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Sustiva

Sustiva

CLINICAL PHARMACOLOGY

Mechanism Of Action

Efavirenz is an antiviral drug [see Microbiology].

Pharmacokinetics

Absorption

Peak efavirenz plasma concentrations of 1.6-9.1 μM were attained by 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose-related increases in Cmax and AUC were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses.

In HIV-1-infected patients at steady state, mean Cmax, mean Cmin, and mean AUC were dose proportional following 200 mg, 400 mg, and 600 mg daily doses. Time-to-peak plasma concentrations were approximately 3-5 hours and steady-state plasma concentrations were reached in 6-10 days. In 35 patients receiving SUSTIVA 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 μM (mean ± SD), steady-state Cmin was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM•h.

Effect of Food on Oral Absorption

Capsules: Administration of a single 600 mg dose of efavirenz capsules with a high-fat/high-caloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean increase of 22% and 17% in efavirenz AUC∞ and a mean increase of 39% and 51% in efavirenz Cmax, respectively, relative to the exposures achieved when given under fasted conditions. [See DOSAGE AND ADMINISTRATION and PATIENT INFORMATION]

Tablets: Administration of a single 600 mg efavirenz tablet with a high-fat/highcaloric meal (approximately 1000 kcal, 500-600 kcal from fat) was associated with a 28% increase in mean AUC∞ of efavirenz and a 79% increase in mean Cmax of efavirenz relative to the exposures achieved under fasted conditions. [See DOSAGE AND ADMINISTRATION and PATIENT INFORMATION]

Bioavailability of capsule contents mixed with food vehicles: In healthy adult subjects, the efavirenz AUC when administered as the contents of three 200 mg capsules mixed with 2 teaspoons of certain food vehicles (applesauce, grape jelly or yogurt, or infant formula) met bioequivalency criteria for the AUC of the intact capsule formulation administered under fasted conditions.

Distribution

Efavirenz is highly bound (approximately 99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n=9) who received SUSTIVA 200 to 600 mg once daily for at least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration. This proportion is approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma.

Metabolism

Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV1. The in vitro studies suggest that CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism.

Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism. Multiple doses of 200-400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22-42% lower) and a shorter terminal half-life of 40-55 hours (single dose half-life 52-76 hours).

Elimination

Efavirenz has a terminal half-life of 52-76 hours after single doses and 40-55 hours after multiple doses. A one-month mass balance/excretion study was conducted using 400 mg per day with a 14C-labeled dose administered on Day 8. Approximately 14-34% of the radiolabel was recovered in the urine and 16-61% was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces.

Special Populations

Pediatric: The pharmacokinetic parameters for efavirenz at steady state in pediatric patients were predicted by a population pharmacokinetic model and are summarized in Table 6 by weight ranges that correspond to the recommended doses.

Table 6: Predicted Steady-State Pharmacokinetics of Recommended Doses of Efavirenz (Capsules/Capsule Sprinkles) in HIV-Infected Pediatric Patients

Body Weight Dose Mean AUC(0-24) μM•h Mean Cmax p.g/mL Mean Cmin p.g/mL
3.5-5 kg 100 mg 220.52 5.81 2.43
5-7.5 kg 150 mg 262.62 7.07 2.71
7.5-10 kg 200 mg 284.28 7.75 2.87
10-15 kg 200 mg 238.14 6.54 2.32
15-20 kg 250 mg 233.98 6.47 2.3
20-25 kg 300 mg 257.56 7.04 2.55
25-32.5 kg 350 mg 262.37 7.12 2.68
32.5-40 kg 400 mg 259.79 6.96 2.69
> 40 kg 600 mg 254.78 6.57 2.82

Gender and race: The pharmacokinetics of efavirenz in patients appear to be similar between men and women and among the racial groups studied.

Renal impairment: The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal.

Hepatic impairment: A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics.

Drug Interaction Studies

Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A and CYP2B6. In vitro studies have shown that efavirenz inhibited CYP isozymes 2C9 and 2C19 with Ki values (8.5-17 μM) in the range of observed efavirenz plasma concentrations. In in vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (Ki values 82-160 μM) only at concentrations well above those achieved clinically. Coadministration of efavirenz with drugs primarily metabolized by CYP2C9, CYP2C19, CYP3A, or CYP2B6 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A and CYP2B6 activity would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations.

