Cabenuva: Package Insert and Label Information (Page 4 of 7)
8.4 Pediatric Use
The safety and effectiveness of CABENUVA have been established in adolescents aged 12 to younger than 18 years and weighing at least 35 kg, which is supported by the following:
- •
- Trials in adults [see Clinical Studies (14.1)]
- •
- MOCHA (NCT03497676) trial in adolescents
MOCHA Trial
The safety, tolerability, and pharmacokinetics of oral and injectable cabotegravir and oral and injectable rilpivirine are being assessed in an ongoing Phase 1/2 multicenter, open-label, non-comparative study, MOCHA (IMPAACT 2017). Data are available from the Week 16 interim analysis from MOCHA. The primary objective at Week 16 was to confirm the use of the adult dose, through the evaluation of safety and pharmacokinetics, for oral and injectable cabotegravir and injectable rilpivirine in HIV-1–infected virologically suppressed adolescents.
Twenty-three HIV-1–infected and virologically suppressed adolescents aged 12 to younger than 18 years and weighing at least 35 kg were assigned to 1 of 2 cohorts, 1C or 1R, based on their background antiretroviral regimen. In cohort 1C, participants (n = 8) received one 30-mg cabotegravir tablet daily for 1 month, followed by monthly cabotegravir injections (Month 1: 600-mg injection, Months 2 and 3: 400-mg injection) for an additional 3 months, while continuing background antiretroviral therapy. In cohort 1R, participants received one 25-mg rilpivirine tablet (n = 15) daily for 1 month, followed by monthly rilpivirine injections (n = 13) (Month 1: 900-mg injection, Months 2 and 3: 600-mg injection) for an additional 3 months, while continuing background antiretroviral therapy.
At baseline, in cohort 1C, the median age of participants was 14.5 years; the median weight was 57.2 kg (range: 43.0, 73.5); 25% were female; 100% were non-White; and no participant had a CD4+ cell count <350 cells per mm3. At baseline, median CD4+ cell count was 725 cells per mm3 (range: 629 to 924). In cohort 1R, the median age of participants was 17 years; the median weight was 63.0 kg (range: 44.1, 98.5); 53% were female; 73% were non-White; and no participant had a CD4+ cell count <350 cells per mm3. At baseline, median CD4+ cell count was 827 cells per mm3 (range: 439 to 1,509).
The safety of CABENUVA in adolescents is expected to be similar to adults, as there was no clinically significant difference in drug exposure for the components of CABENUVA [see Adverse Reactions (6.1)]. The efficacy of CABENUVA in adolescents is extrapolated from adults with support from pharmacokinetic analyses showing similar drug exposure [see Clinical Pharmacology (12.3)].
The safety, efficacy, and pharmacokinetics of CABENUVA have not been established in pediatric patients younger than 12 years of age or weighing <35 kg.
8.5 Geriatric Use
Clinical trials of CABENUVA 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 CABENUVA 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)].
8.6 Renal Impairment
Based on studies with oral cabotegravir and population pharmacokinetic analyses of oral rilpivirine, no dosage adjustment of CABENUVA is necessary for patients with mild (creatinine clearance ≥60 to <90 mL/min) or moderate renal impairment (creatinine clearance ≥30 to <60 mL/min). In patients with severe renal impairment (creatinine clearance 15 to <30 mL/min) or end-stage renal disease (creatinine clearance <15 mL/min), increased monitoring for adverse effects is recommended [see Clinical Pharmacology (12.3)]. In patients with end-stage renal disease not on dialysis, effects on the pharmacokinetics of cabotegravir or rilpivirine are unknown. As cabotegravir and rilpivirine are >99% protein bound, dialysis is not expected to alter exposures of cabotegravir or rilpivirine.
8.7 Hepatic Impairment
Based on separate studies with oral cabotegravir and oral rilpivirine, no dosage adjustment of CABENUVA is necessary for patients with mild or moderate hepatic impairment (Child-Pugh A or B). The effect of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of cabotegravir or rilpivirine is unknown [see Clinical Pharmacology (12.3)].
10 OVERDOSAGE
There is no known specific treatment for overdose with cabotegravir or rilpivirine. If overdose occurs, monitor the patient and apply standard supportive treatment as required, including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. As both cabotegravir and rilpivirine are highly bound to plasma proteins, it is unlikely that either would be significantly removed by dialysis. Consider the prolonged exposure to cabotegravir and rilpivirine (components of CABENUVA) following an injection when assessing treatment needs and recovery [see Warnings and Precautions (5.6)].
