Rukobia
(Fostemsavir Tromethamine)Dosage & Administration
The recommended dosage of RUKOBIA is one 600-mg tablet taken orally twice daily with or without food
Fostemsavir is a prodrug of temsavir, its active moiety. Fostemsavir was generally not detectable in plasma following oral administration. However, temsavir was readily absorbed . Following oral administration, increases in plasma temsavir exposure (Cmaxand AUCtau) appeared dose proportional or slightly greater than dose proportional, over the range of 600 mg to 1,800 mg of RUKOBIA. The pharmacokinetics of temsavir following administration of RUKOBIA are similar between healthy and HIV-1–infected subjects.
The pharmacokinetic properties of temsavir following administration of RUKOBIA are provided in Table 4. The multiple-dose pharmacokinetic parameters are provided in Table 5.
| HSA = Human serum albumin; UGT = Uridine diphosphate glucuronosyl transferases. aDosing in absolute bioavailability study: single-dose administration of fostemsavir extended-release tablet 600 mg followed by single IV infusion of [13C] temsavir 100 mcg. bGeometric mean ratio (fed/fasted) in pharmacokinetic parameters and (90% confidence interval). Standard meal = ~423 kcal, 36% fat, 47% carbohydrates, and 17% protein. High-calorie/high-fat meal = ~985 kcal, 60% fat, 28% carbohydrates, and 12% protein. cVolume of distribution at steady state (Vss) following IV administration. dApparent clearance. eIn vitro studies have shown that temsavir is biotransformed into 2 predominant circulating inactive metabolites: BMS-646915 (hydrolysis metabolite) and BMS-930644 (N-dealkylated metabolite). fDosing in mass balance study: single-dose administration of [14C] fostemsavir oral solution 300 mg containing 100 microCi (3.7 MBq) of total radioactivity. | |
Absorption | |
% Absolute bioavailabilitya | 26.9 |
Tmax(h) | 2.0 |
Effect of standard meal (relative to fasting)b | AUC ratio =1.10 (0.95, 1.26) |
Effect of high-fat meal (relative to fasting)b | AUC ratio =1.81 (1.54, 2.12) |
Distribution | |
% Plasma protein binding | 88.4 (primarily to HSA) |
Blood-to-plasma ratio | 0.74 |
Steady-state volume of distribution (Vss, L)c | 29.5 |
Elimination | |
Major route of elimination | Metabolism |
Clearance (CL and CL/Fd, L/h) | 17.9 and 66.4 |
Half-life (h) | 11 |
Metabolism | |
Metabolic pathwayse | Hydrolysis (esterases) [36.1% of oral dose] Oxidation (CYP3A4) [21.2% of oral dose] UGT [<1% of oral dose] |
Excretion | |
% of dose excreted in urine (unchanged drug)f | 51 (<2) |
% of dose excreted in feces (unchanged drug)f | 33 (1.1) |
| CV = Coefficient of variation; Cmax= Maximum concentration; AUC = Area under the time concentration curve; C12= Concentration at 12 hours. aBased on population pharmacokinetic analyses in heavily treatment-experienced adult subjects with HIV-1 infection receiving 600 mg of RUKOBIA twice daily with or without food in combination with other antiretroviral drugs. | |
Parameter Mean (CV%) | Temsavir a |
Cmax(ng/mL) | 1,770 (39.9) |
AUCtau(ng.h/mL) | 12,900 (46.4) |
Ctroughor C12(ng/mL) | 478 (81.5) |
No clinically significant differences in the pharmacokinetics of temsavir were observed based on age, sex, race/ethnicity (White, Black/African American, Asian, or other). The effect of hepatitis B and/or C virus co-infection on the pharmacokinetics of temsavir is unknown.
The pharmacokinetics of temsavir has not been studied in pediatric subjects and data are limited in subjects aged 65 years or older.
Population pharmacokinetic analyses of subjects with HIV-1 infection aged up to 73 years from studies with RUKOBIA indicated age had no clinically relevant effect on the pharmacokinetics of temsavir
Temsavir is a substrate of CYP3A, esterases, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Drugs that induce or inhibit CYP3A, P-gp, and BCRP may affect temsavir plasma concentrations. Coadministration of fostemsavir with drugs that are strong CYP3A inducers result in decreased concentrations of temsavir. Coadministration of fostemsavir with drugs that are moderate CYP3A inducers and/or strong CYP3A, P-gp and/or BCRP inhibitors are not likely to have a clinically relevant effect on the plasma concentrations of temsavir.
Temsavir is an inhibitor of OATP1B1 and OATP1B3. Additionally, temsavir and 2 metabolites are inhibitors of BCRP. Thus, temsavir is expected to affect the pharmacokinetics of drugs that are substrates of OATP1B1/3 and/or BCRP
At clinically relevant concentrations, significant interactions are not expected when RUKOBIA is coadministered with substrates of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 2D6, and 3A4; UGT1A1, 1A4, 1A6, 1A9, 2B7; P-gp; multidrug resistance protein (MRP)2; bile salt export pump (BSEP); sodium taurocholate co-transporting polypeptide (NTCP); multidrug and toxin extrusion protein (MATE)1/2K; organic anion transporters (OAT)1 and OAT3; organic cation transporters (OCT)1 and OCT2 based on in vitro and clinical drug interaction results .
Drug interaction studies were performed with RUKOBIA and other drugs likely to be coadministered for pharmacokinetic interactions. The effects of temsavir on the pharmacokinetics of coadministered drugs are summarized in Table 6and the effects of coadministration of other drugs on the pharmacokinetics of temsavir are summarized in Table 7.
