Cabenuva
(Cabotegravir And Rilpivirine)Dosage & Administration
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Cabenuva Prescribing Information
Warnings and Precautions, Hypersensitivity Reactions ( Serious or severe hypersensitivity reactions have been reported with cabotegravir- and rilpivirine-containing regimens. Reactions associated with cabotegravir include Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) [see Adverse Reactions ] . Reactions associated with rilpivirine-containing regimens include cases of drug reaction with eosinophilia and systemic symptoms (DRESS)[see Adverse Reactions ] . While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. Administration of cabotegravir and rilpivirine oral lead-in dosing was used in clinical studies to help identify patients who may be at risk of a hypersensitivity reaction[see Dosage and Administration , Contraindications ] . Remain vigilant and discontinue CABENUVA if a hypersensitivity reaction is suspected[see Contraindications , Adverse Reactions ] .Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash, or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, mucosal involvement [oral blisters or lesions], conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. For information regarding the long-acting properties of CABENUVA, [see Warnings and Precautions ] . Administer oral lead-in dosing prior to administration of CABENUVA to help identify patients who may be at risk of a hypersensitivity reaction[see Dosage and Administration , Contraindications ] . | 4/2025 |
CABENUVA is indicated as a complete regimen for the treatment of HIV-1 infection in adults and adolescents 12 years of age and older and weighing at least 35 kg to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine
Cabotegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration that is essential for the HIV replication cycle. The mean 50% inhibitory concentration (IC50) value of cabotegravir in a strand transfer assay using purified recombinant HIV-1 integrase was 3.0 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.
Cabotegravir exhibited antiviral activity against laboratory strains of HIV-1 (subtype B, n = 4) with mean 50 percent effective concentration (EC50) values of 0.22 to 1.7 nM in peripheral blood mononuclear cells (PBMCs) and 293 cells. Cabotegravir demonstrated antiviral activity in PBMCs against a panel of 24 HIV-1 clinical isolates (3 in each of group M subtypes A, B, C, D, E, F, and G and 3 in group O) with a median EC50value of 0.19 nM (range: 0.02 to 1.06 nM, n = 24). The median EC50value against subtype B clinical isolates was 0.05 nM (range: 0.02 to 0.50 nM, n = 3). Against clinical HIV-2 isolates, the median EC50value was 0.12 nM (range: 0.10 to 0.14 nM, n = 3).
Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC50value for HIV-1IIIBof 0.73 nM (0.27 ng/mL). Rilpivirine demonstrated antiviral activity against a broad panel of HIV-1 group M (subtypes A, B, C, D, F, G, and H) primary isolates with EC50values 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 EC50values ranging from 2.88 nM to 8.45 nM (1.06 to 3.10 ng/mL).
In cell culture, cabotegravir was not antagonistic in combination with the NNRTI rilpivirine, or the nucleoside reverse transcriptase inhibitors (NRTIs) emtricitabine (FTC), lamivudine (3TC), or tenofovir disoproxil fumarate (TDF).
The antiviral activity of rilpivirine was not antagonistic when combined with the NNRTIs efavirenz, etravirine, or nevirapine; the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, or zidovudine; the protease inhibitors amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir; the fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc, or the INSTI raltegravir.
Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes 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.
Additionally, 5 of the 8 (63%) cabotegravir plus rilpivirine confirmed virologic failures had treatment-emergent INSTI resistance-associated substitutions and reduced phenotypic susceptibility to cabotegravir: Q148R (n = 2; 5- and 9-fold decreased susceptibility to cabotegravir), G140R (n = 1; 7-fold decreased susceptibility to cabotegravir), N155H (n = 1; 3‑fold decreased susceptibility to cabotegravir), or N155H+R263K (n = 1; 9-fold decreased susceptibility to cabotegravir).
There was another confirmed virologic failure participant at Week 112 in FLAIR who had switched to cabotegravir plus rilpivirine direct to injection at Week 100; there were no INSTI resistance‑associated substitutions detected at failure.
In comparison, in the current antiretroviral regimen arm with 8 confirmed virologic failures, 2 of 7 (29%) who had post-baseline resistance data had treatment-emergent resistance substitutions and phenotypic resistance to their antiretroviral drugs; both had treatment-emergent NRTI substitutions, M184V or I, which conferred resistance to emtricitabine or lamivudine in their regimen, and one of them also had the treatment-emergent NNRTI resistance substitution G190S, which conferred resistance to efavirenz in their regimen.
In the ATLAS-2M trial, there were 11 confirmed virologic failures (2 consecutive HIV-1 RNA ≥200 copies/mL) through Week 48: 9 participants (1.7%) in the every-2-month treatment arm and 2 participants (0.4%) in the monthly treatment arm. Of note, 8 of the 11 (73%) participants met confirmed virologic failure criteria at or before the Week 24 injection visit.
Four of the 9 confirmed virologic failure participants in the every-2-month arm transitioned from the oral current antiretroviral regimen arm of ATLAS into this trial.
In the every-2-month treatment arm, 8 of 9 (89%) confirmed virologic failure participants had NNRTI resistance-associated substitutions (E138E/K+V179V/I, K101E+E138A, A98G+K103N, E138K, V179I+Y188L+P225H, Y188L, K103N+E138A, or K101E) at virologic failure. Decreases in rilpivirine susceptibility for these 8 participant isolates ranged from 2- to 30-fold. Six of the 8 participants with NNRTI resistance-associated substitutions also had INSTI resistance-associated substitutions (L74I+Q148Q/R+N155N/H (n = 2), L74I+T97A+N155H, L74I+N155H, N155H, or L74I+Q148R) at failure with cabotegravir fold changes ranging from 1- to 9-fold. The INSTI polymorphism L74I was detected at baseline in 5 of the virologic failure participants by a HIV-1 proviral DNA assay.
In the monthly treatment arm, both of the confirmed virologic failure participants had NNRTI resistance-associated substitutions (K101E+M230L or Y188F+G190Q) at virologic failure with decreased susceptibility to rilpivirine of 17- and >119.2-fold, respectively. Both participants also had INSTI resistance-associated substitutions (N155N/H or Q148R+E138E/K) at failure with decreased susceptibility to cabotegravir of 2- and 5-fold, respectively. Neither participant had the L74I integrase polymorphism at baseline.
An increased risk of cabotegravir plus rilpivirine confirmed virologic failure is associated with baseline virological factors: HIV-1 subtype A1, the presence of baseline integrase L74I polymorphism, and archived NNRTI resistance-associated substitutions.
Eight of the 18 (44%) cabotegravir plus rilpivirine confirmed virologic failures in FLAIR, ATLAS, and ATLAS-2M had HIV‑1 subtype A1 with 7 of the 8 subtype A1 failures having the integrase polymorphism L74I detected at baseline and failure timepoints . There was no detectable phenotypic resistance to cabotegravir conferred by the presence of L74I at baseline. Subtype A1 is uncommon in the U.S.
The presence of the integrase polymorphism L74I in subtype B commonly seen in the U.S. was not associated with virologic failure. In contrast to FLAIR and ATLAS, where all virologic failures were subtype A, A1, or AG, subtypes of the cabotegravir plus rilpivirine virologic failures in ATLAS-2M included A (n = 1), A1 (n = 3), B (n = 4), C (n = 2), and complex/A1 (n = 1).
The presence of archived NNRTI resistance-associated substitutions at baseline detected using an exploratory HIV-1 proviral DNA assay was associated with a higher virologic failure rate in the every-2-month arm of ATLAS-2M and in the cabotegravir plus rilpivirine arm (monthly) of ATLAS compared to without archived NNRTI resistance-associated substitutions . However, in clinical practice, it is unlikely baseline resistance testing will be performed on virologically suppressed patients (HIV-1 RNA <50 copies/mL). Thus, in patients with an incomplete or uncertain NNRTI treatment history, consideration should be given before starting cabotegravir plus rilpivirine treatment.