Drug interaction studies were performed with efavirenz and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. The effects of coadministration of efavirenz on the Cmax, AUC, and Cmin are summarized in Table 7 (effect of efavirenz on other drugs) and Table 8 (effect of other drugs on efavirenz). For information regarding clinical recommendations see DRUG INTERACTIONS.

Table 7: Effect of Efavirenz on Coadministered Drug Plasma Cmax, AUC, and Cmin

Coadministered Drug Dose Efavirenz Dose Number of Subjects Coadministered Drug (mean % change)
Cmax
(90% CI)
AUC
(90% CI)
Cmin
(90% CI)
Atazanavir 400 mg qd with a light meal d 1-20 600 mg qd with a light meal d 7-20 27 ↓59%
(49-67%)
↓74%
(68-78%)
↓93%
(90-95%)
  400 mg qd d 1-6, then 300 mg qd d 7-20 with ritonavir 100 mg qd and a light meal 600 mg qd 2 h after atazanavir and ritonavir d 7-20 13 ↑14%a
(↓ 17-↑58%)
↑ 39%a
(2-88%)
↑48%a
(24-76%)
  300 mg qd/ritonavir 100 mg qd d 1-10
(pm), then 400 mg qd/ritonavir 100 mg qd d 11-24
(pm)
(simultaneous with efavirenz)
600 mg qd with a light snack d 11-24
(pm)
14 ↑ 17%(8-27%) ↓42%(31-51%)
Indinavir 1000 mg q8h x 10 days 600 mg qd x 10days 20 b ↓33%b
(26-39%)
↓39%b(24-51%)
After morning dose
After afternoon dose b ↓37%b
(26-46%)
↓52%b(47-57%)
After evening dose ↓29%b
(11-43%)
↓46%b
(37-54%)
↓57%b(50-63%)
Lopinavir/ ritonavir 400/100 mg capsule q12h x 9 days 600 mg qd x 9 days 600 mg qd x 9 days 11,7c d ↓ 19%d
(↓ 36-↑ 3%)
↓ 39%d
(3-62%)
500/125 mg tablet q12h x 10 days with efavirenz compared to 400/100 mg q12h alone 19 ↑ 12%d
(2-23%)
d ↓ 10%d
(↓ 22-↑ 4%)
  600/150 mg tablet q12h x 10 days with efavirenz compared to 400/100 mg q12h alone 600 mg qd x 9 days 23 ↑ 36%d
(28-44%)
↑ 36%d(28-44%) ↑ 32%d
(21-44%)
Nelfinavir 750 mg q8h x 7 days 600 mg qd x 7 days 10 ↑ 21%
(10-33%)
↑ 20%
(8-34%)
Metabolite AG-1402 ↓ 40%
(30-48%)
↓ 37%
(25-48%)
↓ 43%
(21-59%)
Ritonavir 500 mg q12h x 8days 600 mg qd x 10days 11 ↑24%
(12-38%)
↑18%
(6-33%)
↑42%e(9-86%)
After AM dose
After PM dose ↑ 24%e
(3-50%)
Saquinavir SGCf 1200 mg q8h x 10 days 600 mg qd x 10days 12 ↓50%
(28-66%)
↓ 62%
(45-74%)
↓56%e
(16-77%)
Lamivudine 150 mg q12h x 14 days 600 mg qd x 14days 9 ↑265%
(37-873%)
Tenofovirg 300 mg qd 600 mg qd x 14days 29
Zidovudine 300 mg q12h x 14 days 600 mg qd x 14days 9 ↑ 225%
(43-640%)
Maraviroc 100 mg bid 600 mg qd 12 ↓ 51%
(37-62%)
↓ 45%
(38-51%)
↓ 45%
(28-57%)
Raltegravir 400 mg single dose 600 mg qd 9 ↓ 36%
(2-59%)
↓ 36%
(20-48%)
↓ 21%
(↓ 51-↑ 28%)
Boceprevir 800 mg tid x 6days 600 mg qd x 16days NA ↓ 8%
(↓ 22-↑ 8%)
↓ 19%
(11-25%)
↓ 44%
(26-58%)
Telaprevir 750 mg q8h x 10days 600 mg qd x 20days 21 ↓ 9%
(↓ 18-↑ 2%)
↓ 26%
(16-35%)
↓ 47%
(35-56%)
Azithromycin 600 mg single dose 400 mg qd x 7 days 14 ↑ 22%
(4-42%)
NA
Clarithromycin 14-OH metabolite 500 mg q12h x 7days 400 mg qd x 7 days 11 ↓ 26%
(15-35%)
↓ 39%
(30-46%)
↓ 53%
(42-63%)
↑ 49%
(32-69%)
↑ 34%
(18-53%)
↑ 26%
(9-45%)
Fluconazole 200 mg x 7 days 400 mg qd x 7 days 10
Itraconazole Hydroxy- itraconazole 200 mg q12h x 28 days 600 mg qd x 14days 18 ↓ 37%