Dosing recommendations as a result of established and other potentially significant drug-drug interactions with RUKOBIA are provided in Table 3
| CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available. AUC = AUCtaufor repeat-dose studies and AUC(0-inf)for single-dose study. aTemsavir is the active moiety. | ||||||
Coadministered Drug(s) and Dose(s) | Dose of RUKOBIA | n | Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drugs with/without RUKOBIA No Effect = 1.00 | |||
Cmax | AUC | C tau | ||||
Atazanavir + | 300 mg once daily/ | 600 mg twice daily | 18 | 1.03 (0.96, 1.10) | 1.09 (1.03, 1.15) | 1.19 (1.10, 1.30) |
Ritonavir | 100 mg once daily | 1.02 (0.96, 1.09) | 1.07 (1.03, 1.10) | 1.22 (1.12, 1.32) | ||
Darunavir + | 600 mg twice daily/ | 600 mg twice daily | 13 | 0.98 (0.93, 1.04) | 0.94 (0.89, 1.00) | 0.95 (0.87, 1.04) |
Ritonavir | 100 mg twice daily | 1.00 (0.86, 1.16) | 1.15 (0.99, 1.33) | 1.19 (1.06, 1.35) | ||
Darunavir + | 600 mg twice daily/ | 600 mg twice daily | 13 | 0.95 (0.90, 1.01) | 0.94 (0.89, 0.99) | 0.88 (0.77, 1.01) |
Ritonavir + | 100 mg twice daily/ | 1.14 (0.96, 1.35) | 1.09 (0.98, 1.22) | 1.07 (0.97, 1.17) | ||
Etravirine | 200 mg twice daily | 1.18 (1.10, 1.27) | 1.28 (1.20, 1.36) | 1.28 (1.18, 1.39) | ||
Etravirine | 200 mg twice daily | 600 mg twice daily | 14 | 1.11 (1.04, 1.19) | 1.11 (1.05, 1.17) | 1.14 (1.08, 1.21) |
Tenofovir disoproxil fumarate | 300 mg once daily | 600 mg twice daily | 18 | 1.18 (1.12, 1.25) | 1.19 (1.12, 1.25) | 1.28 (1.20, 1.38) |
Rosuvastatin | 10-mg single dose | 600 mg twice daily | 18 | 1.78 (1.52, 2.09) | 1.69 (1.44, 1.99) | NA |
Ethinyl estradiol/ | 0.030 mg once daily/ | 600 mg twice daily | 26 | 1.39 (1.28, 1.51) | 1.40 (1.29, 1.51) | NA |
Norethindrone | 1.5 mg once daily | 1.08 (1.01, 1.16) | 1.08 (1.03, 1.14) | NA | ||
Maraviroc | 300 mg twice daily | 600 mg twice daily | 13 | 1.01 (0.84, 1.20) | 1.25 (1.08, 1.44) | 1.37 (1.26, 1.48) |
Methadone | 40 to 120 mg | 600 mg | 16 | |||
R(-) Methadone | once daily | twice daily | 1.15 (1.11, 1.20) | 1.13 (1.07, 1.19) | 1.09 (1.01, 1.17) | |
S(+) Methadone | 1.15 (1.10, 1.19) | 1.15 (1.09, 1.21) | 1.10 (1.02, 1.19) | |||
Total Methadone | 1.15 (1.11, 1.19) | 1.14 (1.09, 1.20) | 1.10 (1.02, 1.18) | |||
Buprenorphine/ Naloxone | 8/2 to 24/6 mg once daily | 600 mg twice daily | 16 | |||
Buprenorphine | 1.24 (1.06, 1.46) | 1.30 (1.17, 1.45) | 1.39 (1.18, 1.63) | |||
Norbuprenorph- | 1.24 (1.03, 1.51) | 1.39 (1.16, 1.67) | 1.36 (1.10, 1.69) | |||
| CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available. AUC = AUCtaufor repeat-dose studies and AUC(0-inf)for single-dose study. Ctau= C12for single-dose study. aTemsavir is the active moiety. | ||||||
Coadministered Drug(s) and Dose(s) | Dose of RUKOBIA | n | Geometric Mean Ratio (90% CI) of Temsavir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00 | |||
Cmax | AUC | Ctau | ||||
Atazanavir + | 300 mg once daily/ | 600 mg twice daily | 36 | 1.68 (1.58, 1.79) | 1.54 (1.44, 1.65) | 1.57 (1.28, 1.91) |
Ritonavir | 100 mg once daily | |||||
Darunavir + | 600 mg twice daily/ | 600 mg twice daily | 14 | 1.52 (1.28, 1.82) | 1.63 (1.42, 1.88) | 1.88 (1.09, 3.22) |
Ritonavir | 100 mg twice daily | |||||
Darunavir + | 600 mg twice daily/ | 600 mg twice daily | 18 | 1.53 (1.32, 1.77) | 1.34 (1.17, 1.53) | 1.33 (0.98, 1.81) |
Ritonavir + | 100 mg twice daily/ | |||||
Etravirine | 200 mg twice daily | |||||
Etravirine | 200 mg twice daily | 600 mg twice daily | 14 | 0.52 (0.45, 0.59) | 0.50 (0.44, 0.57) | 0.48 (0.32, 0.72) |
Ritonavir | 100 mg once daily | 600 mg twice daily | 18 | 1.53 (1.31, 1.79) | 1.45 (1.29, 1.61) | 1.44 (1.00, 2.08) |
Raltegravir + | 400 mg twice daily/ | 1,200 mg once daily | 17 | 1.23 (0.92, 1.64) | 1.07 (0.84, 1.34) | 1.17 (0.59, 2.32) |
Tenofovir disoproxil fumarate | 300 mg once daily | |||||
Rifabutin + | 150 mg once daily/ | 600 mg twice daily | 23 | 1.50 (1.38, 1.64) | 1.66 (1.52, 1.81) | 2.58 (1.95, 3.42) |
Ritonavir | 100 mg once daily | |||||
Rifabutin | 300 mg once daily | 600 mg twice daily | 22 | 0.73 (0.65, 0.83) | 0.70 (0.64, 0.76) | 0.59 (0.46, 0.77) |
Rifampin | 600 mg once daily | 1,200-mg single dose | 15 | 0.24 (0.21, 0.28) | 0.18 (0.16, 0.2) | NA |
Cobicistat | 150 mg once daily | 600 mg twice daily | 16 | 1.71 (1.54, 1.90) | 1.93 (1.75, 2.12) | 2.36 (2.03, 2.75) |
Darunavir + | 800 mg once daily/ | 600 mg twice daily | 15 | 1.79 (1.62, 1.98) | 1.97 (1.78, 2.18) | 2.24 (1.75, 2.88) |
Cobicistat | 150 mg once daily | |||||
Tenofovir disoproxil fumarate | 300 mg once daily | 600 mg twice daily | 18 | 0.99 (0.86, 1.13) | 1.00 (0.91, 1.11) | 1.13 (0.77, 1.66) |
Maraviroc | 300 mg twice daily | 600 mg twice daily | 14 | 1.13 (0.96, 1.32) | 1.10 (0.99, 1.23) | 0.90 (0.69, 1.17) |
Famotidine | 40-mg single dose | 600-mg single dose | 24 | 1.01 (0.85, 1.21) | 1.04 (0.87, 1.25) | 0.90 (0.64, 1.28) |
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Rukobia Prescribing Information
RUKOBIA, in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations
The efficacy of RUKOBIA in heavily treatment-experienced adult subjects with HIV-1 infection is based on 96-week data from a Phase 3, partially-randomized, international, double-blind, placebo-controlled trial (BRIGHTE [ NCT02362503]).
