FDA Approves APRETUDE (cabotegravir) for HIV-1 Pre-Exposure Prophylaxis

FDA approved APRETUDE (cabotegravir extended-release injectable suspension), for intramuscular use. APRETUDE is an HIV-1 integrase strand transfer inhibitor (INSTI) indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Individuals must have a negative HIV-1 test prior to initiating APRETUDE (with or without an oral lead-in with oral cabotegravir) for HIV-1 PrEP. APRETUDE is the first injectable treatment for HIV-1 PrEP.  According to the U.S. Centers for Disease Control and Prevention, notable gains have been made in increasing PrEP use for HIV prevention in the U.S. and preliminary data show that in 2020, about 25% of the 1.2 million people for whom PrEP is recommended were prescribed it, compared to only about 3% in 2015. Additionally, PrEP requires high levels of adherence to be effective and certain high-risk individuals and groups, such as young men who have sex with men, are less likely to adhere to daily medication. Other interpersonal factors, such as substance use disorders, depression, poverty and efforts to conceal medication also can impact adherence. The approval of APRETUDE adds an important tool in the effort to end the HIV epidemic by providing the first option to prevent HIV-1 infection that does not involve taking a daily oral medication. Below is a summary of the key highlights from the product labeling. The VOCABRIA (oral cabotegravir) label was also updated to describe the use for HIV-1 PrEP. DOSAGE and ADMINISTRATION: Dosage and Administration Overview APRETUDE contains cabotegravir extended-release injectable suspension in a single-dose vial APRETUDE must be administered by a healthcare provider by gluteal intramuscular injection APRETUDE may be initiated with oral cabotegravir prior to the intramuscular injections or the patient may proceed directly to injection of APRETUDE without an oral lead-in HIV-1 Screening for Individuals Receiving APRETUDE for HIV-1 PrEP Individuals must be tested for HIV-1 infection prior to initiating APRETUDE or oral cabotegravir, and with each subsequent injection of APRETUDE, using a test approved or cleared by the FDA for the diagnosis of acute or primary HIV-1 infection. If an antigen/antibody-specific test is used and provides negative results, then such negative results should be confirmed using an RNA-specific assay, even if the results of the RNA-assay are available after APRETUDE or oral cabotegravir administration. Optional Oral Lead-in Dosing to Assess Tolerability of APRETUDE The healthcare provider and individual may decide to use an oral lead-in with oral cabotegravir prior to the initiation of APRETUDE to assess the tolerability of cabotegravir or the healthcare provider and individual may proceed directly to injection of APRETUDE without the use of an oral lead-in. No safety and efficacy data are available for use of APRETUDE without an oral lead-in. However, in HIV-1 treatment clinical trials, data show that an oral lead-in is not needed to ensure adequate plasma cabotegravir exposure upon initiation of injections and that the safety and efficacy results of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) were similar when administered with and without an oral lead-in. Gluteal Intramuscular Injection Dosing with APRETUDE – Refer to the Prescribing Information for Complete Details Initiation Injections If an oral lead-in is used, initiation injections should be administered on the last day of oral lead in or within 3 days thereafter. The recommended initiation injection doses of APRETUDE in individuals is a single 600 mg (3-mL) intramuscular injection of APRETUDE given 1 month apart for 2 consecutive months. Individuals may be given the second APRETUDE initiation injection up to 7 days before or after the date the individual is scheduled to receive the injections. Continuation Injections After the 2 initiation injection doses given consecutively 1 month apart, the recommended continuation injection dose of APRETUDE is a single 600-mg (3-mL) intramuscular injection of APRETUDE every 2 months. Individuals may be given APRETUDE up to 7 days before or after the date the individual is scheduled to receive the injections. Recommended Dosing Schedule for Missed Injections Adherence to the injection dosing schedule is strongly recommended. Individuals who miss a scheduled injection visit should be clinically reassessed to ensure resumption of APRETUDE remains appropriate Planned Missed Injections If an individual plans to miss a scheduled every-2-month continuation injection visit by more than 7 days, take daily oral cabotegravir for a duration of up to 2 months to replace 1 missed scheduled every-2-month injection. The recommended oral daily dose is one 30-mg tablet of oral cabotegravir. The first dose of oral PrEP should be taken approximately 2 months after the last injection dose of APRETUDE. Restart injection with APRETUDE on the day oral dosing completes or within 3 days; thereafter, as recommended in Table 3 of the product labeling. For oral PrEP durations greater than 2 months, an alternative oral regimen is recommended. Unplanned Missed Injections If a scheduled injection visit is missed or delayed