(20-51%)
↓ 39%
(21-53%)
↓ 44%
(27-58%)
↓ 35%
(12-52%)
↓ 37%
(14-55%)
↓ 43%
(18-60%)
Posaconazole 400 mg
(oral suspension) bid x 10 and 20 days
400 mg qd x 10 and 20 days 11 ↓ 45%
(34-53%)
↓50%
(40-57%)
NA
Rifabutin 300 mg qd x 14 days 600 mg qd x 14 days 9 ↓ 32%
(15-46%)
↓ 38%
(28-47%)
↓45%
(31-56%)
Voriconazole 400 mg po q12h x 1 day, then 200 mg po q12h x 8 days 400 mg qd x 9 days NA ↓61%h ↓77%h NA
300 mg po q12h days 2-7 300 mg qd x 7 days NA ↓ 36%
i
(21-49%)
↓ 55%i
(45-62%)
NA
400 mg po q12h days 2-7 300 mg qd x 7 days NA ↑ 23%i
(↓ 1-↑ 53%)
↓ 7%i
(↓ 23-↑ 13%)
NA
Artemether/ lumefantrine Artemether Artemether 20 mg/ lumefantrine 120 mg tablets
(6 4-tablet doses over 3 days)
600 mg qd x 26days 12 ↓ 21% ↓ 51% NA
dihydroartemisinin ↓ 38% ↓ 46% NA
lumefantrine ↓ 21% NA
Atorvastatin 10 mg qd x 4 days 600 mg qd x 15days 14 ↓ 14%
(1-26%)
↓ 43%
(34-50%)
↓ 69%
(49-81%)
Total active
(including metabolites)
↓ 15%
(2-26%)
↓ 32%
(21-41%)
↓ 48%
(23-64%)
Pravastatin 40 mg qd x 4 days 600 mg qd x 15days 13 ↓ 32%
(↓ 59-↑ 12%)
↓ 44%
(26-57%)
↓ 19%
(0-35%)
Simvastatin 40 mg qd x 4 days 600 mg qd x 15days 14 ↓ 72%
(63-79%)
↓ 68%
(62-73%)
↓ 45%
(20-62%)
Total active
(including metabolites)
I 68%
(55-78%)
I 60%
(52-68%)
NAj
Carbamazepine Epoxide metabolite 200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 29days 600 mg qd x 14days 12 ↓ 20%
(15-24%)
↓ 27%
(20-33%)
↓ 35%
(24-44%)
↓ 13%
(↓ 30-↑ 7%)
Cetirizine 10 mg single dose 600 mg qd x 10days 11 ↓ 24%
(18-30%)
NA
Diltiazem 240 mg x 21 days 600 mg qd x 14days 13 ↓ 60%
(50-68%)
↓ 69%
(55-79%)
↓ 63%
(44-75%)
Desacetyl diltiazem ↓ 64%
(57-69%)
↓ 75%
(59-84%)
↓ 62%
(44-75%)
N-monodes- methyl diltiazem ↓ 28%
(7-44%)
↓ 37%
(17-52%)
↓ 37%
(17-52%)
Ethinyl estradiol/ Norgestimate Ethinyl estradiol Norelgestromin 0.035 mg/0.25 mg x 14 days 600 mg qd x 14days 21
21 ↓ 46%
(39-52%)
↓64%
(62-67%) 34
↓82%
(79-85%)
Levonorgestrel 6 ↓80%
(77-83%)
↓ 83%
(79-87%)
↓ 86%
(80-90%)
Lorazepam 2 mg single dose 600 mg qd x 10days 12 ↑ 16%
(2-32%)
NA
Methadone Stable maintenance 35-100 mg daily 600 mg qd x 14-21 days 11 ↓45%
(25-59%)
↓52%
(33-66%)
NA
Bupropion Hydroxy- bupropion 150 mg single dose
(sustained-release)
600 mg qd x 14 days 13 ↓34%
(21-47%)
↓ 55%
(48-62%)
NA
↑ 50%
(20-80%)
NA
Paroxetine 20 mg qd x 14 days 600 mg qd x 14days 16
Sertraline 50 mg qd x 14 days 600 mg qd x 14days 13 ↓29%
(15-40%)
↓ 39%
(27-50%)
↓ 46%
(31-58%)
↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of < 10%.
a Compared with atazanavir 400 mg qd alone.
bComparator dose of indinavir was 800 mg q8h 10 days.
c Parallel-group design; n for efavirenz + lopinavir/ritonavir, n for lopinavir/ritonavir alone.
dValues are for lopinavir; the pharmacokinetics of ritonavir in this study were unaffected by concurrent efavirenz.
e95% CI.
fSoft Gelatin Capsule.
gTenofovir disoproxil fumarate.
h90% CI not available.
iRelative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days).
j Not available because of insufficient data.
NA = not available.

