Juluca
Name: Juluca
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Juluca Dosage and Administration
Recommended Dosage
The recommended dosage of Juluca is one tablet taken orally once daily with a meal [see Clinical Pharmacology (12.3)]. One tablet of Juluca contains 50 mg of dolutegravir and 25 mg of rilpivirine.
Recommended Dosage with Rifabutin Coadministration
If Juluca is coadministered with rifabutin, take an additional 25-mg tablet of rilpivirine with Juluca once daily with a meal for the duration of the rifabutin coadministration [see Drug Interactions (7.3)].
Dosage Forms and Strengths
Juluca tablets are pink, oval, biconvex tablets debossed with “SV J3T” on one side. Each film-coated tablet contains 50 mg of dolutegravir (equivalent to 52.6 mg dolutegravir sodium) and 25 mg of rilpivirine (equivalent to 27.5 mg rilpivirine hydrochloride).
Use in specific populations
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Juluca during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary
There is insufficient prospective pregnancy data from the APR to adequately assess the risk of birth defects and miscarriage. Given the limited number of pregnancies exposed to dolutegravir-containing regimens reported to the APR, no definitive conclusions can be drawn on the safety of dolutegravir in pregnancy, and continued monitoring is ongoing through the APR. Available data from the APR show no difference in the overall risk of birth defects for rilpivirine compared with the background rate for major birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation.
In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of Juluca (see Data). During organogenesis in the rat and rabbit, systemic exposures (AUC) to dolutegravir were less than (rabbits) and 38 times (rats) and exposures to rilpivirine were 15 (rats) and 70 (rabbits) times the exposure at the recommended human dose (RHD). In rat pre- and post-natal development studies, maternal systemic exposures (AUC) to dolutegravir and rilpivirine were approximately 32 and 63 times, respectively, the exposures of each component in humans at the RHD.
Data
Human Data: Rilpivirine: Based on prospective reports to the APR of 202 exposures to rilpivirine during pregnancy resulting in live births, there was no difference between the overall risk of birth defects for rilpivirine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 0.5% (95% CI: 0.0% to 2.7%) and 0.8% (95% CI: 0.0% to 4.4%) following first and second/third trimester exposure, respectively, to rilpivirine-containing regimens.
Animal Data: Dolutegravir: Dolutegravir was administered orally at up to 1,000 mg per kg daily to pregnant rats and rabbits on gestation Days 6 to 17 and 6 to 18, respectively, and also to rats on gestation Day 6 to lactation/post-partum Day 20. No adverse effects on embryo-fetal (rats and rabbits) development were observed at up to the highest dose tested. During organogenesis systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans and in rats were approximately 38 times the exposure in humans (50 mg once daily). In the rat pre/post-natal development study, decreased body weight of the developing offspring was observed during lactation at a maternally toxic dose (approximately 32 times the human exposure with 50 mg once daily).
Rilpivirine: Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg per kg per day) and rabbits (5, 10, or 20 mg per kg per day) through organogenesis (on gestation Days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans at the recommended dose of 25 mg once daily. In a pre/postnatal development study with rilpivirine, where rats were administered up to 400 mg per kg per day through lactation, no significant adverse effects directly related to drug were noted in the offspring.
Lactation
Risk Summary
The Centers for Disease Control and Prevention recommend that HIV‑1‑infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.
It is not known whether Juluca or components of Juluca are present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, dolutegravir and rilpivirine were present in milk (see Data).
Because of the potential for (1) HIV‑1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving Juluca.
Data
Animal Data: Dolutegravir: Dolutegravir was the primary drug-related component excreted into the milk of lactating rats following a single oral dose of 50 mg per kg on lactation Day 10, with milk concentrations of up to approximately 1.3 times that of maternal plasma concentrations observed 8 hours’ post-dose.
Rilpivirine: In animals, no studies have been conducted to assess the excretion of rilpivirine into milk directly; however, rilpivirine was present in plasma of rat pups exposed through the milk of lactating rats (dosed up to 400 mg per kg per day).
Pediatric Use
The safety and efficacy of Juluca have not been established in pediatric patients.
Geriatric Use
Clinical trials of Juluca did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in administration of Juluca in elderly patients reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].
Renal Impairment
No dosage adjustment is necessary for patients with mild or moderate renal impairment (creatinine clearance greater than or equal to 30 mL/min) [see Clinical Pharmacology (12.3)]. In patients with severe renal impairment (creatinine clearance less than 30 mL/min) or end-stage renal disease, increased monitoring for adverse effects is recommended.