by more than 7 days and oral dosing has not been taken in the interim, clinically reassess the individual to determine if resumption of injection dosing remains appropriate. If the injection dosing schedule will be continued see Table 3 of the product labeling. Summary of Clinical Studies: The safety and efficacy of APRETUDE to reduce the risk of acquiring HIV-1 infection were evaluated in 2 randomized, double-blind, controlled, multinational trials, HPTN 083 in HIV 1 uninfected men and transgender women who have sex with men and have evidence of high-risk behavior for HIV-1 infection and HPTN 084 in HIV-1 uninfected cisgender women at risk of acquiring HIV-1. Participants randomized to receive APRETUDE initiated oral lead-in dosing with 1 oral cabotegravir 30-mg tablet and a placebo daily for up to 5 weeks, followed by APRETUDE 600 mg (3-mL) intramuscular injection at months 1 and 2 and every 2 months thereafter and a daily placebo tablet. Participants randomized to receive TRUVADA initiated oral TRUVADA (TDF 300 mg/FTC 200 mg) and placebo daily for up to 5 weeks, followed by oral TRUVADA daily and placebo intramuscular injection at months 1 and 2 and every 2 months thereafter. The primary endpoint was the rate of incident HIV-1 infections among participants randomized to oral cabotegravir and injections of APRETUDE compared with oral TRUVADA In HPTN 083, a non-inferiority study, 4,566 cisgender men and transgender women who have sex with men were randomized 1:1 and received either APRETUDE (n = 2,281) or TRUVADA (n = 2,285) as blinded study medication up to Week 153. The primary analysis demonstrated the superiority of APRETUDE compared with TRUVADA with a 66% reduction in the risk of acquiring HIV-1 infection, hazard ratio (95% CI) 0.34 (0.18, 0.62); further testing revealed 1 of the infections on APRETUDE to be prevalent then yielding a 69% reduction in the risk of HIV-1 incident infection relative to TRUVADA, hazard ratio (95% CI) 0.31 (0.16, 0.58). Results from all subgroup analyses were consistent with the overall protective effect. A lower rate of incident HIV 1 infections was observed for participants randomized to APRETUDE compared with participants randomized to TRUVADA. In HPTN 084, a superiority study, 3,224 cisgender women were randomized 1:1 and received either APRETUDE (n = 1,614) or TRUVADA (n = 1,610) as blinded study medication up to Week 153. The primary analysis demonstrated the superiority of APRETUDE compared with TRUVADA with an 88% reduction in the risk of acquiring incident HIV-1 infection, hazard ratio (95% CI) 0.12 (0.05, 0.31); further testing revealed 1 of the infections on APRETUDE to be prevalent then yielding a 90% reduction in the risk of HIV-1 incident infection relative to TRUVADA, hazard ratio (95% CI) 0.10 (0.04, 0.27). Results from pre-planned subgroup analyses were consistent with the overall protective effect. A lower rate of incident HIV-1 infections was observed for participants randomized to APRETUDE compared with participants randomized to TRUVADA. Clinical Virology Data: There were 12 incident infections and 4 prevalent infections among subjects in the APRETUDE arm of HPTN 083. Genotypic data were generated for viruses from 13 of these 16 subjects (4 subjects with prevalent infections and 9 subjects with incident infections) and phenotypic data were generated for 3 of these viruses. INSTI resistance-associated substitutions were detected in 5 viruses from subjects who achieved target plasma concentrations of cabotegravir (≥0.65 mcg/mL [1.6 μM]) and included R263K (2-fold less susceptible to cabotegravir), E138A+Q148R (6-fold less susceptible to cabotegravir), E138K+Q148K, G140A+Q148R (13-fold less susceptible to cabotegravir), and L74I+E138E/K+G140G/S+Q148R+E157Q. There were 3 incident infections and 1 prevalent infection among subjects in the APRETUDE arm of HPTN 084. All 3 incident infections occurred during periods with cabotegravir exposures below the target concentration. No variants expressing INSTI resistance-associated substitutions were detected. CONTRAINDICATIONS APRETUDE is contraindicated in individuals: with unknown or positive HIV-1 status with previous hypersensitivity reaction to cabotegravir receiving the following coadministered drugs for which significant decreases in cabotegravir plasma concentrations may occur due to uridine diphosphate glucuronosyltransferase (UGT1A1) Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin Antimycobacterials: Rifampin, rifapentine Summary of WARNINGS AND PRECAUTIONS Comprehensive management to reduce the risk of HIV-1 acquisition. Potential risk of developing resistance to APRETUDE if an individual acquires HIV-1 either before or while taking APRETUDE or following discontinuation of APRETUDE. Reassess risk of HIV-1 acquisition and test before each injection to confirm HIV-1 negative status. Residual concentrations of cabotegravir may remain in the systemic circulation of individuals up to 12 months or longer. Hypersensitivity reactions have been reported in association with other integrase inhibitors. Discontinue APRETUDE immediately if signs or symptoms of hypersensitivity reactions develop. Hepatotoxicity has been reported in patients receiving