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 [see Microbiology ( 12.4 ), Clinical Studies ( 14.1 )] .
CABENUVA, a 2-drug co-packaged product of cabotegravir, an HIV-1 integrase strand transfer inhibitor (INSTI), and rilpivirine, an HIV-1 non‑nucleoside reverse transcriptase inhibitor (NNRTI), 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.
( 1 )
Contraindications
CABENUVA is contraindicated in patients:
with previous hypersensitivity reaction to cabotegravir or rilpivirine [see Warnings and Precautions ( 5.1 )] .
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 ( 7 ), Clinical Pharmacology ( 12.3 )] : o Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin o Antimycobacterials: Rifabutin, rifampin, rifapentine o Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment) o Herbal product: St John’s wort ( Hypericum perforatum )
Previous hypersensitivity reaction to cabotegravir or rilpivirine. ( 4 )
Coadministration with drugs where significant decreases in cabotegravir and/or rilpivirine plasma concentrations may occur, which may result in loss of virologic response. ( 4 )
Two medicines in one question?
Name two or more medicines and Osler runs an interaction check. A severe interaction is stated at the very top of the answer.
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). Reactions associated with rilpivirine-containing regimens include cases of drug reaction with eosinophilia and systemic symptoms (DRESS). Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop. ( 5.1 )
Serious post-injection reactions with rilpivirine were reported. Monitor and treat as clinically indicated. ( 5.2 )
Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine. Monitoring of liver chemistries is recommended. Discontinue CABENUVA if hepatotoxicity is suspected. ( 5.3 )
Depressive disorders have been reported with CABENUVA. Prompt evaluation is recommended for depressive symptoms. ( 5.4 )
Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients up to 12 months or longer. It is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injections of CABENUVA when dosed monthly and no later than 2 months after the final injections when dosed every 2 months. If virologic failure is suspected, prescribe an alternative regimen as soon as possible. ( 5.6 )
5.1Hypersensitivity 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 ( 6.2 )] . Reactions associated with rilpivirine-containing regimens include cases of drug reaction with eosinophilia and systemic symptoms (DRESS) [see Adverse Reactions ( 6.1 , 6.2 )] .
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 ( 2.3 ), Contraindications ( 4 )] .
Remain vigilant and discontinue CABENUVA if a hypersensitivity reaction is suspected [see Contraindications ( 4 ), Adverse Reactions ( 6 )] . 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 ( 5.6 )] . 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 ( 2.3 ), Contraindications ( 4 )] .
5.2Post-Injection Reactions
In clinical trials, serious post-injection reactions were reported within minutes after the injection of rilpivirine. These events included symptoms such as dyspnea, bronchospasm, agitation, abdominal cramping, rash/urticaria, dizziness, flushing, sweating, oral numbness, changes in blood pressure, and pain (e.g., back and chest). These events were reported in <1% of participants and began to resolve within minutes after the injection, with some patients receiving supportive care.
These events may have been associated with accidental intravenous administration during the intramuscular injection procedure [see Adverse Reactions ( 6.1 )] . Carefully follow the Instructions for Use when preparing and administering CABENUVA. The suspensions should be injected slowly via intramuscular injection, and care should be taken to avoid accidental intravenous administration [see Dosage and Administration ( 2.9 )] .
Observe patients briefly (approximately 10 minutes) after the injection. If a patient experiences a post-injection reaction, monitor and treat as clinically indicated.
5.3Hepatotoxicity
Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors [see Adverse Reactions ( 6.1 )] . Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations. Monitoring of liver chemistries is recommended and treatment with CABENUVA should be discontinued if hepatotoxicity is suspected.
For information regarding the long-acting properties of CABENUVA, [see Warnings and Precautions ( 5.6 )] .
5.4Depressive Disorders
Depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, dysphoria, negative thoughts, suicidal ideation, suicide attempt) have been reported with CABENUVA or the individual drug products [see Adverse Reactions ( 6.1 )] . Promptly evaluate patients with depressive symptoms to assess whether the symptoms are related to CABENUVA and to determine whether the risks of continued therapy outweigh the benefits.
