Apretude
Cabotegravir · Kit
Uses
1 INDICATIONS AND USAGE APRETUDE is indicated for pre‑exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in adults and adolescents weighing at least 35 kg who are at risk for HIV-1 acquisition. 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 [see Dosage and Administration ( 2.2 , 2.4 ), Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . APRETUDE is an HIV-1 integrase strand transfer inhibitor (INSTI) indicated for PrEP to reduce the risk of sexually acquired HIV-1 infection in adults and adolescents weighing at least 35 kg who are at risk for HIV-1 acquisition. 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. ( 1 )
Dosage and administration
• HIV-1 Screening: Screen all individuals for HIV-1 infection immediately prior to initiating APRETUDE for HIV-1 PrEP and prior to each injection while taking APRETUDE. ( 2.2 )
• Prior to initiating APRETUDE, an oral lead-in dosing may be used for approximately 1 month with the recommended dosage to assess the tolerability of APRETUDE. ( 2.4 )
• For gluteal intramuscular injection only. ( 2.5 , 2.7 )
• Recommended Dosing Schedule: Initiate APRETUDE with a single 600-mg (3-mL) injection given 1 month apart for 2 consecutive months on the last day of an oral lead-in if used or within 3 days and continue with the injections every 2 months thereafter. ( 2.5 ) 2.1 Dosage and Administration Overview
• APRETUDE contains cabotegravir extended-release injectable suspension in a single-dose vial [see Dosage Forms and Strengths ( 3 )] .
• APRETUDE must be administered by a healthcare provider by gluteal intramuscular injection [see Dosage and Administration ( 2.7 )] .
• 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 [see Dosage and Administration ( 2.4 )] . 2.2 HIV-1 Screening for Individuals Receiving APRETUDE for HIV-1 Pre-Exposure Prophylaxis 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 [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . 2.3 Adherence to APRETUDE Prior to starting APRETUDE, healthcare providers should carefully select individuals who agree to the required injection dosing and testing schedule and counsel individuals about the importance of adherence to scheduled dosing visits to help reduce the risk of acquiring HIV-1 infection and development of resistance [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.1 , 5.3 ), Microbiology ( 12.4 )] . 2.4 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 [see Dosage and Administration ( 2.5 )] . No safety and efficacy data are available for use of APRETUDE without an oral lead-in [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.1 )]. 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. 2.5 Gluteal Intramuscular Injection Dosing with APRETUDE 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 ( Table 1 and Table 2 ). 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 ( Table 2 ). Individuals may be given APRETUDE up to 7 days before or after the date the individual is scheduled to receive the injections. Table 1. Recommended Dosing Schedule (with Oral Lead-In) for Pre-Exposure Prophylaxis in Adults and Adolescents Weighing at Least 35 kg a Should be administered on the last day of oral lead-in or within 3 days thereafter. b Individuals may be given APRETUDE up to 7 days before or after the date the individual is scheduled to receive the injections. Oral Lead-In (at Least 28 Days) (Month Prior to Starting Injections) Intramuscular (Gluteal) Initiation Injection (Month 1 and Month 2) Intramuscular (Gluteal) Continuation Injection (Month 4 and Every 2 Months Onwards) Oral cabotegravir 30 mg by mouth once daily for 28 days APRETUDE a 600-mg (3 mL) APRETUDE b 600-mg (3 mL) Table 2. Recommended Dosing Schedule (Direct to Injection) for Pre-Exposure Prophylaxis in Adults and Adolescents Weighing at Least 35 kg a Individuals may be given APRETUDE up to 7 days before or after the date the individual is scheduled to receive the injections. Intramuscular (Gluteal) Initiation Injection (Month 1 and Month 2) Intramuscular (Gluteal) Continuation Injection (Month 4 and Every 2 Months Onwards) APRETUDE a APRETUDE a 600-mg (3 mL) 600-mg (3 mL) 2.6 Recommended Dosing Schedule for Missed Injections Adherence to the injection dosing schedule is strongly recommended [see Dosage and Administration ( 2.3 )] . Individuals who miss a scheduled injection visit should be clinically reassessed to ensure resumption of APRETUDE remains appropriate [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.2 )] . Refer to Table 3 for dosing recommendations after missed injections.
Dosage forms and strengths
Injection: Single-dose vial containing 600 mg/3 mL (200 mg/mL) of cabotegravir extended‑release injectable suspension. Injection: Single-dose vial of 600 mg/3 mL (200 mg/mL) of cabotegravir extended-release injectable suspension. ( 3 )
Contraindications
4 CONTRAINDICATIONS APRETUDE is contraindicated in individuals:
• with unknown or positive HIV-1 status [see Warnings and Precautions ( 5.1 , 5.2 )] .
• with previous hypersensitivity reaction to cabotegravir [see Warnings and Precautions ( 5.4 )] .