| NNRTI = Non-Nucleoside Reverse Transcriptase Inhibitor, CAB+RPV = Cabotegravir + Rilpivirine, CAR = Current Antiretroviral Regimen, RAS = Resistance-Associated Substitutions, NA = Not Available. aBaseline and/or Screening result used. bPer Standard Monogram Nomenclature Reports. Based on June 2020 Los Alamos National Library panel, the majority of HIV-1 subtype A1 was reclassified as HIV-1 subtype A6. cL74I and L74L/I mixture. dBaseline/Screening NNRTI substitutions at L100, K101, K103, V106, V108, E138, V179, Y181, Y188, G190, H221, P225, M230. | ||||||
FLAIR CAB+RPV N = 283 | FLAIR CAR N = 283 | ATLAS CAB+RPV N = 308 | ATLAS CAR N = 308 | ATLAS-2M Q4W N = 523 | ATLAS-2M Q8W N = 522 | |
Total confirmed virologic failures | 5 | 4 | 3 | 4 | 2 | 9 |
Subtype A1b | 4/8 (50%) | 1/4 (25%) | 1/17 (6%) | 0/21 (0%) | 0/30 (0%) | 4/31 (13%) |
| 4/5 (80%) | 1/3 (33%) | 1/16 (6%) | 0/19 (0%) | 2/28 (0%) | 3/26 (12%) |
| 0/3 (0%) | 0/1 (0%) | 0/1 (0%) | 0/2 (0%) | 0/2 (0%) | 1/5 (20%) |
Other subtypes | 2/268 | 3/272 | 2/240 | 4/252 | 2/409 | 5/415 |
| 0/49 (0%) | 1/43 | 1/29 (3%) | 1/39 (2.6%) | 0/42 (0%) | 2/48 (4%) |
| 0/219 | 2/229 | 1/211 | 3/213 | 2/367 | 3/367 |
Missing data | 7 | 7 | 51 | 35 | 84 | 76 |
With NNRTI RASd | NA | NA | 3/78 | 2/83 | 1/128 | 7/117 |
Without NNRTI RAS | NA | NA | 0/179 | 2/190 | 1/310 | 2/327 |
Missing data | NA | NA | 51 | 35 | 84 | 76 |
Virologic failure isolates from cabotegravir plus rilpivirine treatment in FLAIR, ATLAS, and ATLAS-2M exhibited cross-resistance to INSTIs and NNRTIs. All confirmed virologic isolates with genotypic evidence of cabotegravir resistance had cross-resistance to elvitegravir and raltegravir but retained phenotypic susceptibility to dolutegravir and when tested bictegravir. Virologic failure isolates with rilpivirine resistance had cross-resistance with NNRTIs delavirdine, doravirine, efavirenz, etravirine, and nevirapine.
Cabotegravir was active against viruses harboring the NNRTI substitutions K103N or Y188L, or the NRTI substitutions M184V, D67N/K70R/T215Y, or V75I/F77L/F116Y/Q151M.
The efficacy of CABENUVA has been evaluated in 2 Phase 3 randomized, multicenter, active-controlled, parallel-arm, open-label, non-inferiority trials:
• Trial 201584 (FLAIR [NCT02938520]), (n = 629): antiretroviral treatment (ART)‑naive participants with HIV-1 received a dolutegravir INSTI-containing regimen for 20 weeks (either dolutegravir/abacavir/lamivudine or dolutegravir plus 2 other NRTIs if participants were HLA‑B*5701 positive). Participants who were virologically suppressed (HIV-1 RNA <50 copies/mL, n = 566) were then randomized (1:1) to receive either a cabotegravir plus rilpivirine regimen or remain on the current antiretroviral regimen. Participants randomized to receive cabotegravir plus rilpivirine initiated treatment with daily oral lead-in dosing with one 30-mg VOCABRIA (cabotegravir) tablet plus one 25-mg EDURANT (rilpivirine) tablet for at least 4 weeks followed by monthly injections with CABENUVA for an additional 44 weeks[see Dosage and Administration ].• Trial 201585 (ATLAS [NCT02951052]), (n = 616): ART-experienced, virologically-suppressed (for at least 6 months; median prior treatment duration was 4.3 years) participants (HIV-1 RNA <50 copies/mL) with HIV-1 were randomized and received either a cabotegravir plus rilpivirine regimen or remained on their current antiretroviral regimen. Participants randomized to receive cabotegravir plus rilpivirine initiated treatment with daily oral lead-in dosing with one 30-mg VOCABRIA (cabotegravir) tablet plus one 25-mg EDURANT (rilpivirine) tablet for at least 4 weeks followed by monthly injections with CABENUVA for an additional 44 weeks[see Dosage and Administration ].
The primary analysis was conducted after all participants completed their Week 48 visit or discontinued the trial prematurely.
At baseline, in FLAIR and ATLAS the median age was 34 years and 40 years, 22% and 32% were female, and 24% and 31% were non-White, respectively. In both studies, 7% had CD4+ cell count <350 cells/mm3; these characteristics were similar between treatment arms. In ATLAS, participants received an NNRTI (50%), integrase inhibitor (33%), or protease inhibitor (17%) as their baseline third-agent class prior to randomization; this was similar between treatment arms. Participants with hepatitis B co-infection were excluded from the trial.
The primary endpoint of FLAIR and ATLAS was the proportion of participants with plasma HIV-1 RNA ≥50 copies/mL at Week 48.
The primary endpoint and other Week 48 outcomes, including outcomes by key baseline factors, for FLAIR and ATLAS are shown in Tables 17and 18.
| CAB = Cabotegravir, RPV = Rilpivirine, CAR = Current Antiretroviral Regimen, n = Number of participants in each treatment group, CI = Confidence Interval. aIncludes participants who discontinued for lack of efficacy and discontinued while not suppressed. | ||||
Virologic Outcomes | FLAIR Monthly Dosing | ATLAS Monthly Dosing | ||
CAB plus RPV (n = 283) | CAR (n = 283) | CAB plus RPV (n = 308) | CAR (n = 308) | |
HIV-1 RNA ≥50 copies/mLa | 2% | 2% | 2% | 1% |
Treatment difference | -0.4% | 0.7% | ||
(95% CI: -2.8%, 2.1%) | (95% CI: -1.2%, 2.5%) | |||
HIV-1 RNA <50 copies/mL | 94% | 93% | 93% | 95% |
No virologic data at Week 48 window | 4% | 4% | 6% | 4% |
Discontinued due to adverse event or death | 3% | <1% | 4% | 2% |
Discontinued for other reasons | 1% | 4% | 2% | 2% |
Missing data during window but on study | 0 | 0 | 0 | 0 |
Adjusted for study and randomization stratification factors, treatment difference of HIV-1 RNA ≥50 copies/mL for the pooled data was 0.2% with 95% CI (-1.4%, 1.7%).
| CAB = Cabotegravir, RPV = Rilpivirine, CAR = Current Antiretroviral Regimen. | ||||
Baseline Factors | FLAIR Monthly Dosing | ATLAS Monthly Dosing | ||
CAB plus RPV (N = 283) n/N (%) | CAR (N = 283) n/N (%) | CAB plus RPV (N = 308) n/N (%) | CAR (N = 308) n/N (%) | |
Baseline CD4+ (cells/mm3) | ||||
<350 | 0/19 | 1/27 (4%) | 0/23 | 1/27 (4%) |
≥350 to <500 | 3/64 (5%) | 0/60 | 2/56 (4%) | 0/60 |
≥500 | 3/200 (2%) | 6/196 (3%) | 3/299 (1%) | 2/224 (<1%) |
Gender | ||||
Male | 3/220 (1%) | 6/219 (3%) | 3/209 (1%) | 3/204 (1%) |
Female | 3/63 (5%) | 1/64 (2%) | 2/99 (2%) | 0/104 |
Race | ||||
White | 6/216 (3%) | 5/201 (2%) | 3/214 (1%) | 2/207 (<1%) |
African American/African Heritage | 0/47 | 2/56 (4%) | 2/62 (3%) | 1/77 (1%) |
Asian/Other | 0/20 | 0/24 | 0/32 | 0/24 |
Body mass index | ||||
<30 kg/m2 | 3/243 (1%) | 7/246 (3%) | 3/248 (1%) | 1/242 (<1%) |
≥30 kg/m2 | 3/40 (8%) | 0/37 | 2/60 (3%) | 2/66 (3%) |
Age (years) | ||||
<50 | 5/250 (2%) | 6/254 (2%) | 4/242 (2%) | 2/212 (<1%) |
≥50 | 1/33 (3%) | 1/29 (3%) | 1/66 (2%) | 1/96 (1%) |
Baseline antiviral therapy at randomization | ||||
Protease inhibitor-containing regimen | 0 | 0 | 1/51 (2%) | 0/54 |
Integrase inhibitor-containing regimen | 6/283 (2%) | 7/283 (2%) | 0/102 | 2/99 (2%) |
Non-nucleoside reverse transcriptase inhibitor-containing regimen | 0 | 0 | 4/155 (3%) | 1/155 (<1%) |
Participants in both the FLAIR and ATLAS trials were virologically suppressed prior to Day 1 or at study entry, respectively, and no clinically relevant change from baseline in CD4+ cell counts was observed.
In FLAIR at Week 96, the proportion of participants with HIV-1 RNA ≥50 copies/mL was 3.2 % for both the cabotegravir plus rilpivirine (n = 283) and current antiretroviral regimen (n = 283) treatment arms; adjusted treatment difference was 0.0% with 95% CI (-2.9%, 2.9%). The proportion of participants with HIV-1 RNA <50 copies/mL was 87% and 89% for the cabotegravir plus rilpivirine and the current antiretroviral regimen arms, respectively; adjusted treatment difference was -2.8% with 95% CI (-8.2%, 2.5%).