Hepatic Impairment
No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir or rilpivirine is unknown [see Clinical Pharmacology (12.3)].
Juluca - Clinical Pharmacology
Mechanism of Action
Juluca is a fixed-dose combination of the HIV-1 antiretroviral agents, dolutegravir and rilpivirine [see Microbiology (12.4)].
Pharmacodynamics
Cardiac Electrophysiology
The effect of Juluca on the QT interval has not been studied.
In a randomized, placebo-controlled, crossover trial, 42 healthy subjects received single-dose oral administration of placebo, dolutegravir 250-mg suspension (exposures approximately 3–fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). Dolutegravir did not prolong the QTc interval over 24 hours’ post-dose.
The effect of rilpivirine at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo- and active- (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical concern). When 75 mg and 300 mg once daily of rilpivirine (3 times and 12 times the recommended dosage in Juluca, respectively) were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean Cmax observed with the recommended 25-mg once-daily dose of rilpivirine [see Drug Interactions (7.4)].
Effects on Renal Function
The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo.
Pharmacokinetics
Absorption, Distribution, Metabolism, and Excretion
The pharmacokinetic (PK) properties of the components of Juluca are provided in Table 5. The multiple-dose pharmacokinetic parameters are provided in Table 6.
| Dolutegravir | Rilpivirine | |
| Absorption | ||
| Tmax (h) | 3 | 4 |
| Effect of moderate-fat meal (relative to fasting)a | AUC Ratio | AUC Ratio |
| Effect of high-fat meal (relative to fasting)a | AUC Ratio | AUC Ratio |
| Distribution | ||
| % Bound to human plasma proteins | ~99 | ~99 |
| Source of protein binding data | in vitro | in vitro |
| Blood-to-plasma ratio | 0.5 | 0.7 |
| Metabolism | ||
| Primarily metabolized | UGT1A1 CYP3A (minor) | CYP3A |
| Elimination | ||
| Major route of elimination | Metabolism | Metabolism |
| t1/2 (h) | 14 | 50 |
| % of dose excreted as total 14C (unchanged drug) in urineb | 31 (<1) | 6.5 (<1) |
| % of dose excreted as total 14C (unchanged drug) in fecesb | 64 (53) | 85 (25) |
a Geometric mean ratio (fed/fasted) in PK parameters and (90% confidence interval). High-calorie/high-fat meal = ~900 kcal, 56% fat. Moderate-fat meal = ~625 kcal, 32% fat. When rilpivirine was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal.
b Dosing in mass balance studies: single-dose administration of [14C] dolutegravir or [14C] rilpivirine.
| Parameter Mean (CV%) | Dolutegravira | Rilpivirinea |
| Cmax (mcg/mL) | 3.67 (20) | 0.13 (54)b |
| AUCtau (mcg/h/mL) | 53.6 (27) | 2.2 (38) |
| Ctrough (mcg/mL) | 1.11 (46) | 0.08 (44) |
a Based on population pharmacokinetic analyses using pooled data from ART treatment-naïve adults receiving 50 mg dolutegravir once daily or 25 mg rilpivirine once daily.
b Observed Cmax in a pharmacokinetic substudy in ART treatment-naïve adults receiving 25 mg rilpivirine once daily.
Specific Populations
Pediatric Patients: The pharmacokinetics of dolutegravir plus rilpivirine has not been studied in pediatric subjects [see Use in Specific Populations (8.4)].
Geriatric Patients: Population pharmacokinetic analyses from studies with the individual components indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir or rilpivirine. Pharmacokinetic data in subjects 65 years of age and older are limited [see Use in Specific Populations (8.5)].
Patients with Renal Impairment: Population pharmacokinetic analyses indicated that mild and moderate renal impairment had no clinically relevant effect on the exposure of dolutegravir. Dolutegravir AUC, Cmax, and C24 were lower by 40%, 23%, and 43%, respectively, in subjects (n = 8) with severe renal impairment (creatinine clearance less than 30 mL/min) as compared with matched healthy controls. Dolutegravir has not been studied in patients requiring dialysis [see Use in Specific Populations (8.6)].
Population pharmacokinetic analyses indicated that mild renal impairment had no clinically relevant effect on the exposure of rilpivirine. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment, end-stage renal disease, or patients requiring dialysis.