The BRIGHTE trial was conducted in 371 heavily treatment-experienced subjects with multi-class HIV-1 resistance. All subjects were required to have a viral load ≥400 copies/mL and ≤2 classes of antiretroviral medications remaining at baseline due to resistance, intolerability, contraindication, or other safety concerns. Subjects were enrolled in either a randomized or nonrandomized cohort defined as follows:
• Within the randomized cohort (n = 272), subjects had 1, but no more than 2, fully active and available antiretroviral agent(s) at screening which could be combined as part of an efficacious background regimen. Randomized subjects received either blinded RUKOBIA 600 mg twice daily (n = 203) or placebo (n = 69) in addition to their current failing regimen for 8 days of functional monotherapy. Beyond Day 8, randomized subjects received open-label RUKOBIA 600 mg twice daily plus an investigator-selected OBT. This cohort provides primary evidence of efficacy of RUKOBIA.• Within the nonrandomized cohort (n = 99), subjects had no fully active and approved antiretroviral agent(s) available at screening. Nonrandomized subjects were treated with open-label RUKOBIA 600 mg twice daily plus OBT from Day 1 onward. The use of an investigational drug(s) as a component of the OBT was permitted in the nonrandomized cohort.
Overall, the majority of subjects were male (78%), White (70%), and the median age was 49 years (range: 17 to 73 years). At baseline, the median HIV-1 RNA was 4.6 log10copies/mL and the median CD4+ cell count was 80 cells/mm3(100 and 41 cells/mm3for randomized and nonrandomized subjects, respectively). Seventy-five percent (75%) of all treated subjects had a CD4+ cell count <200 cells/mm3at baseline (with 30% <20 cells/mm3). Overall, 86% had a history of Acquired Immune Deficiency Syndrome (AIDS) and 8% had a history of hepatitis B and/or C virus co-infection at baseline. Seventy one percent (71%) of subjects had been treated for HIV for >15 years; 85% had been exposed to ≥5 different HIV treatment regimens upon entry into the trial.
Fifty-two percent (52%) of subjects in the randomized cohort had 1 fully active agent within their initial failing background regimen, 42% had 2, and 6% had no fully active agent. Within the nonrandomized cohort, 81% of subjects had no fully active agent(s) in their original regimen and 19% had 1 fully active agent, including 15% (n = 15) who received ibalizumab, which was an investigational agent at the time of the BRIGHTE trial start-up.
The primary efficacy endpoint was the adjusted mean decline in HIV-1 RNA from Day 1 to Day 8 with RUKOBIA versus placebo in the randomized cohort. The results of the primary endpoint analysis demonstrated superiority of RUKOBIA compared with placebo, as shown in Table 11.
| aTwo subjects who received RUKOBIA with missing Day 1 HIV-1 RNA values were not included in the analysis. bMean adjusted by Day 1 log10HIV-1 RNA. cDifference: RUKOBIA minus placebo. d P -value <0.0001 for the adjusted and unadjusted mean difference of viral load change from baseline for RUKOBIA compared with placebo. | ||
RUKOBIA 600 mg Twice Daily (n = 201a) | Placebo (n = 69) | |
Adjusted Meanb(95% CI) | -0.791 | -0.166 |
Differencec(95% CI) | -0.625 | - |
At Day 8, 65% (131/203) and 46% (93/203) of subjects who received RUKOBIA had a reduction in viral load from baseline >0.5 log10copies/mL and >1 log10copies/mL, respectively, compared with 19% (13/69) and 10% (7/69) of subjects, respectively, in the placebo group.
By subgroup analysis, randomized subjects who received RUKOBIA with baseline HIV-1 RNA >1,000 copies/mL achieved a mean decline in viral load of 0.86 log10copies/mL at Day 8 compared with 0.20 log10copies/mL in subjects treated with blinded placebo. Subjects with baseline HIV-1 RNA ≤1,000 copies/mL achieved a mean decline in viral load of 0.22 log10copies/mL at Day 8 compared with a mean increase of 0.10 log10copies/mL in subjects treated with blinded placebo.
Virologic outcomes by ITT-E Snapshot Analysis at Weeks 24 and 96 in the BRIGHTE trial are shown in Table 12and Table 13for the randomized cohort. There was considerable variability in the number of antiretrovirals (fully active and otherwise) included in OBT regimens. The majority of subjects (84%) received dolutegravir as a component of OBT, of which approximately half (51% overall) also received darunavir with ritonavir or cobicistat. Virologic outcomes by ITT-E Snapshot Analysis at Week 48 were consistent with those observed at Week 24.
RUKOBIA 600 mg Twice Daily plus OBT | ||
Week 24 (n = 272) | Week 96 (n = 272) | |
HIV-1 RNA <40 copies/mL | 53% | 60% |
HIV-1 RNA ≥40 copies/mL | 40% | 30% |
Data in window not <40 copies/mL | 32% | 12% |
Discontinued for lack of efficacy | <1% | 4% |
Discontinued for other reasons while not suppressed | 1% | 6% |
Change in antiretroviral treatment regimen | 6% | 8% |
No virologic data | 7% | 10% |
Reasons: | ||
Discontinued study/study drug due to adverse event or death | 4% | 6% |
Discontinued study/study drug for other reasons | 2% | 3% |
Missing data during window but on study | 1% | 2% |
OBT = Optimized background therapy.
| OBT = Optimized background therapy; DTG = Dolutegravir; DRV = Darunavir. aIncludes subjects who never initiated OBT, were incorrectly assigned to the randomized cohort, or had 1 or more active antiretroviral agents available at screening but did not use these as part of the initial OBT. | ||
| bDarunavir was coadministered with ritonavir or cobicistat. | ||
RUKOBIA 600 mg Twice Daily plus OBT | ||
Week 24 (n = 272) | Week 96 (n = 272) | |
Baseline plasma viral load (copies/mL) | ||
<100,000 | 60% (116/192) | 65% (124/192) |
≥100,000 | 35% (28/80) | 49% (39/80) |
Baseline CD4+ (cells/mm3) | ||
<20 | 32% (23/72) | 46% (33/72) |
20 to <50 | 48% (12/25) | 56% (14/25) |
50 to <200 | 58% (59/102) | 61% (62/102) |
≥200 | 68% (50/73) | 74% (54/73) |
Number of fully active and available antiretroviral classes in initial background regimen | ||
0a | 31% (5/16) | 19% (3/16) |
1 | 56% (80/142) | 65% (92/142) |
2 | 52% (59/114) | 60% (68/114) |
Use of DTG and DRVbas a component of OBT | ||
DTG and DRV | 58% (68/117) | 64% (75/117) |
With DTG, without DRV | 54% (61/112) | 63% (71/112) |
Without DTG, with DRV | 29% (5/17) | 47% (8/17) |
Without DTG/DRV | 38% (10/26) | 35% (9/26) |
Gender | ||
Male | 52% (104/200) | 59% (118/200) |
Female | 56% (40/72) | 63% (45/72) |
Race | ||
White | 49% (90/185) | 56% (103/185) |
Black or African-American/Others | 62% (54/87) | 69% (60/87) |
Age (years) | ||
<50 | 50% (81/162) | 59% (96/162) |
≥50 | 57% (63/110) | 61% (67/110) |
In the randomized cohort, HIV-1 RNA <200 copies/mL was achieved in 68% and 64% of subjects at Weeks 24 and 96, respectively (ITT-E, Snapshot algorithm). Mean changes in CD4+ cell count from baseline increased over time: 90 cells/mm3at Week 24 and 205 cells/mm3at Week 96. Based on a sub-analysis in the randomized cohort, subjects with the lowest baseline CD4+ cell counts (<20 cells/mm3) had a similar increase in CD4+ cell count over time compared with subjects with higher baseline CD4+ cell count (>200 to <500 cells/mm3).
