Cabotegravir and Rilpivirine

INDICATIONS AND USAGE 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 )

DOSAGE AND ADMINISTRATION • Refer to full prescribing information for detailed information on dosage and administration recommendations. ( 2 ) • 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 ) • For gluteal intramuscular injection only. ( 2.4 , 2.5 , 2.9 ) • 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 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 ) 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 ( 3 )] . • CABENUVA must be administered by a healthcare provider by gluteal intramuscular injection [see Dosage and Administration ( 2.9 )] . • 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 ( 2.3 )] . • CABENUVA can be injected monthly or every 2 months [see Dosage and Administration ( 2.4 , 2.5 )] . 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 ( 6.1 ), Microbiology ( 12.4 ), Clinical Studies ( 14.1 )] . 2.2 Adherence to CABENUVA Prior 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 ( 2.1 ), Warnings and Precautions ( 5.6 ), Microbiology ( 12.4 )] . 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 kg The 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 1 and 2 for recommended oral lead-in and monthly or every-2-month intramuscular injection dosing schedule for CABENUVA [see Dosage and Administration ( 2.4 , 2.5 )] . 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 kg Initiation 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 ( 2.3 )] . 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 ( 2.9 )] . 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 ( Table 1 ). 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 ( 2.9 )] . 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 a The optional oral therapy should be continued until the day the first injection is administered. b Given on the last day of current antiretroviral therapy or oral lead-in if used. Drug Optional Oral Lead-In a (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 Injections Initiate Injections at Month 1 b One Month after Initiation Injection and Monthly Onwards Cabotegravir 30 mg once daily with a meal 600 mg (3 mL) 400 mg (2 mL) Rilpivirine 25 mg once daily with a meal 900 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 kg Initiation 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 ( 2.3 )] . 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 ( Table 2 ). 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 ( 2.9 )] . 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 ( Table 2 ). 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 ( 2.9 )] . 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 a The optional oral therapy should be continued until the day the first injection is administered. b For 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). c Given on the last day of current antiretroviral therapy or oral lead-in if used. Drug Optional Oral Lead-In a (at Least 28 Days) Intramuscular (Gluteal) Injections b Month (at Least 28 Days) Prior to Starting Injections Initiate Injections c at Month 1, Month 2, and then Every 2 Months Onwards (Starting

WARNINGS AND PRECAUTIONS • 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 ) 5.1 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 ( 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 )] . 5.2 Post-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. 5.3 Hepatotoxicity 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 )] . 5.4 Depressive 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. 5.5 Risk 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 )] . 5.6 Long-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.

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 )

DRUG 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 ) 7.1 Concomitant 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 )] . 7.2 Use 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 )] . 7.3 Potential 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. 7.5 Drugs 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.

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 . 6.1 Clinical 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% 7

Mechanism of Action CABENUVA contains 2 long-acting HIV-1 antiretroviral drugs, cabotegravir and rilpivirine [see Microbiology ( 12.4 )] .