In the FLAIR study during the Extension Phase (Week 100 to Week 124), the efficacy of CABENUVA was evaluated in patients who switched (at Week 100) from their current antiretroviral regimen to CABENUVA, with and without an oral lead-in phase. A total of 121 participants chose to start the treatment with oral lead-in and 111 participants chose direct to injection. Participants were not randomized during the Extension Phase. At Week 124, the proportion of participants with HIV-1 RNA ≥50 copies/mL was 0.8% and 0.9% for the oral lead-in and direct to injection groups, respectively. The rates of virologic suppression (HIV-1 RNA <50 copies/mL) were similar in both the oral lead-in (93%) and direct to injection (99%) groups.
The efficacy of CABENUVA dosed every 2 months has been evaluated in 1 Phase 3b randomized, multicenter, parallel-arm, open-label, non-inferiority trial:
• Trial 207966 (ATLAS-2M [NCT03299049]), (n = 1,045): ART‑experienced, virologically suppressed participants with HIV-1, including 504 participants from the ATLAS trial (randomized to CAB plus RPV [n = 253] or CAR [n = 251]; prior exposure to cabotegravir plus rilpivirine [n = 391]), were randomized and received a cabotegravir plus rilpivirine regimen administered as injection doses of cabotegravir 400 mg plus rilpivirine 600 mg either monthly or cabotegravir 600 mg plus rilpivirine 900 mg every 2 months. Participants without prior exposure to cabotegravir plus rilpivirine initiated treatment with daily oral lead-in dosing with one 30-mg VOCABRIA (cabotegravir) tablet plus one 25-mg EDURANT (rilpivirine) tablet for at least 4 weeks followed by monthly or every-2-month injections with CABENUVA for an additional 44 weeks.
The primary analysis was conducted after all participants completed their Week 48 visit or discontinued the study prematurely.
At baseline, the median age was 42 years, 27% were female, 27% were non-White, and 6% had a CD4+ cell count <350 cells per mm3; these characteristics were similar between the treatment arms. Participants received either an NNRTI (29%), an integrase inhibitor besides cabotegravir plus rilpivirine (26%), a protease inhibitor (7%), or cabotegravir plus rilpivirine (37%) as their baseline third-agent class prior to randomization.
The primary endpoint of ATLAS-2M was the proportion of participants with a plasma HIV-1 RNA ≥50 copies/mL at Week 48.
The primary endpoint and other Week 48 outcomes, including outcomes by key baseline factors, for ATLAS-2M are shown in Tables 19and 20.
| aIncludes participants who discontinued for lack of efficacy, discontinued while not suppressed. n = Number of participants in each treatment group, CI = Confidence Interval. | ||
Virologic Outcomes | Cabotegravir plus Rilpivirine | |
Every-2-Month Dosing n = 522 | Monthly Dosing n = 523 | |
HIV-1 RNA ≥50 copies/mLa | 2% | 1% |
Treatment difference | 0.8 | |
(95% CI: -0.6%, 2.2%) | ||
HIV-1 RNA <50 copies/mL | 94% | 94% |
No virologic data at Week 48 window | 4% | 6% |
Discontinued study due to adverse event or death | 2% | 3% |
Discontinued for other reasons | 2% | 3% |
Missing data during window but on study | 0 | 0 |
Baseline Factors | Cabotegravir plus Rilpivirine | |
Every-2-Month Dosing (N = 522) n/N (%) | Monthly Dosing (N = 523) n/N (%) | |
Baseline CD4+ (cells/mm3) | ||
<350 | 1/35 (3%) | 1/27 (4%) |
≥350 to <500 | 1/96 (1%) | 0/89 |
≥500 | 7/391 (2%) | 4/407 (1%) |
Gender | ||
Male | 4/385 (1%) | 5/380 (1%) |
Female | 5/137 (4%) | 0/143 |
Race | ||
White | 5/370 (1%) | 5/393 (1%) |
Black/African American Asian/Other | 4/101 (4%) 0/51 | 0/90 0/40 |
Body mass index | ||
<30 kg/m2 | 3/409 (1%) | 3/425 (1%) |
≥30 kg/m2 | 6/113 (5%) | 2/98 (2%) |
Age (years) | ||
<35 | 4/137 (3%) | 1/145 (1%) |
35 to <50 | 3/242 (1%) | 2/239 (1%) |
≥50 | 2/143 (1%) | 2/139 (1%) |
Prior exposure to cabotegravir plus rilpivirine | ||
None | 5/327 (2%) | 5/327 (2%) |
1 to 24 Weeks | 3/69 (4%) | 0/68 |
>24 Weeks | 1/126 (1%) | 0/128 |
Baseline third-agent class | ||
Protease inhibitor-containing regimen | 1/40 (3%) | 1/30 (3%) |
Integrase inhibitor-containing regimen | 3/136 (2%) | 2/141 (1%) |
NNRTI-containing regimen | 1/151 (1%) | 2/156 (1%) |
Cabotegravir plus rilpivirine | 4/195 (2%) | 0/196 |
• Refer to full prescribing information for detailed information on dosage and administration recommendations. ()2 DOSAGE AND ADMINISTRATION• Refer to full prescribing information for detailed information on dosage and administration recommendations.• Prior to initiating treatment with CABENUVA, oral lead-in dosing may be considered to assess the tolerability of cabotegravir and rilpivirine with the recommended dosage used for approximately 1 month.• For gluteal intramuscular injection only.• Recommended Monthly Dosing Schedule: Initiate injections of CABENUVA (600 mg of cabotegravir and 900 mg of rilpivirine) on the last day of current antiretroviral therapy or oral lead-in and continue with injections of CABENUVA (400 mg of cabotegravir and 600 mg of rilpivirine) every month thereafter.• Recommended Every-2-Month Dosing Schedule: Initiate injections of CABENUVA (600 mg of cabotegravir and 900 mg of rilpivirine) on the last day of current antiretroviral therapy or oral lead-in for 2 consecutive months and continue with injections of CABENUVA every 2 months thereafter.
2.1 Dosage and Administration Overview• CABENUVA contains cabotegravir extended-release injectable suspension in a single-dose vial and rilpivirine extended-release injectable suspension in a single-dose vial[see Dosage Forms and Strengths ].• CABENUVA must be administered by a healthcare provider by gluteal intramuscular injection[see Dosage and Administration ].• CABENUVA may be initiated with oral cabotegravir and oral rilpivirine prior to the intramuscular injections or the patient may proceed directly to injection of CABENUVA without an oral lead-in[see Dosage and Administration ].• CABENUVA can be injected monthly or every 2 months[see Dosage and Administration ]. Healthcare providers should discuss these 2 dosing options with the patient prior to starting CABENUVA and decide which injection dosing frequency would be the most appropriate option for the patient[see Adverse Reactions , Microbiology , Clinical Studies ].
2.2 Adherence to CABENUVAPrior to starting CABENUVA, healthcare providers should carefully select patients who agree to the required monthly or every‑2-month injection dosing schedule and counsel patients about the importance of adherence to scheduled dosing visits to help maintain viral suppression and reduce the risk of viral rebound and potential development of resistance with missed doses
[see Dosage and Administration , Warnings and Precautions , Microbiology ].2.3 Optional Oral Lead-In Dosing to Assess Tolerability of CABENUVA in Adults and Adolescents 12 Years of Age and Older and Weighing at Least 35 kgThe healthcare provider and patient may decide to use an oral lead-in with oral cabotegravir and oral rilpivirine prior to the initiation of CABENUVA to assess the tolerability of cabotegravir and rilpivirine, or the healthcare provider and patient may proceed directly to injection of CABENUVA without the use of an oral lead-in.