11 DESCRIPTION
CABENUVA contains cabotegravir extended-release injectable suspension, an HIV INSTI, co-packaged with rilpivirine extended-release injectable suspension, an HIV NNRTI.
Cabotegravir
The chemical name for cabotegravir is (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide. The empirical formula is C19 H17 F2 N3 O5 and the molecular weight is 405.35 g/mol. It has the following structural formula:
Cabotegravir extended-release injectable suspension is a white to light pink free-flowing suspension for intramuscular injection in a sterile single-dose vial. Each vial contains 2 mL or 3 mL of the following: cabotegravir 200 mg/mL and the inactive ingredients mannitol (35 mg/mL), polyethylene glycol (PEG) 3350 (20 mg/mL), polysorbate 20 (20 mg/mL), and Water for Injection.
The vial stoppers are not made with natural rubber latex.
Rilpivirine
The chemical name for rilpivirine is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile. Its molecular formula is C22 H18 N6 and its molecular weight is 366.42. Rilpivirine has the following structural formula:
Rilpivirine extended-release injectable suspension is a white to off-white suspension for intramuscular injection. Each sterile single-dose vial contains 2 mL or 3 mL of the following: rilpivirine 300 mg/mL and the following inactive ingredients: citric acid monohydrate (1 mg/mL), poloxamer 338 (50 mg/mL), Water for Injection, glucose monohydrate to ensure isotonicity, sodium dihydrogen phosphate monohydrate, and sodium hydroxide to adjust pH.
The vial stoppers are not made with natural rubber latex.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
CABENUVA contains 2 long-acting HIV-1 antiretroviral drugs, cabotegravir and rilpivirine [see Microbiology (12.4)].
12.2 Pharmacodynamics
Cardiac Electrophysiology
At a dose of cabotegravir 150 mg orally every 12 hours (10 times the recommended total daily oral lead-in dosage of CABENUVA), the QT interval is not prolonged to any clinically relevant extent. Administration of 3 doses of cabotegravir 150 mg orally every 12 hours resulted in a geometric mean Cmax approximately 2.8-, 5.4-, and 5.6-fold above the geometric mean steady-state Cmax associated with the recommended 30‑mg dose of oral cabotegravir, the recommended 400‑mg dose given monthly, and the recommended 600-mg dose given every 2 months of cabotegravir extended-release injectable suspension, respectively.
At the recommended dose of rilpivirine 25 mg orally once daily, the QT interval is not prolonged to any clinically relevant extent. The rilpivirine 25-mg once-daily mean steady-state Cmax was 247 ng/mL, which is 1.7-fold higher than the mean steady-state Cmax observed with the recommended 600-mg dose of rilpivirine extended-release injectable suspension given monthly and 1.6-fold higher than the mean steady-state Cmax observed with the recommended 900-mg dose of rilpivirine extended-release injectable suspension given every 2 months.
When rilpivirine 75-mg and 300-mg once-daily oral doses (3 and 12 times, respectively, the recommended oral lead-in dosage) were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval were 10.7 (15.3) and 23.3 (28.4) msec, respectively, after baseline and placebo adjustment. Steady-state administration of rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 4.4- and 11.6-fold, respectively, higher than the mean steady-state Cmax observed with the recommended 600-mg dose of rilpivirine extended-release injectable suspension given monthly and approximately 4.1- and 10.7-fold, respectively, higher than the mean steady-state Cmax observed with the recommended 900-mg dose of rilpivirine extended-release injectable suspension given every 2 months. The corresponding Cmax ratios are 2.6 and 6.7 when compared with the recommended oral rilpivirine dosage [see Warnings and Precautions (5.5)].