In the nonrandomized cohort, HIV-1 RNA <40 copies/mL was achieved in 37% of subjects at Weeks 24 and 96. At these timepoints, the proportion of subjects with HIV-1 RNA <200 copies/mL was 42% and 39%, respectively (ITT-E, Snapshot algorithm). Mean changes in CD4+ cell count from baseline increased over time: 41 cells/mm3at Week 24 and 119 cells/mm3at Week 96.
The recommended dosage of RUKOBIA is one 600-mg tablet taken orally twice daily with or without food
Fostemsavir is a prodrug of temsavir, its active moiety. Fostemsavir was generally not detectable in plasma following oral administration. However, temsavir was readily absorbed . Following oral administration, increases in plasma temsavir exposure (Cmaxand AUCtau) appeared dose proportional or slightly greater than dose proportional, over the range of 600 mg to 1,800 mg of RUKOBIA. The pharmacokinetics of temsavir following administration of RUKOBIA are similar between healthy and HIV-1–infected subjects.
The pharmacokinetic properties of temsavir following administration of RUKOBIA are provided in Table 4. The multiple-dose pharmacokinetic parameters are provided in Table 5.
| HSA = Human serum albumin; UGT = Uridine diphosphate glucuronosyl transferases. aDosing in absolute bioavailability study: single-dose administration of fostemsavir extended-release tablet 600 mg followed by single IV infusion of [13C] temsavir 100 mcg. bGeometric mean ratio (fed/fasted) in pharmacokinetic parameters and (90% confidence interval). Standard meal = ~423 kcal, 36% fat, 47% carbohydrates, and 17% protein. High-calorie/high-fat meal = ~985 kcal, 60% fat, 28% carbohydrates, and 12% protein. cVolume of distribution at steady state (Vss) following IV administration. dApparent clearance. eIn vitro studies have shown that temsavir is biotransformed into 2 predominant circulating inactive metabolites: BMS-646915 (hydrolysis metabolite) and BMS-930644 (N-dealkylated metabolite). fDosing in mass balance study: single-dose administration of [14C] fostemsavir oral solution 300 mg containing 100 microCi (3.7 MBq) of total radioactivity. | |
Absorption | |
% Absolute bioavailabilitya | 26.9 |
Tmax(h) | 2.0 |
Effect of standard meal (relative to fasting)b | AUC ratio =1.10 (0.95, 1.26) |
Effect of high-fat meal (relative to fasting)b | AUC ratio =1.81 (1.54, 2.12) |
Distribution | |
% Plasma protein binding | 88.4 (primarily to HSA) |
Blood-to-plasma ratio | 0.74 |
Steady-state volume of distribution (Vss, L)c | 29.5 |
Elimination | |
Major route of elimination | Metabolism |
Clearance (CL and CL/Fd, L/h) | 17.9 and 66.4 |
Half-life (h) | 11 |
Metabolism | |
Metabolic pathwayse | Hydrolysis (esterases) [36.1% of oral dose] Oxidation (CYP3A4) [21.2% of oral dose] UGT [<1% of oral dose] |
Excretion | |
% of dose excreted in urine (unchanged drug)f | 51 (<2) |
% of dose excreted in feces (unchanged drug)f | 33 (1.1) |
| CV = Coefficient of variation; Cmax= Maximum concentration; AUC = Area under the time concentration curve; C12= Concentration at 12 hours. aBased on population pharmacokinetic analyses in heavily treatment-experienced adult subjects with HIV-1 infection receiving 600 mg of RUKOBIA twice daily with or without food in combination with other antiretroviral drugs. | |
Parameter Mean (CV%) | Temsavir a |
Cmax(ng/mL) | 1,770 (39.9) |
AUCtau(ng.h/mL) | 12,900 (46.4) |
Ctroughor C12(ng/mL) | 478 (81.5) |
No clinically significant differences in the pharmacokinetics of temsavir were observed based on age, sex, race/ethnicity (White, Black/African American, Asian, or other). The effect of hepatitis B and/or C virus co-infection on the pharmacokinetics of temsavir is unknown.
The pharmacokinetics of temsavir has not been studied in pediatric subjects and data are limited in subjects aged 65 years or older.
Population pharmacokinetic analyses of subjects with HIV-1 infection aged up to 73 years from studies with RUKOBIA indicated age had no clinically relevant effect on the pharmacokinetics of temsavir
Temsavir is a substrate of CYP3A, esterases, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Drugs that induce or inhibit CYP3A, P-gp, and BCRP may affect temsavir plasma concentrations. Coadministration of fostemsavir with drugs that are strong CYP3A inducers result in decreased concentrations of temsavir. Coadministration of fostemsavir with drugs that are moderate CYP3A inducers and/or strong CYP3A, P-gp and/or BCRP inhibitors are not likely to have a clinically relevant effect on the plasma concentrations of temsavir.
Temsavir is an inhibitor of OATP1B1 and OATP1B3. Additionally, temsavir and 2 metabolites are inhibitors of BCRP. Thus, temsavir is expected to affect the pharmacokinetics of drugs that are substrates of OATP1B1/3 and/or BCRP
At clinically relevant concentrations, significant interactions are not expected when RUKOBIA is coadministered with substrates of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 2D6, and 3A4; UGT1A1, 1A4, 1A6, 1A9, 2B7; P-gp; multidrug resistance protein (MRP)2; bile salt export pump (BSEP); sodium taurocholate co-transporting polypeptide (NTCP); multidrug and toxin extrusion protein (MATE)1/2K; organic anion transporters (OAT)1 and OAT3; organic cation transporters (OCT)1 and OCT2 based on in vitro and clinical drug interaction results .
Drug interaction studies were performed with RUKOBIA and other drugs likely to be coadministered for pharmacokinetic interactions. The effects of temsavir on the pharmacokinetics of coadministered drugs are summarized in Table 6and the effects of coadministration of other drugs on the pharmacokinetics of temsavir are summarized in Table 7.