Patients with Hepatic Impairment: Dolutegravir exposures were similar in subjects (n = 8) with moderate hepatic impairment (Child-Pugh Score B) as compared with matched healthy controls. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied.
Rilpivirine exposure was 47% higher in subjects (n = 8) with mild hepatic impairment (Child-Pugh Score A) and 5% higher in subjects (n = 8) with moderate hepatic impairment (Child-Pugh Score B) compared with matched controls. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of rilpivirine has not been studied [see Use in Specific Populations (8.7)].
Patients with HBV/HCV Co-infection: Population pharmacokinetic analyses indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure of dolutegravir or rilpivirine. Subjects with hepatitis B co-infection were excluded from studies with dolutegravir plus rilpivirine.
Gender and Race: Population pharmacokinetic analyses from studies with the individual components revealed that gender and race had no clinically relevant effect on the pharmacokinetics of dolutegravir or rilpivirine.
Drug Interaction Studies
Drug interaction trials were conducted with dolutegravir or rilpivirine as individual components and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. In vitro, dolutegravir did not inhibit (IC50 greater than 50 microM) the following: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, UGT2B7, P-gp, BCRP, bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4.
In vitro, dolutegravir, inhibited the renal OCT2 (IC50 = 1.93 microM) and MATE1 (IC50 = 6.34 microM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 such as dofetilide and metformin. [see Contraindications (4), Drug Interactions (7.4)].
In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter OAT1 (IC50 = 2.12 microM) and OAT3 (IC50 = 1.97 microM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3.
Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3.
Rilpivirine is primarily metabolized by CYP3A. Rilpivirine 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.
Dosing recommendations as a result of established and other potentially significant drug-drug interactions with dolutegravir or rilpivirine are provided in Table 4 [see Drug Interactions (7.4)].
| a The number of subjects represents the maximum number of subjects that were evaluated. | |||||||||||
| Coadministered Drug(s) and Dose(s) | Dose of Dolutegravir | n | Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir No Effect = 1.00 | ||||||||
| Cmax | AUC | Cτ or C24 | |||||||||
| Daclatasvir 60 mg once daily | 50 mg once daily | 12 | 1.03 (0.84 to 1.25) | 0.98 (0.83 to 1.15) | 1.06 (0.88 to 1.29) | ||||||
| Ethinyl estradiol 0.035 mg | 50 mg twice daily | 15 | 0.99 (0.91 to 1.08) | 1.03 (0.96 to 1.11) | 1.02 (0.93 to 1.11) | ||||||
| Metformin 500 mg twice daily | 50 mg once daily | 15a | 1.66 (1.53 to 1.81) | 1.79 (1.65 to 1.93) | _ | ||||||
| Metformin 500 mg twice daily | 50 mg twice daily | 15a | 2.11 (1.91 to 2.33) | 2.45 (2.25 to 2.66) | _ | ||||||
| Methadone 16 to 150 mg | 50 mg twice daily | 11 | 1.00 (0. 94 to 1.06) | 0.98 (0.91 to 1.06) | 0.99 (0.91 to 1.07) | ||||||
| Midazolam 3 mg | 25 mg once daily | 10 | _ | 0.95 (0.79 to 1.15) | _ | ||||||
| Norelgestromin 0.25 mg | 50 mg twice daily | 15 | 0.89 (0.82 to 0.97) | 0.98 (0.91 to 1.04) | 0.93 (0.85 to 1.03) | ||||||
| a Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily. b Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily. c The number of subjects represents the maximum number of subjects that were evaluated. | |||||||||||||||||
