8 to ↑34) ↑19 (↑6 to ↑33) Raltegravir     400 mg twice daily for 14 days 1,400 mg twice daily for 14 days (fasted) 14 ↓27 (↓46 to ↔) ↓36 (↓53 to ↓13) ↓43g (↓59 to ↓21) 1,400 mg twice daily for 14 daysh 14 ↓15 (↓27 to ↓1) ↓17 (↓27 to ↓6) ↓32g (↓53 to ↓1) 700 mg twice daily plus ritonavir 100 mg twice daily for 14 days (fasted) 14 ↓14 (↓39 to ↑20) ↓17 (↓38 to ↑12) ↓20g (↓45 to ↑17) 700 mg twice daily plus ritonavir 100 mg twice daily for 14 daysh 12 ↓25 (↓42 to ↓2) ↓25 (↓44 to ↔) ↓33g (↓52 to ↓7) Raltegravir     400 mg twice daily for 14 days 1,400 mg once daily plus ritonavir 100 mg once daily for 14 days (fasted) 13 ↓18 (↓34 to ↔) ↓24 (↓41 to ↔) ↓50g (↓64 to ↓31) 1,400 mg once daily plus ritonavir 100 mg once daily 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 every other day for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 15 ↑36c (↑18 to ↑55) ↑35c (↑17 to ↑56) ↑17c (↓1 to ↑39) Tenofovir     300 mg once daily for 4 to 48 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 4 to 48 weeks 45 NA NA ↔i Tenofovir     300 mg once daily for 4 to 48 weeks 1,400 mg once daily plus ritonavir 200 mg once daily for 4 to 48 weeks 60 NA NA ↔i Table 11. Drug Interactions: Pharmacokinetic Parameters for Amprenavir after Administration of AGENERASE in the Presence of the Coadministered Drug(s) a Compared with parallel control group. b Median 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. Coadministered Drug(s) and Dose(s) Dose of AGENERASEa n % Change in Amprenavir Pharmacokinetic Parameters (90% CI) Cmax AUC Cmin Abacavir     300 mg twice daily for 2 to 3 weeks 900 mg twice daily for 2 to 3 weeks 4 ↔a ↔a ↔a Clarithromycin     500 mg twice daily for 4 days 1,200 mg twice daily for 4 days 12 ↑15 (↑1 to ↑31) ↑18 (↑8 to ↑29) ↑39 (↑31 to ↑47) Delavirdine     600 mg twice daily for 10 days 600 mg twice daily for 10 days 9 ↑40b ↑130b ↑125b Ethinyl estradiol/ norethindrone     0.035 mg/1 mg for 1 cycle 1,200 mg twice daily for 28 days 10 ↔ ↓22 (↓35 to ↓8) ↓20 (↓41 to ↑8) Indinavir     800 mg 3 times a day for 2 weeks (fasted) 750 or 800 mg 3 times a day 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 once daily for >30 days 1,200 mg twice daily for 10 days 16 ↓27c ↓30c ↓25c Nelfinavir     750 mg 3 times a day for 2 weeks (fed) 750 or 800 mg 3 times a day for 2 weeks (fed) 6 ↓14 (↓38 to ↑20) ↔ ↑189 (↑52 to ↑448) Rifabutin     300 mg once daily for 10 days 1,200 mg twice daily for 10 days 5 ↔ ↓15 (↓28 to 0) ↓15 (↓38 to ↑17) Rifampin     300 mg once daily for 4 days 1,200 mg twice daily for 4 days 11 ↓70 (↓76 to ↓62) ↓82 (↓84 to ↓78) ↓92 (↓95 to ↓89) Saquinavir     800 mg 3 times a day for 2 weeks (fed) 750 or 800 mg 3 times a day 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 Table 12. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of LEXIVA a Concomitant medication is also shown in this column where appropriate. b Comparison arm of atazanavir 300 mg once daily plus ritonavir 100 mg once daily 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. f Compared with lopinavir 400 mg/ritonavir 100 mg twice daily for 2 weeks. g Dose normalized to methadone 100 mg. The unbound concentration of the active moiety, R‑methadone, was unchanged. h Subjects were receiving nevirapine for at least 12 weeks prior to trial. i Comparison arm of rifabutin 300 mg once daily 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. 