If oral lead-in is used, the recommended oral lead-in daily dose is one 30-mg tablet of VOCABRIA (cabotegravir) and one 25-mg tablet of EDURANT (rilpivirine) taken with a meal for approximately 1 month (at least 28 days), followed by intramuscular initiation injections of CABENUVA. See Tables 1and 2for recommended oral lead-in and monthly or every-2-month intramuscular injection dosing schedule for CABENUVA
[see Dosage and Administration ].2.4 Recommended Monthly Gluteal Intramuscular Injection Dosing with CABENUVA in Adults and Adolescents 12 Years of Age and Older and Weighing at Least 35 kgInitiation Injections (CABENUVA 600-mg/900-mg Kit)Initiate injections on the last day of current antiretroviral therapy or oral lead-in, if used
[see Dosage and Administration ]. The recommended initiation injection doses of CABENUVA are a single 600-mg (3-mL) intramuscular injection of cabotegravir and a single 900-mg (3-mL) intramuscular injection of rilpivirine. Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit[see Dosage and Administration ]. Continuation injections should be initiated a month after the initiation injections.Continuation Injections (CABENUVA 400-mg/600-mg Kit)After the initiation injections, the recommended monthly continuation injection doses of CABENUVA are a single 400-mg (2-mL) intramuscular injection of cabotegravir and a single 600-mg (2-mL) intramuscular injection of rilpivirine at each visit . Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit
[see Dosage and Administration ]. Patients may be given CABENUVA up to 7 days before or after the date the patient is scheduled to receive monthly injections.Table 1. Recommended Dosing Schedule with Optional Oral Lead-In or Direct to Injection for Monthly Injection aThe optional oral therapy should be continued until the day the first injection is administered. bGiven on the last day of current antiretroviral therapy or oral lead-in if used. DrugOptional Oral Lead-Ina(at Least 28 Days)Intramuscular (Gluteal)Initiation Injections(One-Time Dosing)Intramuscular (Gluteal)Continuation Injections(Once-Monthly Dosing)Month (at Least 28 Days) Prior to Starting InjectionsInitiate Injections at Month 1bOne Month after Initiation Injection and Monthly OnwardsCabotegravir
30 mg once daily
with a meal600 mg (3 mL)
400 mg (2 mL)
Rilpivirine
25 mg once daily
with a meal900 mg (3 mL)
600 mg (2 mL)
2.5 Recommended Every-2-Month Gluteal Intramuscular Injection Dosing with CABENUVA in Adults and Adolescents 12 Years of Age and Older and Weighing at Least 35 kgInitiation Injections (CABENUVA 600-mg/900-mg Kit)Initiate injections on the last day of current antiretroviral therapy or oral lead-in, if used
[see Dosage and Administration ]. The recommended initiation injection doses of CABENUVA are a single 600-mg (3-mL) intramuscular injection of cabotegravir and a single 900-mg (3-mL) intramuscular injection of rilpivirine 1 month apart for 2 consecutive months . Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit[see Dosage and Administration ]. Patients may be given CABENUVA up to 7 days before or after the date the patient is scheduled to receive the second initiation injections.Continuation Injections (CABENUVA 600-mg/900-mg Kit)After the 2 initiation doses given consecutively 1 month apart (Months 1 and 2), the recommended continuation injection doses (Month 4 onwards) of CABENUVA are a single 600-mg (3-mL) intramuscular injection of cabotegravir and a single 900-mg (3-mL) intramuscular injection of rilpivirine administered every 2 months . Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit
[see Dosage and Administration ]. Patients may be given CABENUVA up to 7 days before or after the date the patient is scheduled to receive the injections.Table 2. Recommended Dosing Schedule with Optional Oral Lead-In or Direct to Injection for Every-2-Month Injection aThe optional oral therapy should be continued until the day the first injection is administered.
bFor the every-2-month injection dosing schedule in adults, Initiation Injections are injections administered at Month 1 and Month 2 and Continuation Injections are injections administered every 2 months onwards (starting Month 4).
cGiven on the last day of current antiretroviral therapy or oral lead-in if used.DrugOptional Oral Lead-Ina(at Least 28 Days)Intramuscular (Gluteal) InjectionsbMonth (at Least 28 Days) Prior to Starting InjectionsInitiate Injectionscat Month 1, Month 2, and then Every 2 Months Onwards(Starting at Month 4)Cabotegravir
30 mg once daily with a meal
600 mg (3 mL)
Rilpivirine
25 mg once daily with a meal
900 mg (3 mL)
2.6 Dosing Recommendations When Switching from Monthly to Every-2-Month Intramuscular InjectionsPatients switching from a monthly continuation injection schedule (a single 400-mg [2-mL] gluteal intramuscular injection of cabotegravir and a single 600-mg [2-mL] intramuscular injection of rilpivirine) to an every-2-month continuation injection dosing schedule should receive a single 600-mg (3-mL) intramuscular injection of cabotegravir and a single 900-mg (3-mL) intramuscular injection of rilpivirine administered 1 month after the last monthly continuation injections and then every 2 months thereafter. Cabotegravir and rilpivirine injections should be administered at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit
[see Dosage and Administration ].2.7 Dosing Recommendations When Switching from Every-2-Month to Monthly Intramuscular InjectionsPatients switching from an every-2-month continuation injection schedule (a single 600-mg [3-mL] intramuscular injection of cabotegravir and a single 900-mg [3-mL] intramuscular injection of rilpivirine) to a monthly continuation dosing schedule should receive a single 400-mg (2-mL) intramuscular injection of cabotegravir and a single 600-mg (2-mL) intramuscular injection of rilpivirine 2 months after the last every-2‑month continuation injection and then monthly thereafter. Cabotegravir and rilpivirine injections should be administered at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit
[see Dosage and Administration ].2.8 Recommended Dosing Schedule for Missed InjectionsAdherence to the injection dosing schedule is strongly recommended
[see Dosage and Administration ]. Patients who miss a scheduled injection visit should be clinically reassessed to ensure resumption of therapy remains appropriate. Refer to Table 3for dosing recommendations after missed injections.Planned Missed Injections for Patients on the Monthly Dosing ScheduleIf a patient plans to miss a scheduled injection visit by more than 7 days, VOCABRIA in combination with EDURANT once daily may be used for up to 2 months to replace missed injection visits, or any other fully suppressive oral antiretroviral regimen may be used until injections are resumed. The recommended oral daily dose is one 30-mg tablet of VOCABRIA (cabotegravir) and one 25-mg tablet of EDURANT (rilpivirine). Take VOCABRIA with EDURANT at approximately the same time each day with a meal.
The first dose of oral therapy should be taken 1 month (+/-7 days) after the last injection dose of CABENUVA and continued until the day injection dosing is restarted. Refer to Table 3for injection dosing recommendations. For oral therapy with VOCABRIA and EDURANT of durations greater than 2 months, an alternative oral regimen is recommended.
Unplanned Missed Injections for Patients on the Monthly Dosing ScheduleIf monthly injections are missed or delayed by more than 7 days and oral therapy has not been taken in the interim, clinically reassess the patient to determine if resumption of injection dosing remains appropriate
[see Warnings and Precautions ]. If injection dosing will be continued, see Table 3for dosing recommendations.Table 3. Injection Dosing Recommendations after Missed Injections for Patients on the Monthly Dosing Schedulea aRefer to oral dosing recommendations if a patient plans to miss a scheduled injection visit. Time since Last InjectionRecommendationLess than or equal to 2 monthsResume with 400-mg (2-mL) cabotegravir and 600-mg (2-mL) rilpivirine gluteal intramuscular monthly injections as soon as possible.
Greater than 2 monthsRe-initiate the patient with 600-mg (3-mL) cabotegravir and 900-mg (3‑mL) rilpivirine gluteal intramuscular injections then continue to follow the 400‑mg (2‑mL) cabotegravir and 600-mg (2-mL) rilpivirine gluteal intramuscular monthly injection dosing schedule.
Planned Missed Injections for Patients on the Every-2-Month Dosing ScheduleIf a patient plans to miss a scheduled injection visit by more than 7 days, VOCABRIA in combination with EDURANT once daily may be used for up to 2 months to replace 1 missed injection visit, or any other fully suppressive oral antiretroviral regimen may be used until injections are resumed. The recommended oral daily dose is one 30‑mg tablet of VOCABRIA (cabotegravir) and one 25‑mg tablet of EDURANT (rilpivirine). Take VOCABRIA with EDURANT at approximately the same time each day with a meal.
The first dose of oral therapy should be taken approximately 2 months after the last injection dose of CABENUVA and continued until the day injection dosing is restarted. Refer to Table 4for injection dosing recommendations. For oral therapy with VOCABRIA and EDURANT of durations greater than 2 months, an alternative oral regimen is recommended.
Unplanned Missed Injections for Patients on the Every-2-Month Dosing ScheduleIf a scheduled every-2-month injection visit is missed or delayed by more than 7 days and oral therapy has not been taken in the interim, clinically reassess the patient to determine if resumption of injection dosing remains appropriate
[see Warnings and Precautions ]. If the every-2‑month dosing schedule will be continued, see Table 4for dosing recommendations.Table 4. Injection Dosing Recommendations after Missed Injections for Patients on the Every-2-Month Dosing Schedule Missed Injection VisitTime since Last InjectionRecommendationInjection 2 (Month 2)
Less than or equal to 2 months
Resume with 600-mg (3-mL) cabotegravir and 900‑mg (3‑mL) rilpivirine intramuscular injections as soon as possible, then continue to follow the every-2-month injection dosing schedule.
Greater than 2 months
Re-initiate the patient with 600-mg (3-mL) cabotegravir and 900-mg (3‑mL) rilpivirine intramuscular injections, followed by the second initiation injection dose 1 month later. Then continue to follow the every-2-month injection dosing schedule thereafter.
Injection 3 or later (Month 4 onwards)
Less than or equal to 3 months
Resume with 600-mg (3-mL) cabotegravir and 900‑mg (3‑mL) rilpivirine intramuscular injections as soon as possible and continue with the every‑2‑month injection dosing schedule.