| Coadministered Drug(s) and Dose(s) | Dose of Dolutegravir | n | Geometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered Drugs | ||||||||||||||
| Cmax | AUC | Cτ or C24 | |||||||||||||||
| Antacid (MAALOX) simultaneous administration | 50 mg single dose | 16 | 0.28 (0.23 to 0.33) | 0.26 (0.22 to 0.32) | 0.26 (0.21 to 0.31) | ||||||||||||
| Antacid (MAALOX) 2 h after dolutegravir | 50 mg single dose | 16 | 0.82 (0.69 to 0.98) | 0.74 (0.62 to 0.90) | 0.70 (0.58 to 0.85) | ||||||||||||
| Calcium carbonate 1,200 mg simultaneous administration (fasted) | 50 mg single dose | 12 | 0.63 (0.50 to 0.81) | 0.61 (0.47 to 0.80) | 0.61 (0.47 to 0.80) | ||||||||||||
| Calcium carbonate 1,200 mg simultaneous administration (fed) | 50 mg single dose | 11 | 1.07 (0.83 to 1.38) | 1.09 (0.84 to 1.43) | 1.08 (0.81 to 1.42) | ||||||||||||
| Calcium carbonate 1,200 mg 2 h after dolutegravir | 50 mg single dose | 11 | 1.00 (0.78 to 1.29) | 0.94 (0.72 to 1.23) | 0.90 (0.68 to 1.19) | ||||||||||||
| Carbamazepine 300 mg twice daily | 50 mg once daily | 16c | 0.67 (0.61 to 0.73) | 0.51 (0.48 to 0.55) | 0.27 (0.24 to 0.31) | ||||||||||||
| Daclatasvir 60 mg once daily | 50 mg once daily | 12 | 1.29 (1.07 to 1.57) | 1.33 (1.11 to 1.59) | 1.45 (1.25 to 1.68) | ||||||||||||
| Ferrous fumarate 324 mg simultaneous administration (fasted) | 50 mg single dose | 11 | 0.43 (0.35 to 0.52) | 0.46 (0.38 to 0.56) | 0.44 (0.36 to 0.54) | ||||||||||||
| Ferrous fumarate 324 mg simultaneous administration (fed) | 50 mg single dose | 11 | 1.03 (0.84 to 1.26) | 0.98 (0.81 to 1.20) | 1.00 (0.81 to 1.23) | ||||||||||||
| Ferrous fumarate 324 mg 2 h after dolutegravir | 50 mg single dose | 10 | 0.99 (0.81 to 1.21) | 0.95 (0.77 to 1.15) | 0.92 (0.74 to 1.13) | ||||||||||||
| Multivitamin (One-A-Day) simultaneous administration | 50 mg single dose | 16 | 0.65 (0.54 to 0.77) | 0.67 (0.55 to 0.81) | 0.68 (0.56 to 0.82) | ||||||||||||
| Omeprazole 40 mg once daily | 50 mg single dose | 12 | 0.92 (0.75 to 1.11) | 0.97 (0.78 to 1.20) | 0.95 (0.75 to 1.21) | ||||||||||||
| Prednisone 60 mg once daily with taper | 50 mg once daily | 12 | 1.06 (0.99 to 1.14) | 1.11 (1.03 to 1.20) | 1.17 (1.06 to 1.28) | ||||||||||||
| Rifampina 600 mg once daily | 50 mg twice daily | 11 | 0.57 (0.49 to 0.65) | 0.46 (0.38 to 0.55) | 0.28 (0.23 to 0.34) | ||||||||||||
| Rifampinb 600 mg once daily | 50 mg twice daily | 11 | 1.18 (1.03 to 1.37) | 1.33 (1.15 to 1.53) | 1.22 (1.01 to 1.48) | ||||||||||||
| Rifabutin 300 mg once daily | 50 mg once daily | 9 | 1.16 (0.98 to 1.37) | 0.95 (0.82 to 1.10) | 0.70 (0.57 to 0.87) | ||||||||||||
| CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available. a This interaction study has been performed with a dose higher than the recommended dose for rilpivirine (25 mg once daily) assessing the maximal effect on the coadministered drug. b N (maximum number of subjects with data) for AUC(0-∞) = 15. c AUC(0-last). | |||||||||||||||||||||||
| Coadministered Drug(s) and Dose(s) | Dose of Rilpivirine | n | Geometric Mean Ratio (90% CI) of Coadministered Drug Pharmacokinetic Parameters with/without EDURANT | ||||||||||||||||||||
| Cmax | AUC | Cmin | |||||||||||||||||||||
| Acetaminophen 500 mg single dose | 150 mg once dailya | 16 | 0.97 (0.86 to 1.10) | 0.91 (0.86 to 0.97) | NA | ||||||||||||||||||