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 once daily for 10 daysb 700 mg twice daily plus ritonavir 100 mg twice daily for 10 days 21 ↓24 (↓39 to ↓6) ↓22 (↓34 to ↓9) ↔ Atorvastatin     10 mg once daily for 4 days 1,400 mg twice daily for 2 weeks 16 ↑304 (↑205 to ↑437) ↑130 (↑100 to ↑164) ↓10 (↓27 to ↑12) Atorvastatin     10 mg once daily for 4 days 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 16 ↑184 (↑126 to ↑257) ↑153 (↑115 to ↑199) ↑73 (↑45 to ↑108) Esomeprazole     20 mg once daily for 2 weeks 1,400 mg twice daily for 2 weeks 25 ↔ ↑55 (↑39 to ↑73) ND Esomeprazole     20 mg once daily for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 23 ↔ ↔ ND Ethinyl estradiolc     0.035 mg once daily for 21 days 700 mg twice daily plus ritonavir 100 mg twice daily for 21 days 25 ↓28 (↓21 to ↓35) ↓37 (↓30 to ↓42) ND Dolutegravir     50 mg once daily 700 mg twice daily plus ritonavir 100 mg twice daily 12 ↓24 (↓8 to ↓37) ↓35 (↓22 to ↓46) ↓49 (↓37 to ↓59) Ketoconazoled     200 mg once daily for 4 days 700 mg twice daily plus ritonavir 100 mg twice daily for 4 days 15 ↑25 (↑0 to ↑56) ↑169 (↑108 to ↑248) ND Lopinavir/ritonavire     533 mg/133 mg twice daily for 2 weeks 1,400 mg twice daily for 2 weeks 18 ↔f ↔f ↔f Lopinavir/ritonavire     400 mg/100 mg twice daily for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 18 ↑30 (↓15 to ↑47) ↑37 (↓20 to ↑55) ↑52 (↓28 to ↑82) Maraviroc     300 mg twice daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily for 20 days 14 ↑52 (↑27 to ↑82) ↑149 (↑119 to ↑182) ↑374 (↑303 to ↑457) Maraviroc     300 mg once daily for 10 days 1,400 mg once daily plus ritonavir 100 mg once daily for 20 days 14 ↑45 (↑20 to ↑74) ↑126 (↑99 to ↑158) ↑80 (↑53 to ↑113) Methadone     70 to 120 mg once daily for 2 weeks 700 mg twice daily plus ritonavir 100 mg twice daily 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 twice daily for 2 weeksh 1,400 mg twice daily for 2 weeks 17 ↑25 (↑14 to ↑37) ↑29 (↑19 to ↑40) ↑34 (↑20 to ↑49) Nevirapine     200 mg twice daily for 2 weeksh 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 17 ↑13 (↑3 to ↑24) ↑14 (↑5 to ↑24) ↑22 (↑9 to ↑35) Norethindronec     0.5 mg once daily for 21 days 700 mg twice daily plus ritonavir 100 mg twice daily for 21 days 25 ↓38 (↓32 to ↓44) ↓34 (↓30 to ↓37) ↓26 (↓20 to ↓32) Phenytoin     300 mg once daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily 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 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks 15 ↓14 (↓28 to ↑4) ↔ ↑28 (↑12 to ↑46)      (25-O-desacetylrifabutin metabolite) ↑579 (↑479 to ↑698) ↑1,120 (↑965 to ↑1,300) ↑2,510 (↑1,910 to ↑3,300)     Rifabutin + 25-O- desacetylrifabutin metabolite NA ↑64 (↑46 to ↑84) NA Rosuvastatin     10-mg single dose 700 mg twice daily plus ritonavir 100 mg twice daily for 7 days (↑45) (↑8) NA Table 13. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of AGENERASE 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 for single-dose trial; ND = Interaction cannot be determined as Cmin was below the lower limit of quantitation. Coadministered Drug(s) and Dose(s) Dose of AGENERASE n % Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI) Cmax AUC Cmin Abacavir     300 mg twice daily for 2 to 3 weeks 900 mg twice daily for 2 to 3 weeks 4 ↔a ↔a ↔a Clarithromycin     500 mg twice daily for 4 days 1,200 mg twice daily for 4 days 12 ↓10 (↓24 to ↑7) ↔ ↔ Delavirdine     600 mg twice daily for 10 days 600 mg twice daily for 10 days 9 ↓47b ↓61b ↓88b Ethinyl estradiol     0.035 mg for 1 cycle 1,200 mg twice daily for 28 days 10 ↔ ↔ ↑32 (↓3 to ↑79) Indinavir     800 mg 3 times a day for 2 weeks (fasted) 750 mg or 800 mg 3 times a day 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 once daily for >30 days 1,200 mg twice daily 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 3 times a day for 2 weeks (fed) 750 mg or 800 mg 3 times a day for 2 weeks (fed) 6 ↑12a ↑15a ↑14a Norethindrone     1 mg for 1 cycle 1,200 mg twice daily for 28 days 10 ↔ ↑18 (↑1 to ↑38) ↑45 (↑13 to ↑88) Rifabutin     300 mg once daily for 10 days 1,200 mg twice daily for 10 days 5 ↑119 (↑82 to ↑164) ↑193 (↑156 to ↑235) ↑271 (↑171 to ↑409) Rifampin     300 mg once daily for 4 days 1,200 mg twice daily for 4 days 11 ↔ ↔ ND Saquinavir     800 mg 3 times a day for 2 weeks (fed) 750 mg or 800 mg 3 times a day 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