12.3 Pharmacokinetics
Absorption, Distribution, and Elimination
The pharmacokinetic properties of the components of CABENUVA are provided in Table 9. The multiple-dose pharmacokinetic parameters are provided in Table 10. For the pharmacokinetic properties of oral cabotegravir and oral rilpivirine, refer to the full prescribing information for VOCABRIA (cabotegravir) and EDURANT (rilpivirine), respectively.
| CSF = Cerebrospinal fluid, BLQ = Below limit of quantification. | ||
| a When taken orally with a high-fat meal versus fasted, the AUC(0-inf) (geometric mean ratio [90% CI] of cabotegravir and rilpivirine are 1.14 [1.02, 1.28] and 1.72 [1.36, 2.16]), respectively. b The clinical relevance of CSF-to-plasma concentration ratios is unknown. Concentrations were measured at steady-state 1 week after intramuscular administration of cabotegravir and rilpivirine extended-release injectable suspensions given monthly or every 2 months.c Elimination half-life driven by slow absorption rate from the intramuscular injection site.d Dosing in mass balance studies: single-dose oral administration of [14 C] cabotegravir; single-dose oral administration of [14 C] rilpivirine. | ||
| Cabotegravir | Rilpivirine | |
| Absorptiona | ||
| Tmax (days), median | 7 | 3 to 4 |
| Distribution | ||
| % Bound to human plasma proteins | >99.8 | 99.7 |
| Blood-to-plasma ratio | 0.52 | 0.7 |
| CSF-to-plasma concentration ratio (median [range])b | 0.003 | 0.01 |
| (0.002 to 0.004) | (BLQ to 0.02) | |
| Elimination | ||
| t1/2 (weeks), meanc | 5.6 to 11.5 | 13 to 28 |
| Metabolism | ||
| Metabolic pathways | UGT1A1 | CYP3A |
| UGT1A9 (minor) | ||
| Excretion | ||
| Major route of elimination | Metabolism | Metabolism |
| % of dose excreted as total 14 C (unchanged drug) in urined | 27 (0) | 6 (<1) |
| % of dose excreted as total 14 C (unchanged drug) in fecesd | 59 (47) | 85 (26) |
| IM = Intramuscular. | ||||||||
| a Pharmacokinetic parameter values were based on individual post-hoc estimates from separate cabotegravir and rilpivirine population pharmacokinetic models (cabotegravir: pooled FLAIR and ATLAS for the oral, initial, and monthly injection dosing schedule and ATLAS-2M [subjects with no prior exposure to cabotegravir plus rilpivirine] for the every-2-month injection dosing schedule; rilpivirine: pooled FLAIR, ATLAS, and ATLAS-2M [subjects with no prior exposure], except for initial injection (direct to injection) [see footnote e] and for oral rilpivirine [see footnote g]).b tau is dosing interval: 24 hours for oral cabotegravir and rilpivirine, 1 month for cabotegravir and rilpivirine extended-release injectable suspensions given monthly, 2 months for cabotegravir and rilpivirine extended-release injectable suspensions given every 2 months.c Oral lead-in pharmacokinetic parameter values represent steady-state.d Initial injection Cmax values primarily reflect oral dosing because the initial injection was administered on the same day as the last oral dose; however, AUC(0-tau) and the Ctau values reflect the initial injections for cabotegravir and rilpivirine.e Pharmacokinetic parameters for initial injection (direct to injection) based on observed data from FLAIR Extension Phase (n = 110), AUC not calculated based on observed data, Cmax = 1 week following initial injection, Ctau = 1 month following initial injection.f Monthly and every-2-month injection pharmacokinetic parameter values represent Week 48 data.g Oral rilpivirine: AUC(0-tau) based on population pharmacokinetic estimates of rilpivirine 25 mg once daily from pooled Phase 3 trials with EDURANT (rilpivirine); Ctau based on observed data from FLAIR, ATLAS, and ATLAS-2M; Cmax based on observed data for rilpivirine 25 mg once daily from a pharmacokinetic substudy in pooled Phase 3 trials with EDURANT (rilpivirine). | ||||||||
| Drug | Dosing Phase | Dosage Regimen | Geometric Mean (5th , 95th Percentile)a | |||||