| Atorvastatin 40 mg once daily | 150 mg once dailya | 16 | 1.35 (1.08 to 1.68) | 1.04 (0.97 to 1.12) | 0.85 (0.69 to 1.03) | ||||||||||||||||||
| 2-hydroxy-atorvastatin | 1.58 (1.33 to 1.87) | 1.39 (1.29 to 1.50) | 1.32 (1.10 to 1.58) | ||||||||||||||||||||
| 4-hydroxy-atorvastatin | 1.28 (1.15 to 1.43) | 1.23 (1.13 to 1.33) | NA | ||||||||||||||||||||
| Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine | 150 mg once dailya | 16 | 0.98 (0.85 to 1.13) | 1.03 (0.95 to 1.13) | NA | ||||||||||||||||||
| Digoxin 0.5 mg single dose | 25 mg once daily | 22 | 1.06 (0.97 to 1.17) | 0.98 (0.93 to 1.04)c | NA | ||||||||||||||||||
| Ethinylestradiol 0.035 mg once daily | 25 mg once daily | 17 | 1.17 (1.06 to 1.30) | 1.14 (1.10 to 1.19) | 1.09 (1.03 to 1.16) | ||||||||||||||||||
| Norethindrone 1 mg once daily | 0.94 (0.83 to 1.06) | 0.89 (0.84 to 0.94) | 0.99 (0.90 to 1.08) | ||||||||||||||||||||
| Ketoconazole 400 mg once daily | 150 mg once dailya | 14 | 0.85 (0.80 to 0.90) | 0.76 (0.70 to 0.82) | 0.34 (0.25 to 0.46) | ||||||||||||||||||
| Methadone 60-100 mg once daily, individualized dose | 25 mg once daily | 13 | |||||||||||||||||||||
| R(‑) methadone | 0.86 (0.78 to 0.95) | 0.84 (0.74 to 0.95) | 0.78 (0.67 to 0.91) | ||||||||||||||||||||
| S(+) methadone | 0.87 (0.78 to 0.97) | 0.84 (0.74 to 0.96) | 0.79 (0.67 to 0.92) | ||||||||||||||||||||
| Metformin 850 mg single dose | 25 mg once daily | 20 | 1.02 (0.95 to -1.10) | 0.97 (0.90 to 1.06)b | NA | ||||||||||||||||||
| Omeprazole 20 mg once daily | 150 mg once dailya | 15 | 0.86 (0.68 to 1.09) | 0.86 (0.76 to 0.97) | NA | ||||||||||||||||||
| Rifampin 600 mg once daily | 150 mg once dailya | 16 | 1.02 (0.93 to 1.12) | 0.99 (0.92 to 1.07) | NA | ||||||||||||||||||
| 25-desacetylrifampin | 1.00 (0.87 to 1.15) | 0.91 (0.77 to 1.07) | NA | ||||||||||||||||||||
| Sildenafil 50 mg single dose | 75 mg once dailya | 16 | 0.93 (0.80 to 1.08) | 0.97 (0.87 to 1.08) | NA | ||||||||||||||||||
| N-desmethyl-sildenafil | 0.90 (0.80 to 1.02) | 0.92 (0.85 to 0.99)c | NA | ||||||||||||||||||||
| Simeprevir 150 mg once daily | 25 mg once daily | 21 | 1.10 (0.97 to 1.26) | 1.06 (0.94 to 1.19) | 0.96 (0.83 to 1.11) | ||||||||||||||||||
| CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available; ↔ = No change. a This interaction study has been performed with a dose higher than the recommended dose for rilpivirine (25 mg once daily) assessing the maximal effect on the coadministered drug. b Comparison based on historic controls. | |||||||||||||||||||||||||||||
| Coadministered Drug(s) and Dose(s) | Dose of Rilpivirine | n | Geometric Mean Ratio (90% CI) of Rilpivirine Pharmacokinetic Parameters with/without Coadministered Drugs | ||||||||||||||||||||||||||
| Cmax | AUC | Cmin | |||||||||||||||||||||||||||
| Acetaminophen 500 mg single dose | 150 mg once dailya | 16 | 1.09 (1.01 to 1.18) | 1.16 (1.10 to 1.22) | 1.26 (1.16 to 1.38) | ||||||||||||||||||||||||
| Atorvastatin 40 mg once daily | 150 mg once dailya | 16 | 0.91 (0.79 to 1.06) | 0.90 (0.81 to 0.99) | 0.90 (0.84 to 0.96) | ||||||||||||||||||||||||
| Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine | 150 mg once dailya | 16 | 1.17 (1.08 to 1.27) | 1.25 (1.16 to 1.35) | 1.18 (1.09 to 1.28) | ||||||||||||||||||||||||
| Ethinylestradiol/ Norethindrone 0.035 mg once daily/ 1 mg once daily | 25 mg once daily | 15 | ↔b | ↔b | ↔b | ||||||||||||||||||||||||
| Famotidine 40 mg single dose taken 12 hours before rilpivirine | 150 mg single dosea | 24 | 0.99 (0.84 to 1.16) | 0.91 (0.78 to 1.07) | NA | ||||||||||||||||||||||||