Table 8: Effect of Coadministered Drug on Efavirenz Plasma Cmax, AUC, and Cmin

Coadministered Drug Dose Efavirenz Dose Number of Subjects Efavirenz (mean % change)
C max
(90% CI)
AUC
(90% CI)
Cmin
(90% CI)
Indinavir 800 mg q8h x 14 days 200 mg qd x 14 days 11
Lopinavir/ritonavir 400/100 mg q12h x 9 days 600 mg qd x 9 days 11,12a ↓ 16%
(↓ 38-↑ 15%)
↓ 16%
(↓ 42-↑ 20%)
Nelfinavir 750 mg q8h x 7 days 600 mg qd x 7 days 10 ↓ 12%
(↓ 32-↑ 13%)b
↓ 12%
(↓ 35-↑ 18%)b
↓ 21%
(↓ 53-↑ 33%)
Ritonavir 500 mg q12h x 8 days 600 mg qd x 10 days 9 ↑ 14%
(4-26%)
↑ 21%
(10-34%)
↑ 25%
(7-46%)b
Saquinavir SGCc 1200 mg q8h x10 days 600 mg qd x10 days 13 ↓ 13%
(5-20%)
↓ 12%
(4-19%)
↓ 14%
(2-24%)b
Tenofovird 300 mg qd 600 mg qd x 14 days 30
Boceprevir 800 mg tid x 6 days 600 mg qd x 16 days NA ↑ 11%
(2-20%)
↑ 20%
(15-26%)
NA
Telaprevir 750 mg q8h x 10 days 600 mg qd x 20 days 21 ↓ 16%
(7-24%)
↓ 7%
(2-13%)
↓ 2%
(↓ 6-↑ 2%)
Telaprevir, coadministered with tenofovir disoproxil fumarate
(TDF)
1125 mg q8h x 7 days 600 mg efavirenz /300 mg TDF qd x 7 days 15 ↓ 24%
(15-32%)
↓ 18%
(10-26%)
↓ 10%
(↓ 19-↑ 1%)
1500 mg q12h x 7 days 600 mg efavirenz /300 mg TDF qd x 7 days 16 ↓ 20%
(14-26%)
↓ 15%
(9-21%)
↓ 11%
(4-18%)
Azithromycin 600 mg single dose 400 mg qd x 7 days 14
Clarithromycin 500 mg q12h x 7 days 400 mg qd x 7 days 12 ↑ 11%
(3-19%)
Fluconazole 200 mg x 7 days 400 mg qd x 7 days 10 ↑ 16%
(6-26%)
↑ 22%
(5-41%)
Itraconazole 200 mg q12h x 14 days 600 mg qd x 28 days 16
Rifabutin 300 mg qd x 14 days 600 mg qd x 14 days 11 ↓ 12%
(↓ 24-↑ 1%)
Rifampin 600 mg x 7 days 600 mg qd x 7 days 12 ↓ 20%
(11-28%)
↓ 26%
(15-36%)
↓ 32%
(15-46%)
Voriconazole 400 mg po q12h x 1 day, then 200 mg po q12h x 8 days 400 mg qd x 9 days NA ↑ 38%e ↑ 44%e NA
300 mg po q12h days 2-7 300 mg qd x 7 days NA ↓ 14%f
(7-21%)
f NA
400 mg po q12h days 2-7 300 mg qd x 7 days NA f ↑ 17%f
(6-29%)
NA
Artemether/ Lumefantrine Artemether 20 mg/ lumefantrine 120 mg tablets
(6 4-tablet doses over 3 days)
600 mg qd x 26 days 12 ↓ 17% NA
Atorvastatin 10 mg qd x 4 days 600 mg qd x 15 days 14
Pravastatin 40 mg qd x 4 days 600 mg qd x 15 days 11
Simvastatin 40 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 12%
(↓ 28-↑ 8%)
↓ 12%
(↓ 25-↑ 3%)
Aluminum hydroxide 400 mg, magnesium hydroxide 400 mg, plus simethicone 40 mg 30 mL single dose 400 mg single dose 17 NA
Carbamazepine 200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 15 days 600 mg qd x 35 days 14 ↓ 21%
(15-26%)
↓ 36%
(32-40%)
↓ 47%
(41-53%)
Cetirizine 10 mg single dose 600 mg qd x 10 days 11
Diltiazem 240 mg x 14 days 600 mg qd x 28 days 12 ↑ 16%
(6-26%)
↑ 11%
(5-18%)
↑ 13%
(1-26%)
Famotidine 40 mg single dose 400 mg single dose 17 NA
Paroxetine 20 mg qd x 14 days 600 mg qd x 14 days 12
Sertraline 50 mg qd x 14 days 600 mg qd x 14 days 13 ↑ 11%
(6-16%)
↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of < 10%.
a Parallel-group design; n for efavirenz + lopinavir/ritonavir, n for efavirenz alone.
b 95% CI.
c Soft Gelatin Capsule.
dTenofovir disoproxil fumarate.
e90% CI not available.
fRelative to steady-state administration of efavirenz (600 mg once daily for 9 days).
NA = not available.