cabotegravir. Clinical and laboratory monitoring should be considered. Discontinue APRETUDE if hepatotoxicity is suspected. Depressive disorders have been reported with APRETUDE. Prompt evaluation is recommended for depressive symptoms. ADVERSE REACTIONS The most common adverse reactions (all grades) observed in at least 1% of subjects receiving APRETUDE were injection site reactions, diarrhea, headache, pyrexia, fatigue, sleep disorders, nausea, dizziness, flatulence, abdominal pain, vomiting, myalgia, rash, decreased appetite, somnolence, back pain, and upper respiratory tract infection. Injection-Associated Adverse Reactions Local Injection Site Reactions (ISRs) with APRETUDE: The most frequent adverse reactions associated with the intramuscular administration of APRETUDE in HPTN 083 were ISRs. After 20,286 injections, 8,900 ISRs were reported. Of the 2,117 participants who received at least one injection of APRETUDE, 1,740 (82%) participants experienced at least one ISR, of which a total of 3% of participants discontinued APRETUDE because of ISRs. Among the participants who received APRETUDE and experienced at least one ISR, the maximum severity of reactions was mild (Grade 1) in 41% of participants, moderate (Grade 2) in 56% of participants, and severe (Grade 3) in 3% of participants. The median duration of overall ISR events was 4 days. The proportion of participants reporting ISRs at each visit and the severity of the ISRs decreased over time. The most frequent adverse reactions associated with the intramuscular administration of APRETUDE in HPTN 084 were ISRs. After 13,068 injections, 1,171 ISRs were reported. Of the 1,519 participants who received at least one injection of APRETUDE, 578 (38%) participants experienced at least one ISR. No participants discontinued APRETUDE because of ISRs. Among the participants who received APRETUDE and experienced at least one ISR, the maximum severity of reactions was mild (Grade 1) in 66% of participants, moderate (Grade 2) in 34% of participants, and severe (Grade 3) in less than 1% of participants. The median duration of overall ISR events was 8 days. The proportion of participants reporting ISRs at each visit and the severity of the ISRs generally decreased over time. Other Injection-Associated Adverse Reactions: In the HPTN 083 clinical trial, an increased incidence of pyrexia (including pyrexia, feeling hot, chills, influenza-like illness) (4%) was reported by participants receiving APRETUDE compared with participants receiving TRUVADA (<1%). There were no differences reported in the incidence of pyrexia between groups in HPTN 084. Vasovagal or pre-syncopal reactions considered treatment related were reported in <1% of participants after injection with APRETUDE in HPTN 083. None were reported as treatment related by the investigators in HPTN 084. Weight Increase At the Week 41 and Week 97 timepoints in HPTN 083, participants who received APRETUDE gained a median of 1.2 kg (Interquartile Range [IQR]; -1.0, 3.5; n = 1,623) and 2.1 kg (IQR; -0.9, 5.9; n = 601) in weight from baseline. Those who received TRUVADA gained a median of 0 kg (IQR; -2.1, 2.4; n = 1,611) and 1 kg (IQR; -1.9, 4.0; n = 598) in weight from baseline, respectively. At the Week 41 and 97 timepoints in HPTN 084, participants who received APRETUDE gained a median of 2 kg (IQR; 0.0, 5.0; n = 1,151) and 4 kg (IQR; 0.0, 8.0; n = 216) in weight from baseline, respectively. Those who received TRUVADA gained a median of 1 kg (IQR; -1.0, 4.0; n = 1,131) and 3 kg (IQR; -1.0, 6.0; n = 218) in weight from baseline, respectively. Pediatric Use The safety and effectiveness of APRETUDE for HIV-1 PrEP in at-risk adolescents weighing at least 35 kg is supported by data from 2 adequate and well-controlled trials of APRETUDE for HIV-1 PrEP in adults with additional safety and pharmacokinetic data from studies in HIV-1 infected adults who were administered CABENUVA, and in HIV-1 infected pediatric subjects who were administered separate components of CABENUVA in addition to their current antiretroviral therapy. APRETUDE for HIV-1 PrEP is being evaluated in 2 open-label multicenter clinical trials in adolescent individuals. Fifty-nine adolescents have been enrolled. Of these, 54 adolescent participants received one or more injections. In adolescents receiving APRETUDE for HIV-1 PrEP, the safety data were comparable to the safety data reported in adults receiving APRETUDE for HIV-1 PrEP. While using APRETUDE, HIV-1 testing should be conducted prior to initiating APRETUDE (with or without an oral lead-in with oral cabotegravir) and prior to each injection of APRETUDE. Adolescents may benefit from more frequent visits and counseling to support adherence to the dosing and testing schedule. The safety, efficacy, and pharmacokinetics of APRETUDE in pediatric participants younger than 12 years of age or weighing <35 kg have not been established. Please refer to the full prescribing information Manage Subscriptions  |  Unsubscribe All  |  Help This email was sent to ooseims.archieves@blogger.com using GovDelivery Communications Cloud on behalf of: U.S. Food and Drug Administration ·  10903 New Hampshire Ave · Silver Spring, MD ·  20993-0002 ·  1-888-INFO-FDA