| Famotidine 40 mg single dose taken 2 hours before rilpivirine | 150 mg single dosea | 23 | 0.15 (0.12 to 0.19) | 0.24 (0.20 to 0.28) | NA | ||||||||||||||||||||||||
| Famotidine 40 mg single dose taken 4 hours after rilpivirine | 150 mg single dosea | 24 | 1.21 (1.06 to 1.39) | 1.13 (1.01 to 1.27) | NA | ||||||||||||||||||||||||
| Ketoconazole 400 mg once daily | 150 mg once dailyb | 15 | 1.30 (1.13 to 1.48) | 1.49 (1.31 to 1.70) | 1.76 (1.57 to 1.97) | ||||||||||||||||||||||||
| Methadone 60-100 mg once daily, individualised dose | 25 mg once daily | 12 | ↔b | ↔b | ↔b | ||||||||||||||||||||||||
| Omeprazole 20 mg once daily | 150 mg once dailya | 16 | 0.60 (0.48 to 0.73) | 0.60 (0.51 to 0.71) | 0.67 (0.58 to 0.78) | ||||||||||||||||||||||||
| Rifabutin 300 mg once daily | 25 mg once daily | 18 | 0.69 (0.62 to 0.76) | 0.58 (0.52 to 0.65) | 0.52 (0.46 to 0.59) | ||||||||||||||||||||||||
| Rifabutin 300 mg once daily | 50 mg once daily | 18 | 1.43 (1.30 to 1.56) | 1.16 (1.06 to 1.26) | 0.93 (0.85 to 1.01) | ||||||||||||||||||||||||
| (reference arm for comparison was 25-mg-once-daily rilpivirine administered alone) | |||||||||||||||||||||||||||||
| Rifampin 600 mg once daily | 150 mg once dailya | 16 | 0.31 (0.27 to 0.36) | 0.20 (0.18 to 0.23) | 0.11 (0.10 to 0.13) | ||||||||||||||||||||||||
| Sildenafil 50 mg single dose | 75 mg once dailya | 16 | 0.92 (0.85 to 0.99) | 0.98 (0.92 to 1.05) | 1.04 (0.98 to 1.09) | ||||||||||||||||||||||||
| Simeprevir 150 mg once daily | 25 mg once daily | 23 | 1.04 (0.95 to 1.13) | 1.12 (1.05 to 1.19) | 1.25 (1.16 to 1.35) | ||||||||||||||||||||||||
Microbiology
Mechanism of Action
Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.
Rilpivirine is a diarylpyrimidine NNRTI of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β, and γ.
Antiviral Activity in Cell Culture
Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean EC50 values of 0.5 nM to 2.1 nM (0.21 to 0.85 ng per mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade B isolates with a mean EC50 value of 0.52 nM in a viral integrase susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against a panel of HIV-1 clinical isolates (3 in each group of M [clades A, B, C, D, E, F, and G] and 3 in group O) with EC50 values ranging from 0.02 nM to 2.14 nM.
Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC50 value for HIV-1IIIB of 0.73 nM (0.27 ng per mL). Rilpivirine demonstrated antiviral activity against a broad panel of HIV-1 group M (clades A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07 nM to 1.01 nM (0.03 to 0.37 ng/mL) and was less active against group O primary isolates with EC50 values ranging from 2.88 to 8.45 nM (1.06 to 3.10 ng/mL).
Antiviral Activity in Combination with Other Antiviral Agents
Neither dolutegravir nor rilpivirine were antagonistic to all tested anti-HIV agents or with each other when tested in combination.
Resistance
Cell Culture: Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV‑1 strains and clades. Amino acid substitutions E92Q, G118R, S153F or Y, G193E, or R263K emerged in different passages and conferred decreased susceptibility to dolutegravir of up to 4-fold.
Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and clades as well as NNRTI-resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to rilpivirine included: L100I; K101E; V106I and A; V108I; E138K and G, Q, R; V179F and I; Y181C and I; V189I; G190E; H221Y; F227C; and M230I and L.