Dosing recommendations as a result of established and other potentially significant drug-drug interactions with RUKOBIA are provided in Table 3
| CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available. AUC = AUCtaufor repeat-dose studies and AUC(0-inf)for single-dose study. aTemsavir is the active moiety. | ||||||
Coadministered Drug(s) and Dose(s) | Dose of RUKOBIA | n | Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drugs with/without RUKOBIA No Effect = 1.00 | |||
Cmax | AUC | C tau | ||||
Atazanavir + | 300 mg once daily/ | 600 mg twice daily | 18 | 1.03 (0.96, 1.10) | 1.09 (1.03, 1.15) | 1.19 (1.10, 1.30) |
Ritonavir | 100 mg once daily | 1.02 (0.96, 1.09) | 1.07 (1.03, 1.10) | 1.22 (1.12, 1.32) | ||
Darunavir + | 600 mg twice daily/ | 600 mg twice daily | 13 | 0.98 (0.93, 1.04) | 0.94 (0.89, 1.00) | 0.95 (0.87, 1.04) |
Ritonavir | 100 mg twice daily | 1.00 (0.86, 1.16) | 1.15 (0.99, 1.33) | 1.19 (1.06, 1.35) | ||
Darunavir + | 600 mg twice daily/ | 600 mg twice daily | 13 | 0.95 (0.90, 1.01) | 0.94 (0.89, 0.99) | 0.88 (0.77, 1.01) |
Ritonavir + | 100 mg twice daily/ | 1.14 (0.96, 1.35) | 1.09 (0.98, 1.22) | 1.07 (0.97, 1.17) | ||
Etravirine | 200 mg twice daily | 1.18 (1.10, 1.27) | 1.28 (1.20, 1.36) | 1.28 (1.18, 1.39) | ||
Etravirine | 200 mg twice daily | 600 mg twice daily | 14 | 1.11 (1.04, 1.19) | 1.11 (1.05, 1.17) | 1.14 (1.08, 1.21) |
Tenofovir disoproxil fumarate | 300 mg once daily | 600 mg twice daily | 18 | 1.18 (1.12, 1.25) | 1.19 (1.12, 1.25) | 1.28 (1.20, 1.38) |
Rosuvastatin | 10-mg single dose | 600 mg twice daily | 18 | 1.78 (1.52, 2.09) | 1.69 (1.44, 1.99) | NA |
Ethinyl estradiol/ | 0.030 mg once daily/ | 600 mg twice daily | 26 | 1.39 (1.28, 1.51) | 1.40 (1.29, 1.51) | NA |
Norethindrone | 1.5 mg once daily | 1.08 (1.01, 1.16) | 1.08 (1.03, 1.14) | NA | ||
Maraviroc | 300 mg twice daily | 600 mg twice daily | 13 | 1.01 (0.84, 1.20) | 1.25 (1.08, 1.44) | 1.37 (1.26, 1.48) |
Methadone | 40 to 120 mg | 600 mg | 16 | |||
R(-) Methadone | once daily | twice daily | 1.15 (1.11, 1.20) | 1.13 (1.07, 1.19) | 1.09 (1.01, 1.17) | |
S(+) Methadone | 1.15 (1.10, 1.19) | 1.15 (1.09, 1.21) | 1.10 (1.02, 1.19) | |||
Total Methadone | 1.15 (1.11, 1.19) | 1.14 (1.09, 1.20) | 1.10 (1.02, 1.18) | |||
Buprenorphine/ Naloxone | 8/2 to 24/6 mg once daily | 600 mg twice daily | 16 | |||
Buprenorphine | 1.24 (1.06, 1.46) | 1.30 (1.17, 1.45) | 1.39 (1.18, 1.63) | |||
Norbuprenorph- | 1.24 (1.03, 1.51) | 1.39 (1.16, 1.67) | 1.36 (1.10, 1.69) | |||
| CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available. AUC = AUCtaufor repeat-dose studies and AUC(0-inf)for single-dose study. Ctau= C12for single-dose study. aTemsavir is the active moiety. | ||||||
Coadministered Drug(s) and Dose(s) | Dose of RUKOBIA | n | Geometric Mean Ratio (90% CI) of Temsavir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00 | |||
Cmax | AUC | Ctau | ||||
Atazanavir + | 300 mg once daily/ | 600 mg twice daily | 36 | 1.68 (1.58, 1.79) | 1.54 (1.44, 1.65) | 1.57 (1.28, 1.91) |
Ritonavir | 100 mg once daily | |||||
Darunavir + | 600 mg twice daily/ | 600 mg twice daily | 14 | 1.52 (1.28, 1.82) | 1.63 (1.42, 1.88) | 1.88 (1.09, 3.22) |
Ritonavir | 100 mg twice daily | |||||
Darunavir + | 600 mg twice daily/ | 600 mg twice daily | 18 | 1.53 (1.32, 1.77) | 1.34 (1.17, 1.53) | 1.33 (0.98, 1.81) |
Ritonavir + | 100 mg twice daily/ | |||||
Etravirine | 200 mg twice daily | |||||
Etravirine | 200 mg twice daily | 600 mg twice daily | 14 | 0.52 (0.45, 0.59) | 0.50 (0.44, 0.57) | 0.48 (0.32, 0.72) |
Ritonavir | 100 mg once daily | 600 mg twice daily | 18 | 1.53 (1.31, 1.79) | 1.45 (1.29, 1.61) | 1.44 (1.00, 2.08) |
Raltegravir + | 400 mg twice daily/ | 1,200 mg once daily | 17 | 1.23 (0.92, 1.64) | 1.07 (0.84, 1.34) | 1.17 (0.59, 2.32) |
Tenofovir disoproxil fumarate | 300 mg once daily | |||||
Rifabutin + | 150 mg once daily/ | 600 mg twice daily | 23 | 1.50 (1.38, 1.64) | 1.66 (1.52, 1.81) | 2.58 (1.95, 3.42) |
Ritonavir | 100 mg once daily | |||||
Rifabutin | 300 mg once daily | 600 mg twice daily | 22 | 0.73 (0.65, 0.83) | 0.70 (0.64, 0.76) | 0.59 (0.46, 0.77) |
Rifampin | 600 mg once daily | 1,200-mg single dose | 15 | 0.24 (0.21, 0.28) | 0.18 (0.16, 0.2) | NA |
Cobicistat | 150 mg once daily | 600 mg twice daily | 16 | 1.71 (1.54, 1.90) | 1.93 (1.75, 2.12) | 2.36 (2.03, 2.75) |
Darunavir + | 800 mg once daily/ | 600 mg twice daily | 15 | 1.79 (1.62, 1.98) | 1.97 (1.78, 2.18) | 2.24 (1.75, 2.88) |
Cobicistat | 150 mg once daily | |||||
Tenofovir disoproxil fumarate | 300 mg once daily | 600 mg twice daily | 18 | 0.99 (0.86, 1.13) | 1.00 (0.91, 1.11) | 1.13 (0.77, 1.66) |
Maraviroc | 300 mg twice daily | 600 mg twice daily | 14 | 1.13 (0.96, 1.32) | 1.10 (0.99, 1.23) | 0.90 (0.69, 1.17) |
Famotidine | 40-mg single dose | 600-mg single dose | 24 | 1.01 (0.85, 1.21) | 1.04 (0.87, 1.25) | 0.90 (0.64, 1.28) |
Each RUKOBIA extended-release tablet contains 600 mg of fostemsavir (equivalent to 725 mg of fostemsavir tromethamine). The tablets are beige, oval, film-coated, biconvex tablets, debossed with “SV 1V7” on one side.