Microbiology

Mechanism of Action

Efavirenz is an NNRTI of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase. HIV-2 reverse transcriptase and human cellular DNA polymerases α, β, γ, and δ are not inhibited by efavirenz.

Antiviral Activity in Cell Culture

The concentration of efavirenz inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90-95% (EC90-95) ranged from 1.7 to 25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs), and macrophage/monocyte cultures. Efavirenz demonstrated antiviral activity against clade B and most non-clade B isolates (subtypes A, AE, AG, C, D, F, G, J, N), but had reduced antiviral activity against group O viruses. Efavirenz demonstrated additive antiviral activity without cytotoxicity against HIV-1 in cell culture when combined with the NNRTIs delavirdine and nevirapine, NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine), PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir), and the fusion inhibitor enfuvirtide. Efavirenz demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. Efavirenz was not antagonistic with adefovir, used for the treatment of hepatitis B virus infection, or ribavirin, used in combination with interferon for the treatment of hepatitis C virus infection.

Resistance

In cell culture

In cell culture, HIV-1 isolates with reduced susceptibility to efavirenz ( > 380-fold increase in EC90 value) emerged rapidly in the presence of drug. Genotypic characterization of these viruses identified single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in reverse transcriptase.

Clinical studies

Clinical isolates with reduced susceptibility in cell culture to efavirenz have been obtained. One or more substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, and 227 in reverse transcriptase were observed in patients failing treatment with efavirenz in combination with indinavir, or with zidovudine plus lamivudine. The K103N substitution was the most frequently observed. Long-term resistance surveillance (average 52 weeks, range 4-106 weeks) analyzed 28 matching baseline and virologic failure isolates. Sixty-one percent (17/28) of these failure isolates had decreased efavirenz susceptibility in cell culture with a median 88-fold change in efavirenz susceptibility (EC50 value) from reference. The most frequent NNRTI substitution to develop in these patient isolates was K103N (54%). Other NNRTI substitutions that developed included L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and M230I/L (11%).