Virologically Suppressed Subjects: In the pooled SWORD-1 and SWORD-2 trials, 2 subjects in each treatment arm had confirmed virologic failure at any time through Week 48. The 2 subjects in the dolutegravir/rilpivirine arm had detectable resistance substitutions at rebound. One subject had the NNRTI-resistance-associated substitution K101K/E with no decreased susceptibility to rilpivirine (fold-change = 1.2) at Week 36, had no INSTI resistance-associated substitutions or decreased susceptibility to dolutegravir (fold-change less than 2), and had HIV-1 RNA less than 50 copies per mL at the withdrawal visit. The other subject had the dolutegravir resistance-associated substitution G193E at baseline (by exploratory HIV proviral DNA archive sequencing) and Week 24 (by conventional sequencing) without decreased susceptibility to dolutegravir (fold-change = 1.02) at Week 24. No resistance-associated substitutions were observed for the other 2 subjects in the comparative current antiretroviral regimen arms.
Cross-Resistance
Dolutegravir: The susceptibility of dolutegravir was tested against 60 INSTI-resistant site-directed mutant HIV-1 viruses (28 with single substitutions and 32 with 2 or more substitutions). The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M; E92Q/N155H; G140C/Q148R; G140S/Q148H, R or K; Q148R/N155H; T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference).
Rilpivirine: Considering all of the available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of rilpivirine: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, or M230L.
Cross-resistance in site-directed mutant virus has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I, and Y181V conferred 52 times, 15 times, and 12 times decreased susceptibility to rilpivirine, respectively. The combination of E138K and M184I showed 6.7 times reduced susceptibility to rilpivirine compared with 2.8 times for E138K alone. The K103N substitution did not show reduced susceptibility to rilpivirine by itself. However, the combination of K103N and L100I resulted in a 7 times reduced susceptibility to rilpivirine. In another study, the Y188L substitution resulted in a reduced susceptibility to rilpivirine of 9 times for clinical isolates and 6 times for site-directed mutants. Combinations of 2 or 3 NNRTI resistance-associated substitutions gave decreased susceptibility to rilpivirine (fold-change range: 3.7 to 554) in 38% and 66% of mutants, respectively.
Cross-resistance to efavirenz, etravirine, and/or nevirapine is likely after virologic failure and development of rilpivirine resistance.
Clinical Studies
Clinical Trials in Adult Subjects Switching to Juluca
The efficacy of Juluca is supported by data from 2 open-label, controlled trials [SWORD-1 (NCT02429791) and SWORD-2 (NCT02422797)] in virologically suppressed patients switching from their current antiretroviral regimen to dolutegravir plus rilpivirine.
SWORD-1 and SWORD-2 are identical 148-week, Phase 3, randomized, multicenter, parallel-group, non-inferiority trials. A total of 1,024 adult HIV–1-infected subjects who were on a stable suppressive antiretroviral regimen (containing 2 NRTIs plus either an INSTI, an NNRTI, or a PI) for at least 6 months (HIV-1 RNA less than 50 copies per mL), with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or rilpivirine received treatment in the trials. Subjects were randomized 1:1 to continue their current antiretroviral regimen or be switched to dolutegravir plus rilpivirine administered once daily. The primary efficacy endpoint for the SWORD trials was the proportion of subjects with plasma HIV-1 RNA less than 50 copies per mL at Week 48.
At baseline, in the pooled analysis, the median age of subjects was 43 years (range: 21 to 79), 22% female, 20% non-white, 11% were CDC Class C (AIDS), and 11% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment arms. In the pooled analysis, 54%, 26%, and 20% of subjects were receiving an NNRTI, PI, or INSTI (respectively) as their baseline third-treatment-agent class prior to randomization. This distribution was similar between treatment arms.
The primary endpoint and other outcomes (including outcomes by key baseline covariates) for the pooled SWORD-1 and SWORD-2 trials are shown in Table 11. The virologic outcome results for SWORD-1 and SWORD-2 were similar to the pooled SWORD-1 and SWORD-2 virologic outcome results.