5.5Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions
The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions, some of which may lead to adverse events, loss of virologic response of CABENUVA, and possible development of viral resistance [see Contraindications ( 4 ), Drug Interactions ( 7.4 )] . Rilpivirine 75-mg and 300-mg once-daily oral doses (3 and 12 times, respectively, the recommended oral dosage) in healthy adults prolonged the QTc interval with mean steady-state C max values 4.4- and 11.6-fold, respectively, higher than C max values associated with the recommended 600-mg monthly dose of rilpivirine extended-release injectable suspension and 4.1- and 10.7-fold, respectively, higher than C max values associated with the recommended 900-mg every-2-month dose of rilpivirine extended‑release injectable suspension [see Clinical Pharmacology ( 12.2 )] .
CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes [see Drug Interactions ( 7.3 , 7.4 )] . See Table 8 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with, and after discontinuation of, CABENUVA; review concomitant medications during therapy with CABENUVA [see Drug Interactions ( 7.4 )] .
5.6Long-Acting Properties and Potential Associated Risks with
CABENUVA Residual concentrations of both cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). It is important to carefully select patients who agree to the required monthly or every-2-month injection dosing schedule because non-adherence to monthly or every-2-month injections or missed doses could lead to loss of virologic response and development of resistance [see Dosage and Administration ( 2.2 ), Adverse Reactions ( 6.1 ), Drug Interactions ( 7.4 )] .
To minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injections of CABENUVA when dosed monthly and no later than 2 months after the final injections of CABENUVA when dosed every 2 months. If virologic failure is suspected, switch the patient to an alternative regimen as soon as possible.
Interactions
Refer to the full prescribing information for important drug interactions with CABENUVA. ( 4 , 5.5 , 7 )
Because CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. ( 7.1 )
Drugs that induce uridine diphosphate glucuronosyltransferase (UGT)1A1 or cytochrome P450 (CYP)3A4 may decrease the plasma concentrations of the components of CABENUVA. ( 4 , 7.3 , 7.4 )
CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes. ( 7.3 , 7.4 )
7.1Concomitant Use with Other Antiretroviral Medicines Because
CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended [see Indications and Usage ( 1 )] .
7.2Use of Other Antiretroviral Drugs after Discontinuation of
CABENUVA Residual 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 ( 5.6 ), Drug Interactions ( 7.4 ), Clinical Pharmacology ( 12.3 )] .
7.3Potential for Other Drugs to Affect
CABENUVA Refer to the prescribing information for VOCABRIA (cabotegravir) and EDURANT (rilpivirine) for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively. Cabotegravir Cabotegravir 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 ( 4 )] .
Rilpivirine Rilpivirine 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 ( 4 ), Drug Interactions ( 7.4 )]. Coadministration of CABENUVA and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine [see Drug Interactions ( 7.4 ), Clinical Pharmacology ( 12.3 )] .
QT-Prolonging Drugs: At mean steady-state C max values 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 ( 12.2 )] . CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes [see Warnings and Precautions ( 5.5 ), Drug Interactions ( 7.4 )] .
7.4 Established and Other Potentially Significant Drug Interactions Refer 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 ( 4 ), Warnings and Precautions ( 5.5 ), Clinical Pharmacology ( 12.3 )] .
Table 8 includes potentially significant interactions but is not all inclusive. Table 8. Drug Interactions with CABENUVA ↑ = Increase, ↓ = Decrease, ↔ = No change. a See Clinical Pharmacology ( 12.3 ) for magnitude of interaction. Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment Anticonvulsants: 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 ( 4 )] .
Antimycobacterials: Rifampin a Rifapentine ↓Cabotegravir ↓Rilpivirine Antimycobacterial: Rifabutin a ↓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 ( 5.5 )] .
Where possible, consider alternatives, such as azithromycin, which increases rilpivirine concentrations less than other macrolides. Narcotic analgesic: Methadone a ↔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.