There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to RUKOBIA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
There are insufficient human data on the use of RUKOBIA during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. In animal reproduction studies, oral administration of fostemsavir to pregnant rats and rabbits during organogenesis resulted in no adverse developmental effects at clinically relevant temsavir exposures
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%. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%.
In a rat pre- and postnatal development study, fostemsavir was administered orally at doses of 10, 50, or 300 mg/kg/day from Gestation Day 6 through Lactation Day 20. Reduced neonatal survival (7 to 14 days after birth) in the absence of other adverse fetal or neonatal effects was observed at maternal temsavir exposures approximately 130 times those in humans at the MRHD. No adverse fetal or neonatal effects were observed at maternal temsavir exposures approximately 35 times those in humans at the MRHD.
In a distribution study in pregnant rats, fostemsavir-related drug materials (i.e., temsavir and/or temsavir-derived metabolites) crossed the placenta and were detectable in fetal tissue.
RUKOBIA is contraindicated in patients:
• with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA.• coadministered strong cytochrome P450 (CYP)3A inducers, as significant decreases in temsavir (the active moiety of fostemsavir) plasma concentrations may occur which may result in loss of virologic response. These drugs include, but are not limited to[see Drug Interactions (:), Clinical Pharmacology (7 DRUG INTERACTIONS• See full prescribing information for complete list of significant drug interactions.• Doses of oral contraceptives should not contain more than 30 mcg of ethinyl estradiol per day.
7.1 Potential for RUKOBIA to Affect Other DrugsTemsavir may increase plasma concentrations of grazoprevir or voxilaprevir to a clinically relevant extent due to organic anion transporting polypeptide (OATP)1B1/3 inhibition
[see Drug Interactions ].When RUKOBIA was coadministered with oral contraceptives, temsavir increased concentrations of ethinyl estradiol
[see Drug Interactions , Clinical Pharmacology ].7.2 Potential for Other Drugs to Affect RUKOBIACoadministration of RUKOBIA with rifampin, a strong CYP3A4 inducer, significantly decreases temsavir plasma concentrations. The use of RUKOBIA with drugs that are strong inducers of CYP3A4 can significantly decrease temsavir plasma concentrations which may lead to loss of virologic response
[see Contraindications , Drug Interactions , Clinical Pharmacology ].7.3 Established and Other Potentially Significant Drug InteractionsInformation regarding potential drug interactions with RUKOBIA is provided in Table 3. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy
[see Contraindications , Warnings and Precautions , Clinical Pharmacology ].Table 3. Established and Other Potentially Significant Drug Interactionsa ↑ = Increase; ↓ = Decrease; HCV = Hepatitis C virus.
aThis table is not all inclusive.
bSee Clinical Pharmacology for magnitude of interaction.Concomitant Drug Class:Drug NameEffect on Concentration of Temsavir and/or Concomitant DrugClinical CommentAndrogen receptor inhibitor:Enzalutamide
↓Temsavir
Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA
[see Contraindications ].Anticonvulsants:Carbamazepine
Phenytoin↓Temsavir
Antimycobacterial:Rifampinb
↓Temsavir
Antineoplastic:Mitotane
↓Temsavir
Herbal product:St John’s wort (
Hypericum perforatum)↓Temsavir
Hepatitis C virus direct-acting antivirals:Grazoprevir
Voxilaprevir↑Grazoprevir
↑Voxilaprevir
Coadministration may increase exposures of grazoprevir or voxilaprevir; however, the magnitude of increase in exposure is unknown. Increased exposures of grazoprevir may increase the risk of ALT elevations. Use an alternative HCV regimen if possible.
Oral contraceptive:Ethinyl estradiolb
↑Ethinyl estradiol
Ethinyl estradiol daily dose should not exceed 30 mcg. Caution is advised particularly in patients with additional risk factors for thromboembolic events.Statins:Rosuvastatinb
Atorvastatin
Fluvastatin
Pitavastatin
Simvastatin
↑Rosuvastatin
↑Atorvastatin
↑Fluvastatin
↑Pitavastatin
↑Simvastatin
Use the lowest possible starting dose for statins and monitor for statin-associated adverse events.
7.4 Drugs that Prolong QT IntervalCoadministration of RUKOBIA with a drug with a known risk of Torsade de Pointes may increase the risk of Torsade de Pointes
[see Warnings and Precautions , Clinical Pharmacology ]. Use RUKOBIA with caution when coadministered with drugs with a known risk of Torsade de Pointes.7.5 Drugs without Clinically Significant Interactions with RUKOBIABased on drug interaction study results, the following drugs can be coadministered with RUKOBIA without a dose adjustment: atazanavir/ritonavir, buprenorphine/naloxone, cobicistat, darunavir/cobicistat, darunavir/ritonavir with and without etravirine, etravirine, famotidine, maraviroc, methadone, norethindrone, raltegravir, ritonavir, rifabutin with and without ritonavir, tenofovir disoproxil fumarate
[see Clinical Pharmacology ].)]12.3 PharmacokineticsFostemsavir is a prodrug of temsavir, its active moiety. Fostemsavir was generally not detectable in plasma following oral administration. However, temsavir was readily absorbed . Following oral administration, increases in plasma temsavir exposure (Cmaxand AUCtau) appeared dose proportional or slightly greater than dose proportional, over the range of 600 mg to 1,800 mg of RUKOBIA. The pharmacokinetics of temsavir following administration of RUKOBIA are similar between healthy and HIV-1–infected subjects.
Absorption, Distribution, Metabolism, and ExcretionThe pharmacokinetic properties of temsavir following administration of RUKOBIA are provided in Table 4. The multiple-dose pharmacokinetic parameters are provided in Table 5.