| AUC(0-tau) b (mcg•h/mL) | Cmax (mcg/mL) | Ctau b (mcg/mL) | ||||||
| Cabotegravir | Oral lead-inc | 30 mg once daily | 145 (93.5, 224) | 8.0 (5.3, 11.9) | 4.6 (2.8, 7.5) | |||
| Initial injection (after oral lead-in)d | 600 mg IMinitial dose | 1,591 (714; 3,245) | 8.0 (5.3, 11.9) | 1.5 (0.65, 2.9) | ||||
| Initial injection (direct to injection)e | 600 mg IMinitial dose | — | 1.89(0.438, 5.69) | 1.43(0.403, 3.90) | ||||
| Monthly injectionf | 400 mg IMmonthly | 2,415 (1,494; 3,645) | 4.2 (2.5, 6.5) | 2.8 (1.7, 4.6) | ||||
| Every-2-month injectionf | 600 mg IM every 2 months | 3,764 (2,431; 5,857) | 4.0 (2.3, 6.8) | 1.6 (0.8, 3.0) | ||||
| Drug | Dosing Phase | Dosage Regimen | Geometric Mean (5th , 95th Percentile)a | |||||
| AUC(0-tau) b (ng•h/mL) | Cmax (ng/mL) | Ctau b (ng/mL) | ||||||
| Rilpivirine | Oral lead-inc,g | 25 mg once daily | 2,083 (1,125; 3,748) | 116 (48.6, 244) | 79.4 (31.8, 177) | |||
| Initial injection (after oral lead-in)d | 900 mg IMinitial dose | 44,842 (21,712; 87,575) | 144 (93.9, 221) | 41.9 (21.7, 78.9) | ||||
| Initial injection (direct to injection)e | 900 mg IMinitial dose | — | 68(27.5, 220) | 48.9(17.7, 138) | ||||
| Monthly injectionf | 600 mg IMmonthly | 68,324 (39,042; 118,111) | 121 (68.1, 210) | 85.8 (49.6, 147) | ||||
| Every-2-month injectionf | 900 mg IMevery 2 months | 132,450(76,638; 221,783) | 138(80.6, 228) | 68.9(38.0, 119) | ||||
Specific Populations
No clinically significant differences in the pharmacokinetics of cabotegravir or rilpivirine were observed based on age, sex, race/ethnicity, BMI, or UGT1A1 polymorphisms.
Cabotegravir and rilpivirine concentrations in subjects who were hepatitis C virus antibody positive at baseline were similar to those in the overall study population. The effect of hepatitis B virus co-infection on the pharmacokinetics of cabotegravir is unknown. No clinically relevant differences in the pharmacokinetics of oral rilpivirine have been observed with hepatitis B and/or C virus co-infection.
Patients with Renal Impairment: With oral cabotegravir, no clinically significant differences in the pharmacokinetics of cabotegravir are expected in patients with mild, moderate, or severe renal impairment. Cabotegravir has not been studied in patients with end-stage renal disease not on dialysis. As cabotegravir is >99% protein bound, dialysis is not expected to alter exposures of cabotegravir [see Use in Specific Populations (8.6)].
Population pharmacokinetic analyses indicated that mild renal impairment had no clinically relevant effect on the exposure of oral rilpivirine. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or end-stage renal disease not on dialysis. As rilpivirine is >99% protein bound, dialysis is not expected to alter exposures of rilpivirine [see Use in Specific Populations (8.6)].
Patients with Hepatic Impairment: No clinically significant differences in the pharmacokinetics of cabotegravir are expected in mild to moderate (Child-Pugh A or B) hepatic impairment. The effect of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of cabotegravir has not been studied [see Use in Specific Populations (8.7)].
No clinically significant differences in the pharmacokinetics of rilpivirine were observed in mild to moderate (Child-Pugh A or B) hepatic impairment. The effect of severe hepatic impairment (Child-Pugh C) has not been studied [see Use in Specific Populations (8.7)].
Geriatric Patients: The pharmacokinetics of cabotegravir (oral or injectable) and of injectable rilpivirine have not been studied and data are limited in subjects aged 65 years or older [see Use in Specific Populations (8.5)].
Pediatric Patients: Population pharmacokinetic analyses revealed no clinically relevant differences in exposure between HIV-1–infected adolescent (weighing ≥35 kg and aged at least 12 years) and HIV-1–infected and –uninfected adult participants from the cabotegravir or rilpivirine development program.