Greater than 3 months
Re-initiate the patient with 600-mg (3-mL) cabotegravir and 900-mg (3‑mL) rilpivirine intramuscular injections, followed by the second initiation injection dose 1 month later. Then continue with the every-2-month injection dosing schedule thereafter.
2.9 Administration Instructions for InjectionsRefer to the Instructions for Use for complete administration instructions with illustrations. Carefully follow these instructions and ensure that the vial adaptor is used correctly when preparing the suspension for injection to avoid leakage.
A complete dose requires 2 injections: 1 injection of cabotegravir and 1 injection of rilpivirine
[see Dosage and Administration ].Cabotegravir and rilpivirine are suspensions for gluteal intramuscular injection that do not need further dilution or reconstitution.
Administer each injection at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit. The ventrogluteal site is recommended. A dorsogluteal approach (upper outer quadrant) is acceptable, if preferred by the healthcare professional. Do not administer by any other route or anatomical site. Consider the body mass index (BMI) of the patient to ensure that the needle length is sufficient to reach the gluteus muscle. Longer needle lengths (not included in the dosing kit) may be required for patients with higher BMI (example: >30 kg/m2) to ensure that injections are administered intramuscularly as opposed to subcutaneously. The administration order of cabotegravir and rilpivirine injections is not important.
Before preparing the injections, remove CABENUVA from the refrigerator and wait at least 15 minutes to allow the medicines to come to room temperature. The vials may remain in the carton at room temperature for up to 6 hours; do not put back into the refrigerator. If not used within 6 hours, the medication must be discarded.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The cabotegravir vial has a brown tint to the glass that may limit visual inspection. Discard CABENUVA if either medicine exhibits particulate matter or discoloration.
Shake each vial of CABENUVA vigorously so that the suspensions look uniform before injecting. Small air bubbles are expected and acceptable.
Once the suspensions have been drawn into the respective syringes, the injections should be administered as soon as possible, but may remain in the syringes for up to 2 hours. The filled syringes should not be placed in the refrigerator. If the medicine remains in the syringes for more than 2 hours, the filled syringes and needles must be discarded
[see How Supplied/Storage and Handling ].• Prior to initiating treatment with CABENUVA, oral lead-in dosing may be considered to assess the tolerability of cabotegravir and rilpivirine with the recommended dosage used for approximately 1 month. ()2.3 Optional Oral Lead-In Dosing to Assess Tolerability of CABENUVA in Adults and Adolescents 12 Years of Age and Older and Weighing at Least 35 kgThe healthcare provider and patient may decide to use an oral lead-in with oral cabotegravir and oral rilpivirine prior to the initiation of CABENUVA to assess the tolerability of cabotegravir and rilpivirine, or the healthcare provider and patient may proceed directly to injection of CABENUVA without the use of an oral lead-in.
If oral lead-in is used, the recommended oral lead-in daily dose is one 30-mg tablet of VOCABRIA (cabotegravir) and one 25-mg tablet of EDURANT (rilpivirine) taken with a meal for approximately 1 month (at least 28 days), followed by intramuscular initiation injections of CABENUVA. See Tables 1and 2for recommended oral lead-in and monthly or every-2-month intramuscular injection dosing schedule for CABENUVA
[see Dosage and Administration ].• For gluteal intramuscular injection only. (,2.4 Recommended Monthly Gluteal Intramuscular Injection Dosing with CABENUVA in Adults and Adolescents 12 Years of Age and Older and Weighing at Least 35 kgInitiation Injections (CABENUVA 600-mg/900-mg Kit)Initiate injections on the last day of current antiretroviral therapy or oral lead-in, if used
[see Dosage and Administration ]. The recommended initiation injection doses of CABENUVA are a single 600-mg (3-mL) intramuscular injection of cabotegravir and a single 900-mg (3-mL) intramuscular injection of rilpivirine. Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit[see Dosage and Administration ]. Continuation injections should be initiated a month after the initiation injections.Continuation Injections (CABENUVA 400-mg/600-mg Kit)After the initiation injections, the recommended monthly continuation injection doses of CABENUVA are a single 400-mg (2-mL) intramuscular injection of cabotegravir and a single 600-mg (2-mL) intramuscular injection of rilpivirine at each visit . Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit
[see Dosage and Administration ]. Patients may be given CABENUVA up to 7 days before or after the date the patient is scheduled to receive monthly injections.Table 1. Recommended Dosing Schedule with Optional Oral Lead-In or Direct to Injection for Monthly Injection aThe optional oral therapy should be continued until the day the first injection is administered. bGiven on the last day of current antiretroviral therapy or oral lead-in if used. DrugOptional Oral Lead-Ina(at Least 28 Days)Intramuscular (Gluteal)Initiation Injections(One-Time Dosing)Intramuscular (Gluteal)Continuation Injections(Once-Monthly Dosing)Month (at Least 28 Days) Prior to Starting InjectionsInitiate Injections at Month 1bOne Month after Initiation Injection and Monthly OnwardsCabotegravir
30 mg once daily
with a meal600 mg (3 mL)
400 mg (2 mL)
Rilpivirine
25 mg once daily
with a meal900 mg (3 mL)
600 mg (2 mL)
,2.5 Recommended Every-2-Month Gluteal Intramuscular Injection Dosing with CABENUVA in Adults and Adolescents 12 Years of Age and Older and Weighing at Least 35 kgInitiation Injections (CABENUVA 600-mg/900-mg Kit)Initiate injections on the last day of current antiretroviral therapy or oral lead-in, if used
[see Dosage and Administration ]. The recommended initiation injection doses of CABENUVA are a single 600-mg (3-mL) intramuscular injection of cabotegravir and a single 900-mg (3-mL) intramuscular injection of rilpivirine 1 month apart for 2 consecutive months . Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit[see Dosage and Administration ]. Patients may be given CABENUVA up to 7 days before or after the date the patient is scheduled to receive the second initiation injections.Continuation Injections (CABENUVA 600-mg/900-mg Kit)After the 2 initiation doses given consecutively 1 month apart (Months 1 and 2), the recommended continuation injection doses (Month 4 onwards) of CABENUVA are a single 600-mg (3-mL) intramuscular injection of cabotegravir and a single 900-mg (3-mL) intramuscular injection of rilpivirine administered every 2 months . Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit
[see Dosage and Administration ]. Patients may be given CABENUVA up to 7 days before or after the date the patient is scheduled to receive the injections.Table 2. Recommended Dosing Schedule with Optional Oral Lead-In or Direct to Injection for Every-2-Month Injection aThe optional oral therapy should be continued until the day the first injection is administered.
bFor the every-2-month injection dosing schedule in adults, Initiation Injections are injections administered at Month 1 and Month 2 and Continuation Injections are injections administered every 2 months onwards (starting Month 4).
cGiven on the last day of current antiretroviral therapy or oral lead-in if used.DrugOptional Oral Lead-Ina(at Least 28 Days)Intramuscular (Gluteal) InjectionsbMonth (at Least 28 Days) Prior to Starting InjectionsInitiate Injectionscat Month 1, Month 2, and then Every 2 Months Onwards(Starting at Month 4)Cabotegravir
30 mg once daily with a meal
600 mg (3 mL)
Rilpivirine
25 mg once daily with a meal
900 mg (3 mL)
)2.9 Administration Instructions for InjectionsRefer to the Instructions for Use for complete administration instructions with illustrations. Carefully follow these instructions and ensure that the vial adaptor is used correctly when preparing the suspension for injection to avoid leakage.
A complete dose requires 2 injections: 1 injection of cabotegravir and 1 injection of rilpivirine
[see Dosage and Administration ].Cabotegravir and rilpivirine are suspensions for gluteal intramuscular injection that do not need further dilution or reconstitution.
Administer each injection at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit. The ventrogluteal site is recommended. A dorsogluteal approach (upper outer quadrant) is acceptable, if preferred by the healthcare professional. Do not administer by any other route or anatomical site. Consider the body mass index (BMI) of the patient to ensure that the needle length is sufficient to reach the gluteus muscle. Longer needle lengths (not included in the dosing kit) may be required for patients with higher BMI (example: >30 kg/m2) to ensure that injections are administered intramuscularly as opposed to subcutaneously. The administration order of cabotegravir and rilpivirine injections is not important.
Before preparing the injections, remove CABENUVA from the refrigerator and wait at least 15 minutes to allow the medicines to come to room temperature. The vials may remain in the carton at room temperature for up to 6 hours; do not put back into the refrigerator. If not used within 6 hours, the medication must be discarded.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The cabotegravir vial has a brown tint to the glass that may limit visual inspection. Discard CABENUVA if either medicine exhibits particulate matter or discoloration.
Shake each vial of CABENUVA vigorously so that the suspensions look uniform before injecting. Small air bubbles are expected and acceptable.