Table 4. Pharmacokinetic Properties of Temsavir HSA = Human serum albumin; UGT = Uridine diphosphate glucuronosyl transferases.
aDosing in absolute bioavailability study: single-dose administration of fostemsavir extended-release tablet 600 mg followed by single IV infusion of [13C] temsavir 100 mcg.
bGeometric mean ratio (fed/fasted) in pharmacokinetic parameters and (90% confidence interval). Standard meal = ~423 kcal, 36% fat, 47% carbohydrates, and 17% protein. High-calorie/high-fat meal = ~985 kcal, 60% fat, 28% carbohydrates, and 12% protein.
cVolume of distribution at steady state (Vss) following IV administration.
dApparent clearance.
eIn vitro studies have shown that temsavir is biotransformed into 2 predominant circulating inactive metabolites: BMS-646915 (hydrolysis metabolite) and BMS-930644 (N-dealkylated metabolite).
fDosing in mass balance study: single-dose administration of [14C] fostemsavir oral solution 300 mg containing 100 microCi (3.7 MBq) of total radioactivity.Absorption% Absolute bioavailabilitya
26.9
Tmax(h)
2.0
Effect of standard meal (relative to fasting)b
AUC ratio =1.10 (0.95, 1.26)
Effect of high-fat meal (relative to fasting)b
AUC ratio =1.81 (1.54, 2.12)
Distribution% Plasma protein binding
88.4
(primarily to HSA)
Blood-to-plasma ratio
0.74
Steady-state volume of distribution (Vss, L)c
29.5
EliminationMajor route of elimination
Metabolism
Clearance (CL and CL/Fd, L/h)
17.9 and 66.4
Half-life (h)
11
MetabolismMetabolic pathwayse
Hydrolysis (esterases) [36.1% of oral dose]
Oxidation (CYP3A4) [21.2% of oral dose]
UGT [<1% of oral dose]
Excretion% of dose excreted in urine (unchanged drug)f
51 (<2)
% of dose excreted in feces (unchanged drug)f
33 (1.1)
Table 5. Multiple-Dose Pharmacokinetic Parameters of Temsavir CV = Coefficient of variation; Cmax= Maximum concentration; AUC = Area under the time concentration curve; C12= Concentration at 12 hours.
aBased on population pharmacokinetic analyses in heavily treatment-experienced adult subjects with HIV-1 infection receiving 600 mg of RUKOBIA twice daily with or without food in combination with other antiretroviral drugs.Parameter Mean (CV%)TemsaviraCmax(ng/mL)
1,770 (39.9)
AUCtau(ng.h/mL)
12,900 (46.4)
Ctroughor C12(ng/mL)
478 (81.5)
Specific PopulationsNo clinically significant differences in the pharmacokinetics of temsavir were observed based on age, sex, race/ethnicity (White, Black/African American, Asian, or other). The effect of hepatitis B and/or C virus co-infection on the pharmacokinetics of temsavir is unknown.
The pharmacokinetics of temsavir has not been studied in pediatric subjects and data are limited in subjects aged 65 years or older.
Population pharmacokinetic analyses of subjects with HIV-1 infection aged up to 73 years from studies with RUKOBIA indicated age had no clinically relevant effect on the pharmacokinetics of temsavir
[see Use in Specific Populations ].Patients with Renal Impairment:No clinically relevant differences in total and unbound temsavir pharmacokinetics were observed in patients with mild to severe renal impairment. No clinically relevant differences in temsavir pharmacokinetics were observed in patients with end-stage renal disease (ESRD) on hemodialysis compared with the same patients with ESRD off hemodialysis. Temsavir was not readily cleared by hemodialysis with approximately 12.3% of the administered dose removed during the 4-hour hemodialysis session[see Use in Specific Populations ].Patients with Hepatic Impairment:No clinically relevant differences in total and unbound temsavir pharmacokinetics were observed in patients with mild to severe hepatic impairment (Child-Pugh Score A, B, or C)[see Use in Specific Populations ].Drug Interaction StudiesTemsavir is a substrate of CYP3A, esterases, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Drugs that induce or inhibit CYP3A, P-gp, and BCRP may affect temsavir plasma concentrations. Coadministration of fostemsavir with drugs that are strong CYP3A inducers result in decreased concentrations of temsavir. Coadministration of fostemsavir with drugs that are moderate CYP3A inducers and/or strong CYP3A, P-gp and/or BCRP inhibitors are not likely to have a clinically relevant effect on the plasma concentrations of temsavir.
Temsavir is an inhibitor of OATP1B1 and OATP1B3. Additionally, temsavir and 2 metabolites are inhibitors of BCRP. Thus, temsavir is expected to affect the pharmacokinetics of drugs that are substrates of OATP1B1/3 and/or BCRP
[see Drug Interactions ].At clinically relevant concentrations, significant interactions are not expected when RUKOBIA is coadministered with substrates of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 2D6, and 3A4; UGT1A1, 1A4, 1A6, 1A9, 2B7; P-gp; multidrug resistance protein (MRP)2; bile salt export pump (BSEP); sodium taurocholate co-transporting polypeptide (NTCP); multidrug and toxin extrusion protein (MATE)1/2K; organic anion transporters (OAT)1 and OAT3; organic cation transporters (OCT)1 and OCT2 based on in vitro and clinical drug interaction results .
Drug interaction studies were performed with RUKOBIA and other drugs likely to be coadministered for pharmacokinetic interactions. The effects of temsavir on the pharmacokinetics of coadministered drugs are summarized in Table 6and the effects of coadministration of other drugs on the pharmacokinetics of temsavir are summarized in Table 7.
Dosing recommendations as a result of established and other potentially significant drug-drug interactions with RUKOBIA are provided in Table 3
[see Drug Interactions ].Table 6. Effect of Fostemsaviraon the Pharmacokinetics of Coadministered Drugs CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available.
AUC = AUCtaufor repeat-dose studies and AUC(0-inf)for single-dose study.
aTemsavir is the active moiety.Coadministered Drug(s)and Dose(s)Dose of RUKOBIAnGeometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drugs with/without RUKOBIANo Effect = 1.00CmaxAUCCtauAtazanavir +
300 mg
once daily/
600 mg
twice daily
18
1.03
(0.96, 1.10)
1.09
(1.03, 1.15)
1.19
(1.10, 1.30)
Ritonavir
100 mg
once daily
1.02
(0.96, 1.09)
1.07
(1.03, 1.10)
1.22
(1.12, 1.32)
Darunavir +
600 mg
twice daily/
600 mg
twice daily
13
0.98
(0.93, 1.04)
0.94
(0.89, 1.00)
0.95
(0.87, 1.04)
Ritonavir
100 mg
twice daily
1.00
(0.86, 1.16)
1.15
(0.99, 1.33)
1.19
(1.06, 1.35)
Darunavir +
600 mg
twice daily/
600 mg
twice daily
13
0.95
(0.90, 1.01)
0.94
(0.89, 0.99)
0.88
(0.77, 1.01)
Ritonavir +
100 mg
twice daily/
1.14
(0.96, 1.35)
1.09
(0.98, 1.22)
1.07
(0.97, 1.17)
Etravirine
200 mg
twice daily
1.18
(1.10, 1.27)
1.28
(1.20, 1.36)
1.28
(1.18, 1.39)
Etravirine
200 mg
twice daily
600 mg
twice daily
14
1.11
(1.04, 1.19)
1.11
(1.05, 1.17)
1.14
(1.08, 1.21)
Tenofovir disoproxil fumarate
300 mg
once daily
600 mg
twice daily
18
1.18
(1.12, 1.25)
1.19
(1.12, 1.25)
1.28
(1.20, 1.38)
Rosuvastatin
10-mg
single dose
600 mg
twice daily
18
1.78
(1.52, 2.09)
1.69
(1.44, 1.99)
NA
Ethinyl estradiol/
0.030 mg
once daily/
600 mg
twice daily
26
1.39
(1.28, 1.51)
1.40
(1.29, 1.51)
NA
Norethindrone
1.5 mg
once daily
1.08
(1.01, 1.16)
1.08
(1.03, 1.14)
NA
Maraviroc
300 mg
twice daily
600 mg
twice daily
13
1.01
(0.84, 1.20)
1.25
(1.08, 1.44)
1.37
(1.26, 1.48)
Methadone
40 to 120 mg
600 mg
16
R(-) Methadone
once daily
twice daily
1.15
(1.11, 1.20)
1.13
(1.07, 1.19)
1.09
(1.01, 1.17)
S(+) Methadone
1.15
(1.10, 1.19)
1.15
(1.09, 1.21)
1.10
(1.02, 1.19)
Total Methadone
1.15
(1.11, 1.19)
1.14
(1.09, 1.20)
1.10
(1.02, 1.18)
Buprenorphine/
Naloxone
8/2 to 24/6 mg
once daily
600 mg
twice daily
16
Buprenorphine
1.24
(1.06, 1.46)
1.30
(1.17, 1.45)
1.39
(1.18, 1.63)
Norbuprenorph-
ine1.24
(1.03, 1.51)
1.39
(1.16, 1.67)
1.36
(1.10, 1.69)
Table 7. Effect of Coadministered Drugs on the Pharmacokinetics of Temsavirafollowing Coadministration with Fostemsavir CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available.