| IM = intramuscular, PO = by mouth. | ||||||||||||||
| a Pharmacokinetic parameter values were based on population pharmacokinetic model simulations in a virtual HIV-1–infected adolescent population weighing 35 to 156 kg. | ||||||||||||||
| b tau is dosing interval: 24 hours for oral administration, 1 month for the initial injection and monthly intramuscular injections, and 2 months for every-2-months intramuscular injections of extended‑release injectable suspension. | ||||||||||||||
| c Oral lead-in pharmacokinetic parameter values represent steady-state. | ||||||||||||||
| d Initial injection Cmax values primarily reflect oral dosing because the initial injection was administered on the same day as the last oral dose; however, the AUC(0-tau) and Ctau values reflect the initial injection. | ||||||||||||||
| e Monthly and every-2-month injection pharmacokinetic parameter values represent Week 48 data. | ||||||||||||||
| Drug | Dosing Phase | Dosage Regimen | Geometric Mean (5th , 95th Percentile)a | |||||||||||
| AUC(0-tau) b (mcg•h/mL) | Cmax (mcg/mL) | Ctau b (mcg/mL) | ||||||||||||
| Cabotegravir | Oral lead-inc | 30 mg once daily | 193(106, 346) | 14.4(8.02, 25.5) | 5.79(2.48, 12.6) | |||||||||
| Initial injectiond | 600 mg IMinitial dose | 2,123(881; 4,938) | 11.2(5.63, 21.5) | 1.84(0.64, 4.52) | ||||||||||
| Every-1-month injectione | 400 mg IM every 1 month | 3,222 (1,879; 5,406) | 7.88 (4.41, 13.8) | 3.65 (1.63, 7.49) | ||||||||||
| Every-2-months injectione | 600 mg IMevery 2 months | 4,871(2,827; 8,232) | 7.23(3.76, 14.1) | 2.01(0.64, 4.73) | ||||||||||
| Drug | Dosing Phase | Dosage Regimen | Geometric Mean (5th , 95th Percentile) | |||||||||||
| AUC(0-tau) b (ng•h/mL) | Cmax (ng/mL) | Ctau b (ng/mL) | ||||||||||||
| Rilpivirine | Oral lead-inc | 25 mg POonce daily | 2,389(1,259; 4,414) | 144(80.8, 234) | 82.5(37.5, 167) | |||||||||
| Initial injectiond | 900 mg IMinitial dose | 41,515(19,301; 82,646) | 156(93.4, 246) | 39.7(20.0, 78.2) | ||||||||||
| Every-1-month injectione | 600 mg IMevery month | 74,717(40,243; 136,114) | 128(67.8, 233) | 97.3(51.1, 175) | ||||||||||
| Every-2-months injectione | 900 mg IMevery 2 months | 114,139(61,432; 206,214) | 111(57.6, 212) | 63.1(32.9, 117) | ||||||||||
Drug Interaction Studies
Cabotegravir is not a clinically relevant inhibitor of the following enzymes and transporters: CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4; UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B15, and 2B17; P-glycoprotein (P‑gp); breast cancer resistance protein (BCRP); bile salt export pump (BSEP); organic cation transporter (OCT)1, OCT2; organic anion transporter polypeptide (OATP)1B1, OATP1B3; multidrug and toxin extrusion transporter (MATE) 1, MATE 2-K; and multidrug resistance protein (MRP)2 or MRP4.
In vitro, cabotegravir inhibited renal OAT1 (IC50 = 0.81 microM) and OAT3 (IC50 = 0.41 microM). Based on physiologically based pharmacokinetic (PBPK) modeling, cabotegravir may increase the AUC of OAT1/3 substrates up to approximately 80%.
In vitro, cabotegravir did not induce CYP1A2, CYP2B6, or CYP3A4.
Simulations using PBPK modeling show that no clinically significant interaction is expected during coadministration of cabotegravir with drugs that inhibit UGT1A1.
In vitro, cabotegravir was not a substrate of OATP1B1, OATP1B3, OATP2B1, or OCT1.
Cabotegravir is a substrate of P-gp and BCRP in vitro; however, because of its high permeability, no alteration in cabotegravir absorption is expected with coadministration of P-gp or BCRP inhibitors.
Rilpivirine is not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes.
Drug interaction studies were not conducted with injectable cabotegravir or injectable rilpivirine. Drug interaction studies with oral cabotegravir or oral rilpivirine are summarized in Tables 12, 13, 14, and 15.