Once the suspensions have been drawn into the respective syringes, the injections should be administered as soon as possible, but may remain in the syringes for up to 2 hours. The filled syringes should not be placed in the refrigerator. If the medicine remains in the syringes for more than 2 hours, the filled syringes and needles must be discarded
[see How Supplied/Storage and Handling ].• Recommended Monthly Dosing Schedule: Initiate injections of CABENUVA (600 mg of cabotegravir and 900 mg of rilpivirine) on the last day of current antiretroviral therapy or oral lead-in and continue with injections of CABENUVA (400 mg of cabotegravir and 600 mg of rilpivirine) every month thereafter. ()2.4 Recommended Monthly Gluteal Intramuscular Injection Dosing with CABENUVA in Adults and Adolescents 12 Years of Age and Older and Weighing at Least 35 kgInitiation Injections (CABENUVA 600-mg/900-mg Kit)Initiate injections on the last day of current antiretroviral therapy or oral lead-in, if used
[see Dosage and Administration ]. The recommended initiation injection doses of CABENUVA are a single 600-mg (3-mL) intramuscular injection of cabotegravir and a single 900-mg (3-mL) intramuscular injection of rilpivirine. Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit[see Dosage and Administration ]. Continuation injections should be initiated a month after the initiation injections.Continuation Injections (CABENUVA 400-mg/600-mg Kit)After the initiation injections, the recommended monthly continuation injection doses of CABENUVA are a single 400-mg (2-mL) intramuscular injection of cabotegravir and a single 600-mg (2-mL) intramuscular injection of rilpivirine at each visit . Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit
[see Dosage and Administration ]. Patients may be given CABENUVA up to 7 days before or after the date the patient is scheduled to receive monthly injections.Table 1. Recommended Dosing Schedule with Optional Oral Lead-In or Direct to Injection for Monthly Injection aThe optional oral therapy should be continued until the day the first injection is administered. bGiven on the last day of current antiretroviral therapy or oral lead-in if used. DrugOptional Oral Lead-Ina(at Least 28 Days)Intramuscular (Gluteal)Initiation Injections(One-Time Dosing)Intramuscular (Gluteal)Continuation Injections(Once-Monthly Dosing)Month (at Least 28 Days) Prior to Starting InjectionsInitiate Injections at Month 1bOne Month after Initiation Injection and Monthly OnwardsCabotegravir
30 mg once daily
with a meal600 mg (3 mL)
400 mg (2 mL)
Rilpivirine
25 mg once daily
with a meal900 mg (3 mL)
600 mg (2 mL)
• Recommended Every-2-Month Dosing Schedule: Initiate injections of CABENUVA (600 mg of cabotegravir and 900 mg of rilpivirine) on the last day of current antiretroviral therapy or oral lead-in for 2 consecutive months and continue with injections of CABENUVA every 2 months thereafter. ()2.5 Recommended Every-2-Month Gluteal Intramuscular Injection Dosing with CABENUVA in Adults and Adolescents 12 Years of Age and Older and Weighing at Least 35 kgInitiation Injections (CABENUVA 600-mg/900-mg Kit)Initiate injections on the last day of current antiretroviral therapy or oral lead-in, if used
[see Dosage and Administration ]. The recommended initiation injection doses of CABENUVA are a single 600-mg (3-mL) intramuscular injection of cabotegravir and a single 900-mg (3-mL) intramuscular injection of rilpivirine 1 month apart for 2 consecutive months . Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit[see Dosage and Administration ]. Patients may be given CABENUVA up to 7 days before or after the date the patient is scheduled to receive the second initiation injections.Continuation Injections (CABENUVA 600-mg/900-mg Kit)After the 2 initiation doses given consecutively 1 month apart (Months 1 and 2), the recommended continuation injection doses (Month 4 onwards) of CABENUVA are a single 600-mg (3-mL) intramuscular injection of cabotegravir and a single 900-mg (3-mL) intramuscular injection of rilpivirine administered every 2 months . Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit
[see Dosage and Administration ]. Patients may be given CABENUVA up to 7 days before or after the date the patient is scheduled to receive the injections.Table 2. Recommended Dosing Schedule with Optional Oral Lead-In or Direct to Injection for Every-2-Month Injection aThe optional oral therapy should be continued until the day the first injection is administered.
bFor the every-2-month injection dosing schedule in adults, Initiation Injections are injections administered at Month 1 and Month 2 and Continuation Injections are injections administered every 2 months onwards (starting Month 4).
cGiven on the last day of current antiretroviral therapy or oral lead-in if used.DrugOptional Oral Lead-Ina(at Least 28 Days)Intramuscular (Gluteal) InjectionsbMonth (at Least 28 Days) Prior to Starting InjectionsInitiate Injectionscat Month 1, Month 2, and then Every 2 Months Onwards(Starting at Month 4)Cabotegravir
30 mg once daily with a meal
600 mg (3 mL)
Rilpivirine
25 mg once daily with a meal
900 mg (3 mL)
Injection:
• Kit of single-dose vials of 400 mg/2 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 600 mg/2 mL (300 mg/mL) of rilpivirine extended-release injectable suspension. ()3 DOSAGE FORMS AND STRENGTHSInjection:
• Kit of single-dose vials of 400 mg/2 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 600 mg/2 mL (300 mg/mL) of rilpivirine extended-release injectable suspension.• Kit of single-dose vials of 600 mg/3 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 900 mg/3 mL (300 mg/mL) of rilpivirine extended-release injectable suspension.
Injection:
• Kit of single-dose vials of 400 mg/2 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 600 mg/2 mL (300 mg/mL) of rilpivirine extended-release injectable suspension.• Kit of single-dose vials of 600 mg/3 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 900 mg/3 mL (300 mg/mL) of rilpivirine extended-release injectable suspension.
• Kit of single-dose vials of 600 mg/3 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 900 mg/3 mL (300 mg/mL) of rilpivirine extended-release injectable suspension. ()3 DOSAGE FORMS AND STRENGTHSInjection:
• Kit of single-dose vials of 400 mg/2 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 600 mg/2 mL (300 mg/mL) of rilpivirine extended-release injectable suspension.• Kit of single-dose vials of 600 mg/3 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 900 mg/3 mL (300 mg/mL) of rilpivirine extended-release injectable suspension.
Injection:
• Kit of single-dose vials of 400 mg/2 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 600 mg/2 mL (300 mg/mL) of rilpivirine extended-release injectable suspension.• Kit of single-dose vials of 600 mg/3 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 900 mg/3 mL (300 mg/mL) of rilpivirine extended-release injectable suspension.
• Pregnancy: After oral use of rilpivirine, exposures were generally lower during pregnancy compared with the postpartum period. ()8.1 PregnancyPregnancy Exposure RegistryThere is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to CABENUVA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk SummaryThere are insufficient human data on the use of CABENUVA during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. Discuss the benefit-risk of using CABENUVA with individuals of childbearing potential or during pregnancy.
Cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA; therefore, consideration should be given to the potential for fetal exposure during pregnancy
[see Warnings and Precautions , Drug Interactions ].Cabotegravir use in pregnant individuals has not been evaluated. 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 a United States (U.S.) reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP)
(see Data).The rate of miscarriage is not reported in the APR. 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 MACDP is 2.7%. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates mothers and infants from a limited geographic area and does not include outcomes for births that occurred at <20 weeks’ gestation.
In animal reproduction studies with oral cabotegravir, a delay in the onset of parturition and increased stillbirths and neonatal deaths were observed in a rat pre- and postnatal development study at >28 times the exposure at the recommended human dose (RHD). No evidence of adverse developmental outcomes was observed with oral cabotegravir in rats or rabbits (>28 times or similar to the exposure at the RHD, respectively) given during organogenesis
(see Data).No adverse developmental outcomes were observed when rilpivirine was administered orally at exposures 15 (rats) and 70 (rabbits) times the exposure in humans at the RHD
(see Data).Clinical ConsiderationsLower exposures with oral rilpivirine were observed during pregnancy. Viral load should be monitored closely if the patient remains on CABENUVA during pregnancy. Cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA; therefore, consideration should be given to the potential for fetal exposure during pregnancy
[see Warnings and Precautions , Drug Interactions ].DataHuman Data:Rilpivirine:Based on prospective reports to the APR of over 580 exposures to oral rilpivirine-containing regimens during the first trimester of pregnancy and over 200 during second/third trimester of pregnancy, the prevalence of birth defects in live births was 1.5% (95% CI: 0.7% to 2.9%) and 1.5% (95% CI: 0.3% to 4.2%) following first and second/third trimester exposures, respectively, compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. In a clinical trial, total oral rilpivirine exposures were generally lower during pregnancy compared with the postpartum period. Refer to the prescribing information for EDURANT (rilpivirine) for additional information on rilpivirine.Animal Data: Cabotegravir:Cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from 15 days before cohabitation, during cohabitation, and from Gestation Days 0 to 17. There were no effects on fetal viability when fetuses were delivered by caesarean, although a minor decrease in fetal body weight was observed at 1,000 mg/kg/day (>28 times the exposure in humans at the RHD). No drug-related fetal toxicities were observed at 5 mg/kg/day (approximately 13 times the exposure in humans at the RHD), and no drug-related fetal malformations were observed at any dose.Cabotegravir was administered orally to pregnant rabbits at 0, 30, 500, or 2,000 mg/kg/day from Gestation Days 7 to 19. No drug-related fetal toxicities were observed at 2,000 mg/kg/day (approximately 0.7 times the exposure in humans at the RHD).