AUC = AUCtaufor repeat-dose studies and AUC(0-inf)for single-dose study.
Ctau= C12for single-dose study.
aTemsavir is the active moiety.Coadministered Drug(s)and Dose(s)Dose of RUKOBIAnGeometric Mean Ratio (90% CI) of Temsavir Pharmacokinetic Parameters with/without Coadministered DrugsNo Effect = 1.00CmaxAUCCtauAtazanavir +
300 mg
once daily/
600 mg
twice daily
36
1.68
(1.58, 1.79)
1.54
(1.44, 1.65)
1.57
(1.28, 1.91)
Ritonavir
100 mg
once daily
Darunavir +
600 mg
twice daily/
600 mg
twice daily
14
1.52
(1.28, 1.82)
1.63
(1.42, 1.88)
1.88
(1.09, 3.22)
Ritonavir
100 mg
twice daily
Darunavir +
600 mg
twice daily/
600 mg
twice daily
18
1.53
(1.32, 1.77)
1.34
(1.17, 1.53)
1.33
(0.98, 1.81)
Ritonavir +
100 mg
twice daily/
Etravirine
200 mg
twice daily
Etravirine
200 mg
twice daily
600 mg
twice daily
14
0.52
(0.45, 0.59)
0.50
(0.44, 0.57)
0.48
(0.32, 0.72)
Ritonavir
100 mg
once daily
600 mg
twice daily
18
1.53
(1.31, 1.79)
1.45
(1.29, 1.61)
1.44
(1.00, 2.08)
Raltegravir +
400 mg
twice daily/
1,200 mg
once daily
17
1.23
(0.92, 1.64)
1.07
(0.84, 1.34)
1.17
(0.59, 2.32)
Tenofovir disoproxil fumarate
300 mg
once daily
Rifabutin +
150 mg
once daily/
600 mg
twice daily
23
1.50
(1.38, 1.64)
1.66
(1.52, 1.81)
2.58
(1.95, 3.42)
Ritonavir
100 mg
once daily
Rifabutin
300 mg
once daily
600 mg
twice daily
22
0.73
(0.65, 0.83)
0.70
(0.64, 0.76)
0.59
(0.46, 0.77)
Rifampin
600 mg
once daily
1,200-mg
single dose
15
0.24
(0.21, 0.28)
0.18
(0.16, 0.2)
NA
Cobicistat
150 mg
once daily
600 mg
twice daily
16
1.71
(1.54, 1.90)
1.93
(1.75, 2.12)
2.36
(2.03, 2.75)
Darunavir +
800 mg
once daily/
600 mg
twice daily
15
1.79
(1.62, 1.98)
1.97
(1.78, 2.18)
2.24
(1.75, 2.88)
Cobicistat
150 mg
once daily
Tenofovir disoproxil fumarate
300 mg
once daily
600 mg
twice daily
18
0.99
(0.86, 1.13)
1.00
(0.91, 1.11)
1.13
(0.77, 1.66)
Maraviroc
300 mg
twice daily
600 mg
twice daily
14
1.13
(0.96, 1.32)
1.10
(0.99, 1.23)
0.90
(0.69, 1.17)
Famotidine
40-mg
single dose
600-mg
single dose
24
1.01
(0.85, 1.21)
1.04
(0.87, 1.25)
0.90
(0.64, 1.28)
o Androgen receptor inhibitor: Enzalutamideo Anticonvulsants: Carbamazepine, phenytoino Antimycobacterial: Rifampino Antineoplastic: Mitotaneo Herbal product: St John’s wort (Hypericum perforatum)
• Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapies. ()5.1 Immune Reconstitution SyndromeImmune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RUKOBIA
[see Adverse Reactions ]. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such asMycobacterium aviuminfection, cytomegalovirus,Pneumocystis jiroveciipneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.
• QTc prolongation: Use RUKOBIA with caution in patients with a history of QTc prolongation or with relevant pre-existing cardiac disease or who are taking drugs with a known risk of Torsade de Pointes. ()5.2 QTc Prolongation with Higher than Recommended DosagesRUKOBIA at 2,400 mg twice daily, 4 times the recommended daily dose, has been shown to significantly prolong the QTc interval of the electrocardiogram
[see Drug Interactions , Clinical Pharmacology ]. RUKOBIA should be used with caution in patients with a history of QTc interval prolongation, when coadministered with a drug with a known risk of Torsade de Pointes, or in patients with relevant pre-existing cardiac disease. Elderly patients may be more susceptible to drug-induced QT interval prolongation.• Elevations in hepatic transaminases in patients with hepatitis B (HBV) or C (HCV) virus co-infection: Elevations in hepatic transaminases were observed in a greater proportion of subjects with HBV and/or HCV co-infection compared with those with HIV mono-infection. ()5.3 Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-InfectionMonitoring of liver chemistries is recommended in patients with hepatitis B (HBV) and/or C (HCV) virus co-infection. Elevations in hepatic transaminases were observed in a greater proportion of subjects with HBV and/or HCV co-infection compared with those with HIV mono-infection. Some of these elevations in transaminases were consistent with hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn
[see Adverse Reactions ]. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting RUKOBIA in patients co-infected with hepatitis B.