| n = Maximum number of subjects with data, CI = Confidence Interval. | ||||||||||||||||||||
| Coadministered Drug(s) and Dose(s) | Dose of Cabotegravir | n | Geometric Mean Ratio (90% CI) of Cabotegravir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00 | |||||||||||||||||
| Cmax | AUC | Ctau or C24 | ||||||||||||||||||
| Etravirine | 30 mg | 12 | 1.04 | 1.01 | 1.00 | |||||||||||||||
| 200 mg twice daily | once daily | (0.99, 1.09) | (0.96, 1.06) | (0.94, 1.06) | ||||||||||||||||
| Rifabutin | 30 mg | 12 | 0.83 | 0.77 | 0.74 | |||||||||||||||
| 300 mg once daily | once daily | (0.76, 0.90) | (0.74, 0.83) | (0.70, 0.78) | ||||||||||||||||
| Rifampin | 30-mg | 15 | 0.94 | 0.41 | 0.50 | |||||||||||||||
| 600 mg once daily | single dose | (0.87, 1.02) | (0.36, 0.46) | (0.44, 0.57) | ||||||||||||||||
| Rilpivirine | 30 mg | 11 | 1.05 | 1.12 | 1.14 | |||||||||||||||
| 25 mg once daily | once daily | (0.96, 1.15) | (1.05, 1.19) | (1.04, 1.24) | ||||||||||||||||
| n = Maximum number of subjects with data, CI = Confidence Interval, ↔ = 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 No Effect = 1.00 | |||||||||||||||||||||||
| Cmax | AUC | Cmin | ||||||||||||||||||||||||
| Acetaminophen | 150 mg | 16 | 1.09 | 1.16 | 1.26 | |||||||||||||||||||||
| 500-mg single dose | once dailya | (1.01 to 1.18) | (1.10 to 1.22) | (1.16 to 1.38) | ||||||||||||||||||||||
| Atorvastatin | 150 mg | 16 | 0.91 | 0.90 | 0.90 | |||||||||||||||||||||
| 40 mg once daily | once dailya | (0.79 to 1.06) | (0.81 to 0.99) | (0.84 to 0.96) | ||||||||||||||||||||||
| Chlorzoxazone | 150 mg | 16 | 1.17 | 1.25 | 1.18 | |||||||||||||||||||||
| 500-mg single dose taken 2 hours after rilpivirine | once dailya | (1.08 to 1.27) | (1.16 to 1.35) | (1.09 to 1.28) | ||||||||||||||||||||||
| Darunavir/ritonavir | 150 mg | 14 | 1.79 | 2.30 | 2.78 | |||||||||||||||||||||
| 800/100 mg once daily | once dailya | (1.56 to 2.06) | (1.98 to 2.67) | (2.39 to 3.24) | ||||||||||||||||||||||
| Didanosine | 150 mg | 21 | 1.00 | 1.00 | 1.00 | |||||||||||||||||||||
| 400 mg once daily delayed-release capsules taken 2 hours before rilpivirine | once dailya | (0.90 to 1.10) | (0.95 to 1.06) | (0.92 to 1.09) | ||||||||||||||||||||||
| Ethinyl estradiol/norethindrone | 25 mgonce daily | 15 | ↔b | ↔b | ↔b | |||||||||||||||||||||
| 0.035 mg once daily/1 mg once daily | ||||||||||||||||||||||||||
| Ketoconazole | 150 mg | 15 | 1.30 | 1.49 | 1.76 | |||||||||||||||||||||
| 400 mg once daily | once dailyb | (1.13 to 1.48) | (1.31 to 1.70) | (1.57 to 1.97) | ||||||||||||||||||||||
| Lopinavir/ritonavir | 150 mg | 15 | 0.96 | 0.99 | 0.89 | |||||||||||||||||||||
| 400/100 mg twice daily (soft gel capsule) | once dailya | (0.88 to 1.05) | (0.89 to 1.10) | (0.73 to 1.08) | ||||||||||||||||||||||
| Methadone | 25 mg | 12 | ↔b | ↔b | ↔b | |||||||||||||||||||||
| 60 to 100 mg once daily, individualized dose | once daily | |||||||||||||||||||||||||
| Raltegravir | 25 mg | 23 | 1.12 | 1.12 | 1.03 | |||||||||||||||||||||
| 400 mg twice daily | once daily | (1.04 to 1.20) | (1.05 to 1.19) | (0.96 to 1.12) | ||||||||||||||||||||||
| Rifabutin | 25 mg | 18 | 0.69 | 0.58 | 0.52 | |||||||||||||||||||||