7.5Drugs without Clinically Significant Interactions Cabotegravir Based
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 ( 12.3 )] . Rilpivirine Based 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 ( 12.3 )] .
Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin.
Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Exposure Registry
There 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 Summary There 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 ( 5.6 ), Drug Interactions ( 7.2 )] . 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 Considerations Lower 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 ( 5.6 ), Drug Interactions ( 7.2 )] .
Data Human 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.
Adverse reactions
The following adverse reactions are described below and in other sections of the labeling:
Hypersensitivity reactions [see Warnings and Precautions ( 5.1 )]
Post-injection reactions [see Warnings and Precautions ( 5.2 )]
Hepatotoxicity [see Warnings and Precautions ( 5.3 )]
Depressive disorders [see Warnings and Precautions ( 5.4 )] The most common adverse reactions (Grades 1 to 4) observed in ≥2% of participants receiving CABENUVA were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect rates observed in practice. Clinical Trials Experience in Adults The safety assessment of CABENUVA is based on the analysis of pooled 48-week data from 1,182 virologically suppressed participants with HIV-1 infection in 2 international, multicenter, open-label pivotal trials, FLAIR and ATLAS, and 1,045 virologically suppressed participants from the ATLAS-2M trial [see Clinical Studies ( 14.1 )] .
Additional safety information from other ongoing or earlier clinical trials in the cabotegravir and rilpivirine program have been considered in assessing the overall safety profile of CABENUVA. Adverse reactions were reported following exposure to CABENUVA extended-release injectable suspensions (median time exposure at the time of analysis: 54 weeks in FLAIR and ATLAS, and 64 weeks in ATLAS-2M) and data from VOCABRIA (cabotegravir) tablets and EDURANT (rilpivirine) tablets administered in combination as oral lead-in therapy (median time exposure: 5.3 weeks in FLAIR and ATLAS, and 5.6 weeks in ATLAS-2M).
Adverse reactions included those attributable to both the oral and injectable formulations of cabotegravir and rilpivirine administered as a combination regimen. Refer to the prescribing information for EDURANT (rilpivirine) for other adverse reactions associated with oral rilpivirine. The most common adverse reactions regardless of severity reported in ≥2% of adult participants from FLAIR and ATLAS at Week 48 are presented in Table 5 .
Selected laboratory abnormalities are included in Table 7 . At Week 96, the overall safety profile for FLAIR was consistent with that observed at Week 48, with no new safety findings identified. In the extension phase of the FLAIR study at Week 124, the overall safety profile was consistent with that observed at Week 48 and when injection therapy with CABENUVA was initiated directly without the oral lead-in phase. Overall, 4% of participants in the group receiving CABENUVA and 2% of participants in the control group in FLAIR and ATLAS discontinued due to adverse events.
Non-injection-site-related adverse events leading to discontinuation and occurring in more than 1 participant were headache, diarrhea, hepatitis A, and acute hepatitis B (all with an incidence <1%). In ATLAS-2M, 2% of participants in both treatment groups discontinued due to adverse events. Non-injection-site–related adverse events leading to discontinuation and occurring in more than 1 participant in ATLAS-2M were fatigue, pyrexia, headache, presyncope, acute hepatitis B, hyperhidrosis, and abnormal dreams that occurred with an incidence of ≤1% in either treatment group.
Table 5. Adverse Reactions a (Grades 1 to 4) Reported in at Least 2% of Participants with HIV-1 Infection in FLAIR and ATLAS Trials (Week 48 Pooled Analyses) a Adverse reactions defined as “treatment-related” as assessed by the investigator. b See Injection-Associated Adverse Reactions for additional information. c Pyrexia: includes pyrexia, feeling hot, chills, influenza-like illness, body temperature increased. d Fatigue: includes fatigue, malaise, asthenia. e Musculoskeletal pain: includes musculoskeletal pain, musculoskeletal discomfort, back pain, myalgia, pain in extremity. f Sleep disorders: includes insomnia, poor quality sleep, somnolence. g Rash: includes erythema, pruritus, pruritus generalized, purpura, rash, rash- erythematous, generalized, macular.