Cross-Resistance

Cross-resistance among NNRTIs has been observed. Clinical isolates previously characterized as efavirenz-resistant were also phenotypically resistant in cell culture to delavirdine and nevirapine compared to baseline. Delavirdine-and/or nevirapine-resistant clinical viral isolates with NNRTI resistance-associated substitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X, P225H, F227L, or M230L) showed reduced susceptibility to efavirenz in cell culture. Greater than 90% of NRTI-resistant clinical isolates tested in cell culture retained susceptibility to efavirenz.

Animal Toxicology

Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4-to 13-fold greater than those in humans given the recommended dose [see WARNINGS AND PRECAUTIONS].

Clinical Studies

Adults

Study 006, a randomized, open-label trial, compared SUSTIVA (600 mg once daily) + zidovudine (ZDV, 300 mg q12h) + lamivudine (LAM, 150 mg q12h) or SUSTIVA (600 mg once daily) + indinavir (IDV, 1000 mg q8h) with indinavir (800 mg q8h) + zidovudine (300 mg q12h) + lamivudine (150 mg q12h). Twelve hundred sixty-six patients (mean age 36.5 years [range 18-81], 60% Caucasian, 83% male) were enrolled. All patients were efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The median baseline CD4+ cell count was 320 cells/mm³ and the median baseline HIV-1 RNA level was 4.8 log10 copies/mL. Treatment outcomes with standard assay (assay limit 400 copies/mL) through 48 and 168 weeks are shown in Table 9. Plasma HIV RNA levels were quantified with standard (assay limit 400 copies/mL) and ultrasensitive (assay limit 50 copies/mL) versions of the AMPLICOR HIV-1 MONITOR assay. During the study, version 1.5 of the assay was introduced in Europe to enhance detection of non-clade B virus.

Table 9: Outcomes of Randomized Treatment Through 48 and 168 Weeks, Study 006

Outcome SUSTIVA + ZDV+ LAM
(n=422)
SUSTIVA + IDV
(n=429)
IDV + ZDV + LAM
(n=415)
Week 48 Week 168 Week 48 Week 168 Week 48 Week 168
Respondera 69% 48% 57% 40% 50% 29%
Virologic failureb 6% 12% 15% 20% 13% 19%
Discontinued for adverse events 7% 8% 6% 8% 16% 20%
Discontinued for other reasonsc 17% 31% 22% 32% 21% 32%
CD4+ cell count (cells/mm³ )
  Observed subjects (n) (279) (205) (256) (158) (228) (129)
  Mean change from baseline 190 329 191 319 180 329
aPatients achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48 or Week 168.
bIncludes patients who rebounded, patients who were on study at Week 48 and failed to achieve confirmed HIV-1 RNA < 400 copies/mL at time of discontinuation, and patients who discontinued due to lack of efficacy.
c Includes consent withdrawn, lost to follow-up, noncompliance, never treated, missing data, protocol violation, death, and other reasons. Patients with HIV-1 RNA levels < 400 copies/mL who chose not to continue in the voluntary extension phases of the study were censored at date of last dose of study medication.

For patients treated with SUSTIVA + zidovudine + lamivudine, SUSTIVA + indinavir, or indinavir + zidovudine + lamivudine, the percentage of responders with HIV-1 RNA < 50 copies/mL was 65%, 50%, and 45%, respectively, through 48 weeks, and 43%, 31%, and 23%, respectively, through 168 weeks. A Kaplan-Meier analysis of time to loss of virologic response (HIV RNA < 400 copies/mL) suggests that both the trends of virologic response and differences in response continue through 4 years.