In a rat pre- and postnatal development study, cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from Gestation Day 6 to Lactation Day 21. A delay in the onset of parturition and increases in the number of stillbirths and neonatal deaths by Lactation Day 4 were observed at 1,000 mg/kg/day (>28 times the exposure in humans at the RHD); there were no alterations to growth and development of surviving offspring. In a cross-fostering study, similar incidences of stillbirths and early postnatal deaths were observed when rat pups born to cabotegravir-treated mothers were nursed from birth by control mothers. There was no effect on neonatal survival of control pups nursed from birth by cabotegravir-treated mothers. A lower dose of 5 mg/kg/day (13 times the exposure at the RHD) was not associated with delayed parturition or neonatal mortality in rats. Studies in pregnant rats showed that cabotegravir crosses the placenta and can be detected in fetal tissue.
Rilpivirine:Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and rabbits (5, 10, or 20 mg/kg/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 the exposure in humans at the RHD. In a pre- and postnatal development study, rilpivirine was administered orally up to 400 mg/kg/day through lactation. No adverse effects were noted in the offspring at maternal exposures up to 63 times the exposure in humans at the RHD.
CABENUVA is contraindicated in patients:
• with previous hypersensitivity reaction to cabotegravir or rilpivirine[see Warnings and Precautions (.)]5.1 Hypersensitivity ReactionsSerious or severe hypersensitivity reactions have been reported with cabotegravir- and rilpivirine-containing regimens. Reactions associated with cabotegravir include Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)[see Adverse Reactions ]. Reactions associated with rilpivirine-containing regimens include cases of drug reaction with eosinophilia and systemic symptoms (DRESS)[see Adverse Reactions ]. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. Administration of cabotegravir and rilpivirine oral lead-in dosing was used in clinical studies to help identify patients who may be at risk of a hypersensitivity reaction[see Dosage and Administration , Contraindications ]. Remain vigilant and discontinue CABENUVA if a hypersensitivity reaction is suspected[see Contraindications , Adverse Reactions ].Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash, or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, mucosal involvement [oral blisters or lesions], conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. For information regarding the long-acting properties of CABENUVA,
[see Warnings and Precautions ]. Administer oral lead-in dosing prior to administration of CABENUVA to help identify patients who may be at risk of a hypersensitivity reaction[see Dosage and Administration , Contraindications ].• receiving the following coadministered drugs for which significant decreases in cabotegravir and/or rilpivirine plasma concentrations may occur due to uridine diphosphate glucuronosyltransferase (UGT)1A1 and/or cytochrome P450 (CYP)3A enzyme induction, which may result in loss of virologic response[see Drug Interactions (:), Clinical Pharmacology (7 DRUG INTERACTIONS• Refer to the full prescribing information for important drug interactions with CABENUVA.• Because CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.• Drugs that induce uridine diphosphate glucuronosyltransferase (UGT)1A1 or cytochrome P450 (CYP)3A4 may decrease the plasma concentrations of the components of CABENUVA.• CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes.
7.1 Concomitant Use with Other Antiretroviral MedicinesBecause CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended
[see Indications and Usage ].7.2 Use of Other Antiretroviral Drugs after Discontinuation of CABENUVAResidual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). These residual concentrations are not expected to affect the exposures of antiretroviral drugs that are initiated after discontinuation of CABENUVA
[see Warnings and Precautions , Drug Interactions , Clinical Pharmacology ].7.3 Potential for Other Drugs to Affect CABENUVARefer to the prescribing information for VOCABRIA (cabotegravir) and EDURANT (rilpivirine) for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively.
CabotegravirCabotegravir is primarily metabolized by UGT1A1 with some contribution from UGT1A9. Drugs that are strong inducers of UGT1A1 or UGT1A9 are expected to decrease cabotegravir plasma concentrations and may result in loss of virologic response; therefore, coadministration of CABENUVA with these drugs is contraindicated
[see Contraindications ].RilpivirineRilpivirine is primarily metabolized by CYP3A. Coadministration of CABENUVA and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs
[see Contraindications , Drug Interactions ].Coadministration of CABENUVA and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine[see Drug Interactions , Clinical Pharmacology ].QT-Prolonging Drugs:At mean steady-state Cmaxvalues 4.4- and 11.6-fold higher than those with the recommended 600‑mg dose of rilpivirine extended-release injectable suspension, rilpivirine may prolong the QTc interval[see Clinical Pharmacology ]. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes[see Warnings and Precautions , Drug Interactions ].7.4 Established and Other Potentially Significant Drug InteractionsRefer to the prescribing information for VOCABRIA (cabotegravir) and EDURANT (rilpivirine) for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively.
Information regarding potential drug interactions with cabotegravir and rilpivirine is provided in Table 8. These recommendations are based on either drug interaction trials following oral administration of cabotegravir or rilpivirine or predicted interactions due to the expected magnitude of the interaction and potential for loss of virologic response
[see Contraindications , Warnings and Precautions , Clinical Pharmacology ]. Table 8includes potentially significant interactions but is not all inclusive.Table 8. Drug Interactions with CABENUVA ↑ = Increase, ↓ = Decrease, ↔ = No change.
aSee Clinical Pharmacology for magnitude of interaction.Concomitant Drug Class:Drug NameEffect on ConcentrationClinical CommentAnticonvulsants:Carbamazepine
Oxcarbazepine
Phenobarbital
Phenytoin
↓Cabotegravir
↓Rilpivirine
Coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance
[see Contraindications ].Antimycobacterials:Rifampina
Rifapentine
↓Cabotegravir
↓Rilpivirine
Antimycobacterial:Rifabutina
↓Cabotegravir
↔Rifabutin
↓Rilpivirine
Glucocorticoid (systemic):Dexamethasone
(more than a single-dose treatment)
↓Rilpivirine
Herbal product:St John’s wort (
Hypericum perforatum)↓Rilpivirine
Macrolide or ketolide antibiotics:Azithromycin
Clarithromycin
Erythromycin
↔Cabotegravir
↑Rilpivirine
Macrolides are expected to increase concentrations of rilpivirine and are associated with a risk of Torsade de Pointes
[see Warnings and Precautions ]. Where possible, consider alternatives, such as azithromycin, which increases rilpivirine concentrations less than other macrolides.Narcotic analgesic:Methadonea
↔Cabotegravir
↓Methadone
↔Rilpivirine
No dose adjustment of methadone is required when starting coadministration of methadone with CABENUVA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.
7.5 Drugs without Clinically Significant InteractionsCabotegravirBased on drug interaction study results, the following drugs can be coadministered with cabotegravir (non-antiretrovirals and rilpivirine) or given after discontinuation of cabotegravir (antiretrovirals and non-antiretrovirals) without a dose adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, and rilpivirine
[see Clinical Pharmacology ].RilpivirineBased on drug interaction study results, the following drugs can be coadministered with rilpivirine (non-antiretrovirals and cabotegravir) or given after discontinuation of rilpivirine (antiretrovirals and non-antiretrovirals): acetaminophen, atorvastatin, cabotegravir, chlorzoxazone, dolutegravir, ethinyl estradiol, norethindrone, raltegravir, ritonavir-boosted atazanavir, ritonavir-boosted darunavir, sildenafil, tenofovir alafenamide, and tenofovir disoproxil fumarate
[see Clinical Pharmacology ]. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin.)]12.3 PharmacokineticsAbsorption, Distribution, and EliminationThe 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.