Adverse Reactions Cabotegravir plus Rilpivirine Once Monthly (n = 591) Current Antiretroviral Regimen (n = 591) All Grades At Least Grade 2 All Grades At Least Grade 2 Injection site reactions b 83% 37% 0 0 Pyrexia c 8% 2% 0 0 Fatigue d 5% 1% <1% <1% Headache 4% <1% <1% <1% Musculoskeletal pain e 3% 1% <1% 0 Nausea 3% <1% 1% <1% Sleep disorders f 2% <1% <1% 0 Dizziness 2% <1% <1% 0 Rash g 2% <1% 0 0 In ATLAS-2M, the type and frequency of adverse reactions reported in participants receiving CABENUVA once monthly or CABENUVA once every 2 months for 48 weeks were similar.
Differences between treatment arms were reported for the types of injection-associated adverse reactions (see Injection-Associated Adverse Reactions for additional information). Injection-Associated Adverse Reactions: Local Injection Site Reactions (ISRs): In the 3 Phase 3 studies, FLAIR, ATLAS, and ATLAS‑2M, the most frequent adverse reactions associated with the intramuscular administration of CABENUVA were ISRs. In the pooled analysis of FLAIR and ATLAS, 83% of participants reported any injection site reaction with the monthly dosing regimen, with 1% of participants who discontinued treatment with CABENUVA because of ISRs.
After 14,682 injections, 3,663 ISRs were reported. The severity of ISRs was generally mild (Grade 1: 75% of participants) or moderate (Grade 2: 36% of participants). Four percent (4%) of participants experienced severe (Grade 3) ISRs, and no participant experienced Grade 4 ISRs. The median duration of overall ISR events was 3 days. The most commonly reported ISR in FLAIR and ATLAS was pain/discomfort, with 79% reported in the group receiving CABENUVA.
In ATLAS-2M, 75% of participants reported any injection site reaction in both the monthly and every‑2‑month dosing regimens, with <1% of participants who discontinued treatment with CABENUVA because of ISRs. When dosing monthly, after 15,711 injections, 3,152 ISRs were reported. When dosing every 2 months, after 8,470 injections, 2,507 ISRs were reported. The severity of ISRs was generally mild (Grade 1: 70% and 71% of participants) or moderate (Grade 2: 28% and 27% of participants) in monthly and every‑2‑month dosing regimens, respectively.
Four percent (4%) of participants in the monthly group and 3% of participants in the every‑2‑month group experienced severe (Grade 3) ISRs, and no participant experienced Grade 4 ISRs. The median duration of overall ISR events was 3 days for both dosing regimens. The most commonly reported ISR in ATLAS‑2M was pain/discomfort, with 71% and 73% reported in the monthly and every‑2‑month dosing regimens, respectively. The severity and duration of ISRs, including pain/discomfort, were similar for both dosing regimens and in participants without prior exposure to CABENUVA.
The most commonly reported ISR (Grades 1 to 3) in at least 1% of adult participants in the pooled analyses from FLAIR and ATLAS, and from ATLAS‑2M, are presented in Table 6 . The side‑by‑side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trials. Table 6. Injection Site Reactions (Grades 1 to 3) Reported in at Least 1% of Participants in FLAIR and ATLAS (Pooled Analysis) and ATLAS-2M Trials (Week 48 Analysis) Anesthesia, abscess, cellulitis, and hemorrhage at the injection site were each reported in <1% of participants.
Injection Site Reactions FLAIR and ATLAS ATLAS-2M Cabotegravir plus Rilpivirine Once Monthly (n = 591) Cabotegravir plus Rilpivirine Once Every 2 Months (n = 522) Cabotegravir plus Rilpivirine Once Monthly (n = 523) Any injection site reaction 83%
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