| 300 mg once daily | once daily | (0.62 to 0.76) | (0.52 to 0.65) | (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 | 150 mg | 16 | 0.31 | 0.20 | 0.11 | |||||||||||||||||||||
| 600 mg once daily | once dailya | (0.27 to 0.36) | (0.18 to 0.23) | (0.10 to 0.13) | ||||||||||||||||||||||
| Sildenafil | 75 mg | 16 | 0.92 | 0.98 | 1.04 | |||||||||||||||||||||
| 50-mg single dose | once dailya | (0.85 to 0.99) | (0.92 to 1.05) | (0.98 to 1.09) | ||||||||||||||||||||||
| Tenofovir disoproxil fumarate | 150 mg | 16 | 0.96 | 1.01 | 0.99 | |||||||||||||||||||||
| 300 mg once daily | once dailya | (0.81 to 1.13) | (0.87 to 1.18) | (0.83 to 1.16) | ||||||||||||||||||||||
| n = Maximum number of subjects with data, CI = Confidence Interval, NA = Not available. | ||||||||||||||||||||||||||||||||
| Coadministered Drug(s) and Dose(s) | Dose of Cabotegravir | n | Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Cabotegravir No Effect = 1.00 | |||||||||||||||||||||||||||||
| Cmax | AUC | Ctau or C24 | ||||||||||||||||||||||||||||||
| Ethinyl estradiol | 30 mg | 19 | 0.92 | 1.02 | 1.00 | |||||||||||||||||||||||||||
| 0.03 mg once daily | once daily | (0.83, 1.03) | (0.97, 1.08) | (0.92, 1.10) | ||||||||||||||||||||||||||||
| Levonorgestrel | 30 mg | 19 | 1.05 | 1.12 | 1.07 | |||||||||||||||||||||||||||
| 0.15 mg once daily | once daily | (0.96, 1.15) | (1.07, 1.18) | (1.01, 1.15) | ||||||||||||||||||||||||||||
| Midazolam | 30 mg | 12 | 1.09 | 1.10 | NA | |||||||||||||||||||||||||||
| 3 mg | once daily | (0.94, 1.26) | (0.95, 1.26) | |||||||||||||||||||||||||||||
| Rilpivirine | 30 mg | 11 | 0.96 | 0.99 | 0.92 | |||||||||||||||||||||||||||
| 25 mg once daily | once daily | (0.85, 1.09) | (0.89, 1.09) | (0.79, 1.07) | ||||||||||||||||||||||||||||
| n = Maximum number of subjects with data, CI = Confidence Interval, 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 No Effect = 1.00 | |||||||||||||||||||||||||||||||||||
| Cmax | AUC | Cmin | ||||||||||||||||||||||||||||||||||||
| Acetaminophen | 150 mg | 16 | 0.97 | 0.91 | NA | |||||||||||||||||||||||||||||||||
| 500-mg single dose | once dailya | (0.86 to 1.10) | (0.86 to 0.97) | |||||||||||||||||||||||||||||||||||
| Atorvastatin | 150 mg | 16 | 1.35 | 1.04 | 0.85 | |||||||||||||||||||||||||||||||||
| 40 mg once daily | once dailya | (1.08 to 1.68) | (0.97 to 1.12) | (0.69 to 1.03) | ||||||||||||||||||||||||||||||||||
| 2-hydroxy-atorvastatin | 1.58 | 1.39 | 1.32 | |||||||||||||||||||||||||||||||||||
| (1.33 to 1.87) | (1.29 to 1.50) | (1.10 to 1.58) | ||||||||||||||||||||||||||||||||||||
| 4-hydroxy-atorvastatin | 1.28 | 1.23 | NA | |||||||||||||||||||||||||||||||||||
| (1.15 to 1.43) | (1.13 to 1.33) | |||||||||||||||||||||||||||||||||||||
| Chlorzoxazone | 150 mg | 16 | 0.98 | 1.03 | NA | |||||||||||||||||||||||||||||||||
| 500-mg single dose taken 2 hours after rilpivirine | once dailya | (0.85 to 1.13) | (0.95 to 1.13) | |||||||||||||||||||||||||||||||||||
| Darunavir/ritonavir | 150 mg | 15 | 0.90 | 0.89 | 0.89 | |||||||||||||||||||||||||||||||||
| 800/100 mg once daily | once dailya | (0.81 to 1.00) | (0.81 to 0.99) | (0.68 to 1.16) | ||||||||||||||||||||||||||||||||||