Table 9. Pharmacokinetic Properties of the Components of CABENUVA CSF = Cerebrospinal Fluid, BLQ = Below Limit of Quantification. aWhen 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.
bThe 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.
cElimination half-life driven by slow absorption rate from the intramuscular injection site.
dDosing in mass balance studies: single-dose oral administration of [14C] cabotegravir; single-dose oral administration of [14C] rilpivirine.CabotegravirRilpivirineAbsorptionaTmax(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)
Eliminationt1/2(weeks), meanc
5.6 to 11.5
13 to 28
MetabolismMetabolic pathways
UGT1A1
CYP3A
UGT1A9 (minor)
ExcretionMajor route of elimination
Metabolism
Metabolism
% of dose excreted as total14C (unchanged drug) in urined
27 (0)
6 (<1)
% of dose excreted as total14C (unchanged drug) in fecesd
59 (47)
85 (26)
Table 10. Pharmacokinetic Parameters following Once-Daily Oral Cabotegravir and Rilpivirine and following Initiation and Monthly and Every-2-Month Continuation Intramuscular Injections of the Components of CABENUVA in Adults IM = Intramuscular. aPharmacokinetic 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 [participants with no prior exposure to cabotegravir plus rilpivirine] for the every-2-month injection dosing schedule; rilpivirine: pooled FLAIR, ATLAS, and ATLAS-2M [participants with no prior exposure], except for initial injection (direct to injection) [see footnote e]and for oral rilpivirine[see footnote g]).
btau 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.
cOral lead-in pharmacokinetic parameter values represent steady-state.
dInitial injection Cmaxvalues 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 Ctauvalues reflect the initial injections for cabotegravir and rilpivirine.
ePharmacokinetic 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.
fMonthly and every-2-month injection pharmacokinetic parameter values represent Week 48 data.
gOral rilpivirine: AUC(0-tau)based on population pharmacokinetic estimates of rilpivirine 25 mg once daily from pooled Phase 3 trials with EDURANT (rilpivirine); Ctaubased on observed data from FLAIR, ATLAS, and ATLAS-2M; Cmaxbased on observed data for rilpivirine 25 mg once daily from a pharmacokinetic substudy in pooled Phase 3 trials with EDURANT (rilpivirine).DrugDosingPhaseDosageRegimenGeometric Mean (5th, 95thPercentile)aAUC(0-tau)b(mcg•h/mL)Cmax(mcg/mL)Ctaub(mcg/mL)Cabotegravir
Oral lead-inc
30 mg
once daily145
(93.5, 224)
8.0
(5.3, 11.9)
4.6
(2.8, 7.5)
Initial injection (after oral lead-in)d
600 mg IM
initial dose1,591
(714; 3,245)
8.0
(5.3, 11.9)
1.5
(0.65, 2.9)
Initial injection (direct to injection)e
600 mg IM
initial dose—
1.89
(0.438, 5.69)1.43
(0.403, 3.90)Monthly injectionf
400 mg IM
monthly2,415
(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)
DrugDosingPhaseDosageRegimenGeometric Mean (5th, 95thPercentile)aAUC(0-tau)b(ng•h/mL)Cmax(ng/mL)Ctaub(ng/mL)Rilpivirine
Oral lead-inc,g
25 mg
once daily2,083
(1,125; 3,748)
116
(48.6, 244)
79.4
(31.8, 177)
Initial injection (after oral lead-in)d
900 mg IM
initial dose44,842
(21,712; 87,575)
144
(93.9, 221)
41.9
(21.7, 78.9)
Initial injection (direct to injection)e
900 mg IM
initial dose—
68
(27.5, 220)48.9
(17.7, 138)Monthly injectionf
600 mg IM
monthly68,324
(39,042; 118,111)
121
(68.1, 210)
85.8
(49.6, 147)
Every-2-month injectionf
900 mg IM
every 2 months132,450
(76,638; 221,783)138
(80.6, 228)68.9
(38.0, 119)Specific PopulationsNo 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 participants 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 ].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 ].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 ].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 ].Geriatric Patients:The pharmacokinetics of cabotegravir (oral or injectable) and of injectable rilpivirine have not been studied and data are limited in participants aged 65 years or older[see Use in Specific Populations ].Pediatric Patients:Population pharmacokinetic analyses revealed no clinically relevant differences in exposure between adolescent participants (weighing ≥35 kg and aged at least 12 years) and adult participants with and without HIV-1 from the cabotegravir or rilpivirine development program.Table 11. Pharmacokinetic Parameters following Cabotegravir and Rilpivirine Orally Once Daily, and Initiation, Monthly, and Every-2-Months Continuation Intramuscular Injections in Adolescents Aged 12 to Younger than 18 Years (≥35 kg) IM = Intramuscular, PO = By Mouth. aPharmacokinetic parameter values for cabotegravir were based on individual post-hoc estimates from population pharmacokinetic models in both adolescents with HIV-1 (n = 147) weighing 35.2 to 98.5 kg and adolescents without HIV-1 (n = 62) weighing 39.9 to 167 kg. Pharmacokinetic parameter values for rilpivirine were based on individual post-hoc estimates from a population pharmacokinetic model in adolescents with HIV-1 (n = 148) weighing 35.2 to 98.5 kg. btau 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. cOral lead-in pharmacokinetic parameter values represent steady-state. dInitial injection Cmaxvalues 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 Ctauvalues reflect the initial injection. eMonthly and every-2-month injection pharmacokinetic parameter values represent Week 48 data. DrugDosingPhaseDosageRegimenGeometric Mean (5th, 95thPercentile)aAUC(0-tau)b(mcg•h/mL)Cmax(mcg/mL)Ctaub(mcg/mL)Cabotegravir
Oral lead-inc
30 mg
once daily203
(136, 320)10.7
(7.36, 16.6)6.43
(4.15, 10.5)Initial injectiond
600 mg IM
initial dose2,085
(1,056; 4,259)10.8
(7.42, 16.6)1.88
(0.801, 3.71)Every-1-month injectione
400 mg IM every 1 month
3,416
(2,303; 5,109)
5.73
(3.76, 8.90)
4.24
(2.74, 6.45)
Every-2-months injectione
600 mg IM
every 2 months5,184
(3,511; 7,677)5.10
(3.06, 8.24)2.54
(1.25, 4.19)DrugDosingPhaseDosageRegimenGeometric Mean (5th, 95thPercentile)aAUC(0-tau)b(ng•h/mL)Cmax(ng/mL)Ctaub(ng/mL)Rilpivirine
Oral lead-inc
25 mg PO
once daily2,389
(1,259; 4,414)144
(80.8, 234)76.1
(27.9, 184)Initial injectiond
900 mg IM
initial dose35,259
(20,301; 63,047)135
(85.8, 211)36.5
(22.4, 59.4)Every-1-month injectione
600 mg IM
every month84,280
(49,444; 156,987)146
(84.8, 269)109
(64.8, 202)Every-2-months injectione
900 mg IM
every 2 months110,686
(78,480; 151,744)108
(68.0, 164)61.8
(44.5, 88.0)Drug Interaction StudiesCabotegravir 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.
Table 12. Effect of Coadministered Drugs on the Pharmacokinetics of Cabotegravir n = Maximum number of participants with data, CI = Confidence Interval. CoadministeredDrug(s)and Dose(s)Dose ofCabotegravirnGeometric Mean Ratio (90% CI) ofCabotegravir Pharmacokinetic Parameterswith/without Coadministered DrugsNo Effect = 1.00CmaxAUCCtauor C24Etravirine
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
0.79
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)
Table 13. Effect of Coadministered Drugs on the Pharmacokinetics of Rilpivirine N = Maximum number of participants with data, CI = Confidence Interval, ↔ = No Change.
aThis 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.
bComparison based on historic controls.CoadministeredDrug(s)and Dose(s)Dose ofRilpivirinenGeometric Mean Ratio (90% CI) ofRilpivirine Pharmacokinetic Parameterswith/without Coadministered DrugsNo Effect = 1.00CmaxAUCCminAcetaminophen
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/
norethindrone25 mg
once daily15
↔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
1.29
1.52
1.74
400/100 mg twice daily (soft gel capsule)
once dailya
(1.18 to 1.40)
(1.36 to 1.70)
(1.46 to 2.08)
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
once dailya
16
0.96
1.01
0.99
300 mg once daily
(0.81 to 1.13)
(0.87 to 1.18)
(0.83 to 1.16)
Table 14. Effect of Cabotegravir on the Pharmacokinetics of Coadministered Drugs n = Maximum number of participants with data, CI = Confidence Interval, NA = Not Available. CoadministeredDrug(s)and Dose(s)Dose ofCabotegravirnGeometric Mean Ratio (90% CI) ofPharmacokinetic Parameters ofCoadministered Drugwith/without CabotegravirNo Effect = 1.00CmaxAUCCtauor C24Ethinyl 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)
Table 15. Effect of Rilpivirine on the Pharmacokinetics of Coadministered Drugs n = Maximum number of participants with data, CI = Confidence Interval, NA = Not Available.
aThis 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.
bAUC(0-last)
cn = (maximum number of participants with data) for AUC(0-∞) = 15.CoadministeredDrug(s)and Dose(s)Dose ofRilpivirinenGeometric Mean Ratio (90% CI)of Coadministered Drug PharmacokineticParameters with/without EDURANTNo Effect = 1.00CmaxAUCCminAcetaminophen
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)b
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)c
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-sildenafil0.90
0.92
NA
(0.80 to 1.02)
(0.85 to 0.99)b
Tenofovir disoproxil
150 mg
16
1.19
1.23
1.24
fumarate
once dailya
(1.06 to 1.34)
(1.16 to 1.31)
(1.10 to 1.38)
300 mg once daily
o Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoino Antimycobacterials: Rifabutin, rifampin, rifapentineo Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment)o Herbal product: St John’s wort (Hypericum perforatum)