| a Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation. | ||
| Pooled Data | ||
| Dolutegravir plus Rilpivirine (n = 513) | Current Antiretroviral Regimen (n = 511) | |
| HIV-1 RNA <50 copies/mL | 95% | 95% |
| Treatment Difference | -0.2% (95% CI: -3.0%, 2.5%) | |
| HIV-1 RNA ≥50 copies/mL | <1% | 1% |
| Treatment Difference | -0.6 % (95% CI:-1.7%, 0.6%) | |
| Data in window not <50 copies/mL | 0 | <1% |
| Discontinued for lack of efficacy | <1% | <1% |
| Discontinued for other reasons while not <50 copies/mL | <1% | <1% |
| Change in ART | 0 | <1% |
| No virologic data at Week 48 window | 5% | 4% |
| Discontinued due to adverse event or death | 3% | <1% |
| Discontinued for other reasonsa | 1% | 3% |
| Missing data during window but on study | 0 | <1% |
| Proportion (%) of Subjects with HIV-1 RNA <50 copies/mL by Baseline Category | ||
| Baseline CD4+ (cells/mm3) | ||
| <350 | 88% (n = 58) | 88% (n = 52) |
| ≥350 | 96% (n = 455) | 96% (n = 459) |
| Baseline Third-Treatment-Agent Class | ||
| INSTI | 94% (n = 105) | 95% (n = 97) |
| NNRTI | 96% (n = 275) | 95% (n = 278) |
| PI | 93% (n = 133) | 94% (n = 136) |
| Gender | ||
| Male | 95% (n = 393) | 96% (n = 403) |
| Female | 93% (n = 120) | 91% (n = 108) |
| Race | ||
| White | 94% (n = 421) | 95% (n = 400) |
| African-America/African Heritage/Other | 99% (n = 92) | 95% (n = 111) |
| Age (years) | ||
| <50 | 96% (n = 366) | 94% (n = 369) |
| ≥50 | 93% (n = 147) | 96% (n = 142) |
Treatment differences were maintained across baseline characteristics including, CD4+ cell count, age, gender, race, and baseline third-treatment-agent class.
Juluca side effects
Juluca can cause serious side effects, including:
- Severe skin rash and allergic reactions. Call your healthcare provider right away if you develop a rash during treatment. Stop taking the tablets and get medical help right away if you develop a rash with any of the following signs or symptoms:
- fever
- generally ill feeling
- tiredness
- muscle or joint aches
- blisters or sores in mouth
- blisters or peeling of the skin
- redness or swelling of the eyes
- welling of the mouth, face, lips, or tongue
- problems breathing
- Liver problems. People with a history of hepatitis B or C virus who have certain liver function test changes may have an increased risk of developing new or worsening changes in certain liver tests during treatment. Liver problems, including liver failure, have also happened in people without history of liver disease or other risk factors. Your healthcare provider may do blood tests to check your liver function. Call your healthcare provider right away if you develop any of the following signs or symptoms of liver problems:
- your skin or the white part of your eyes turns yellow (jaundice)
- dark or “tea-colored” urine
- light-colored stools (bowel movements)
- nausea or vomiting
- loss of appetite
- pain, aching, or tenderness on the right side of your stomach area
- Depression or mood changes. Tell your healthcare provider right away or get medical help if you have any of the following symptoms:
- feeling sad or hopeless
- feeling anxious or restless
- have thoughts of hurting yourself (suicide) or have tried to hurt yourself
The most common side effects include diarrhea and headache.
These are not all the possible side effects. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Juluca?
- Store the tablets at room temperature between 68°F to 77°F (20°C to 25°C).
- Store the tablets in the original bottle. Keep the bottle tightly closed and protected from moisture.
- The tablet bottle contains a desiccant to help keep your medicine dry (protect it from moisture). Keep the desiccant in the bottle. Do not remove the desiccant.
Keep all medicines out of the reach of children and pets.
General information about the safe and effective use of Juluca.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use this medicine for a condition for which it was not prescribed. Do not give it to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information that is written for health professionals.
Commonly used brand name(s)
In the U.S.
- Juluca
Available Dosage Forms:
- Tablet
Therapeutic Class: Antiretroviral Agent
Pharmacologic Class: Integrase Inhibitor
What other drugs will affect dolutegravir and rilpivirine?
Some medicines can make dolutegravir and rilpivirine less effective when taken at the same time. If you take any of the following medicines, take your dolutegravir and rilpivirine dose at least 4 hours before or 6 hours after you take the other medicine.
-
antacids or laxatives that contain calcium, magnesium, or aluminum (such as Maalox, Milk of Magnesia, Mylanta, Rolaids, Tums, and others), or the ulcer medicine sucralfate (Carafate);
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buffered medicine; or
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vitamin or mineral supplements that contain calcium or iron (but if you take dolutegravir and rilpivirine with food, you can take these supplements at the same time).
Many drugs can interact with dolutegravir and rilpivirine, and some drugs should not be used together. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Tell your doctor about all your current medicines and any medicine you start or stop using.