| Didanosine | 150 mg | 13 | 0.96 | 1.12 | NA | |||||||||||||||||||||||||||||||||
| 400 mg once daily delayed-release capsules taken 2 hours before rilpivirine | once dailya | (0.80 to 1.14) | (0.99 to 1.27) | |||||||||||||||||||||||||||||||||||
| Digoxin | 25 mg | 22 | 1.06 | 0.98 | NA | |||||||||||||||||||||||||||||||||
| 0.5-mg single dose | once daily | (0.97 to 1.17) | (0.93 to 1.04)c | |||||||||||||||||||||||||||||||||||
| Ethinyl estradiol | 25 mg | 17 | 1.17 | 1.14 | 1.09 | |||||||||||||||||||||||||||||||||
| 0.035 mg once daily | once daily | (1.06 to 1.30) | (1.10 to 1.19) | (1.03 to 1.16) | ||||||||||||||||||||||||||||||||||
| Norethindrone | 0.94 | 0.89 | 0.99 | |||||||||||||||||||||||||||||||||||
| 1 mg once daily | (0.83 to 1.06) | (0.84 to 0.94) | (0.90 to 1.08) | |||||||||||||||||||||||||||||||||||
| Ketoconazole | 150 mg | 14 | 0.85 | 0.76 | 0.34 | |||||||||||||||||||||||||||||||||
| 400 mg once daily | once dailya | (0.80 to 0.90) | (0.70 to 0.82) | (0.25 to 0.46) | ||||||||||||||||||||||||||||||||||
| Lopinavir/ritonavir | 150 mg | 15 | 0.96 | 0.99 | 0.89 | |||||||||||||||||||||||||||||||||
| 400/100 mg twice daily (soft gel capsule) | once dailya | (0.88 to 1.05) | (0.89 to 1.10) | (0.73 to 1.08) | ||||||||||||||||||||||||||||||||||
| Methadone | 25 mg | 13 | ||||||||||||||||||||||||||||||||||||
| 60 to 100 mg once daily, individualized dose | once daily | |||||||||||||||||||||||||||||||||||||
| R(‑) methadone | 0.86 | 0.84 | 0.78 | |||||||||||||||||||||||||||||||||||
| (0.78 to 0.95) | (0.74 to 0.95) | (0.67 to 0.91) | ||||||||||||||||||||||||||||||||||||
| S(+) methadone | 0.87 | 0.84 | 0.79 | |||||||||||||||||||||||||||||||||||
| (0.78 to 0.97) | (0.74 to 0.96) | (0.67 to 0.92) | ||||||||||||||||||||||||||||||||||||
| Metformin | 25 mg | 20 | 1.02 | 0.97 | NA | |||||||||||||||||||||||||||||||||
| 850-mg single dose | once daily | (0.95 to -1.10) | (0.90 to 1.06)b | |||||||||||||||||||||||||||||||||||
| Raltegravir | 25 mg | 23 | 1.10 | 1.09 | 1.27 | |||||||||||||||||||||||||||||||||
| 400 mg twice daily | once daily | (0.77 to 1.58) | (0.81 to 1.47) | (1.01 to 1.60) | ||||||||||||||||||||||||||||||||||
| Rifampin | 150 mg | 16 | 1.02 | 0.99 | NA | |||||||||||||||||||||||||||||||||
| 600 mg once daily | once dailya | (0.93 to 1.12) | (0.92 to 1.07) | |||||||||||||||||||||||||||||||||||
| 25-desacetylrifampin | 1.00 | 0.91 | NA | |||||||||||||||||||||||||||||||||||
| (0.87 to 1.15) | (0.77 to 1.07) | |||||||||||||||||||||||||||||||||||||
| Sildenafil | 75 mg | 16 | 0.93 | 0.97 | NA | |||||||||||||||||||||||||||||||||
| 50-mg single dose | once dailya | (0.80 to 1.08) | (0.87 to 1.08) | |||||||||||||||||||||||||||||||||||
| N -desmethyl-sildenafil | 0.90 | 0.92 | NA | |||||||||||||||||||||||||||||||||||
| (0.80 to 1.02) | (0.85 to 0.99)c | |||||||||||||||||||||||||||||||||||||
| Tenofovir disoproxil fumarate | 150 mg | 16 | 1.19 | 1.23 | 1.24 | |||||||||||||||||||||||||||||||||
| 300 mg once daily | once dailya | (1.06 to 1.34) | (1.16 to 1.31) | (1.10 to 1.38) | ||||||||||||||||||||||||||||||||||
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