ACTG 364 is a randomized, double-blind, placebo-controlled, 48-week study in NRTI-experienced patients who had completed two prior ACTG studies. One-hundred ninety-six patients (mean age 41 years [range 18-76], 74% Caucasian, 88% male) received NRTIs in combination with SUSTIVA (600 mg once daily), or nelfinavir (NFV, 750 mg three times daily), or SUSTIVA (600 mg once daily) + nelfinavir in a randomized, double-blinded manner. The mean baseline CD4+ cell count was 389 cells/mm³ and mean baseline HIV-1 RNA level was 8130 copies/mL. Upon entry into the study, all patients were assigned a new open-label NRTI regimen, which was dependent on their previous NRTI treatment experience. There was no significant difference in the mean CD4+ cell count among treatment groups; the overall mean increase was approximately 100 cells at 48 weeks among patients who continued on study regimens. Treatment outcomes are shown in Table 10. Plasma HIV RNA levels were quantified with the AMPLICOR HIV-1 MONITOR assay using a lower limit of quantification of 500 copies/mL.

Table 10: Outcomes of Randomized Treatment Through 48 Weeks, Study ACTG 364*

Outcome SUSTIVA + NFV + NRTIs
(n=65)
SUSTIVA + NRTIs
(n=65)
NFV + NRTIs
(n=66)
HIV-1 RNA < 500 copies/mLa 71% 63% 41%
HIV-1 RNA ≥ 500 copies/mLb 17% 34% 54%
CDC Category C Event 2% 0% 0%
Discontinuations for adverse eventsc 3% 3% 5%
Discontinuations for other reasonsd 8% 0% 0%
* For some patients, Week 56 data were used to confirm the status at Week 48.
a Subjects achieved virologic response (two consecutive viral loads < 500 copies/mL) and maintained it through Week 48.
bIncludes viral rebound and failure to achieve confirmed < 500 copies/mL by Week 48.
c See ADVERSE REACTIONS for a safety profile of these regimens.
dIncludes loss to follow-up, consent withdrawn, noncompliance.

A Kaplan-Meier analysis of time to treatment failure through 72 weeks demonstrates a longer duration of virologic suppression (HIV RNA < 500 copies/mL) in the SUSTIVA-containing treatment arms.

Pediatric Patients

Study AI266922 is an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of SUSTIVA in combination with didanosine and emtricitabine in antiretroviral-naive and -experienced pediatric patients. Thirty-seven patients 3 months to 6 years of age (median 0.7 years) were treated with SUSTIVA. At baseline, median plasma HIV-1 RNA was 5.88 log10 copies/mL, median CD4+ cell count was 1144 cells/mm³, and median CD4+ percentage was 25%. The median time on study therapy was 60 weeks; 27% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA < 400 copies/mL and < 50 copies/mL at Week 48 were 57% (21/37) and 46% (17/37), respectively. The median increase from baseline in CD4+ count at 48 weeks was 196 cells/mm³ and the median increase in CD4+ percentage was 6%.

Study PACTG 1021 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of SUSTIVA in combination with didanosine and emtricitabine in pediatric patients who were antiretroviral therapy naive. Forty-three patients 3 months to 21 years of age (median 9.6 years) were dosed with SUSTIVA. At baseline, median plasma HIV-1 RNA was 4.8 log10 copies/mL, median CD4+ cell count was 367 cells/mm³, and median CD4+ percentage was 18%. The median time on study therapy was 181 weeks; 16% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA < 400 copies/mL and < 50 copies/mL at Week 48 were 77% (33/43) and 70% (30/43), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 238 cells/mm³ and the median increase in CD4+ percentage was 13%.

Study PACTG 382 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of SUSTIVA in combination with nelfinavir and an NRTI in antiretroviral-naive and NRTI-experienced pediatric patients. One hundred two patients 3 months to 16 years of age (median 5.7 years) were treated with SUSTIVA. Eighty-seven percent of patients had received prior antiretroviral therapy. At baseline, median plasma HIV-1 RNA was 4.57 log10 copies/mL, median CD4+ cell count was 755 cells/mm³, and median CD4+ percentage was 30%. The median time on study therapy was 118 weeks; 25% of patients discontinued before Week 48. Using an ITT analysis, the overall proportion of patients with HIV RNA < 400 copies/mL and < 50 copies/mL at Week 48 were 57% (58/102) and 43% (44/102), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 128 cells/mm³ and the median increase in CD4+ percentage was 5%.

Last reviewed on RxList: 6/5/2014
This monograph has been modified to include the generic and brand name in many instances.

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