• receiving the following coadministered drugs for which significant decreases in cabotegravir plasma concentrations may occur due to uridine diphosphate glucuronosyltransferase (UGT)1A1 enzyme induction, which may result in reduced effectiveness [see Drug Interactions ( 7.2 , 7.3 ), Clinical Pharmacology ( 12.3 )] : o Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin o Antimycobacterials: Rifampin, rifapentine
• Unknown or positive HIV-1 status. ( 4 )
• Previous hypersensitivity reaction to cabotegravir. ( 4 )
• Coadministration with drugs where significant decreases in cabotegravir plasma concentrations may occur. ( 4 )
Warnings and precautions
• Comprehensive management to reduce the risk of HIV-1 acquisition. ( 5.1 )
• 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. ( 5.2 )
• Residual concentrations of cabotegravir may remain in the systemic circulation of individuals up to 12 months or longer. ( 5.3 )
• Serious or severe hypersensitivity reactions have been reported with cabotegravir and include Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Discontinue APRETUDE immediately if signs or symptoms of hypersensitivity reactions develop. ( 5.4 )
• Hepatotoxicity has been reported in individuals receiving cabotegravir. Clinical and laboratory monitoring should be considered. Discontinue APRETUDE if hepatotoxicity is suspected. ( 5.5 )
• Depressive disorders have been reported with APRETUDE. Prompt evaluation is recommended for depressive symptoms. ( 5.6 ) 5.1 Comprehensive Management to Reduce the Risk of HIV-1 Infection Use APRETUDE for HIV-1 PrEP to reduce the risk of HIV-1 infection as part of a comprehensive prevention strategy including adherence to the administration schedule and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs). APRETUDE is not always effective in preventing HIV-1 acquisition [see Clinical Studies ( 14.1 )] . The time from initiation of APRETUDE for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown. Risk for HIV-1 acquisition includes behavioral, biological, or epidemiologic factors including, but not limited to, condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network. Counsel individuals on the use of other prevention measures (e.g., consistent and correct condom use; knowledge of partner(s)’ HIV-1 status, including viral suppression status; regular testing for STIs that can facilitate HIV-1 transmission). Inform individuals about and support their efforts in reducing sexual risk behavior. Use APRETUDE to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV‑1 negative [see Contraindications ( 4 )] . HIV-1 resistance substitutions may emerge in individuals with undiagnosed HIV‑1 infection who are taking only APRETUDE, because APRETUDE alone does not constitute a complete regimen for HIV-1 treatment [see Microbiology ( 12.4 )] ; therefore, care should be taken to minimize the risk of initiating or continuing APRETUDE before confirming the individual is HIV-1 negative.
• Prior to initiating APRETUDE for HIV-1 PrEP, ask seronegative individuals about recent (in past month) potential exposure events (e.g., condomless sex or condom breaking during sex with a partner of unknown HIV-1 status or unknown viremic status, a recent STI), and evaluate for current or recent signs or symptoms consistent with acute HIV-1 infection (e.g., fever, fatigue, myalgia, skin rash).
• If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection. When using APRETUDE for HIV-1 PrEP, HIV-1 testing should be repeated prior to each injection and upon diagnosis of any other STIs [see Dosage and Administration ( 2.2 , 2.5 )] .
• If an HIV-1 test indicates possible HIV-1 infection, or if symptoms consistent with acute HIV-1 infection develop following an exposure event, additional HIV testing to determine HIV status is needed. If an individual has confirmed HIV-1 infection, then the individual must be transitioned to a complete HIV-1 treatment regimen. Counsel individuals without HIV-1 to strictly adhere to the recommended dosing and testing schedule for APRETUDE in order to reduce the risk of HIV-1 acquisition and the potential development of resistance [see Dosage and Administration ( 2.3 , 2.5 ), Microbiology ( 12.4 )] . Some individuals, such as adolescents, may benefit from frequent visits and counseling to support adherence to the dosing and testing schedule [see Use in Specific Populations ( 8.4 ), Microbiology ( 12.4 ), Clinical Studies ( 14 )] . 5.2 Potential Risk of Resistance with APRETUDE There is a potential risk of developing resistance to APRETUDE if an individual acquires HIV-1 either before or while taking APRETUDE or following discontinuation of APRETUDE [see Warnings and Precautions ( 5.1 , 5.3 )] . To minimize this risk, it is essential to clinically reassess individuals for risk of HIV-1 acquisition and to test before each injection to confirm HIV-1 negative status. Individuals who are confirmed to have HIV-1 infection must transition to a complete HIV-1 treatment regimen. Alternative forms of PrEP should be considered following discontinuation of APRETUDE for those individuals at continuing risk of HIV-1 acquisition and initiated within 2 months of the final injection of APRETUDE. 5.3 Long-Acting Properties and Potential Associated Risks with APRETUDE Residual concentrations of cabotegravir may remain in the systemic circulation of individuals for prolonged periods (up to 12 months or longer). It is important to carefully select individuals who agree to the required every-2-month injection dosing schedule because non-adherence to every‑2-monthly injections or missed doses could lead to HIV-1 acquisition and development of resistance. Healthcare providers should take the prolonged-release characteristics of cabotegravir into consideration when APRETUDE is prescribed [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 , 5.2 ), Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.1 , 8.2 ), Overdosage ( 10 )] .
Side effects
The following adverse reactions are described below and in other sections of the labeling:
• Hypersensitivity reactions [see Warnings and Precautions ( 5.4 )]
• Hepatotoxicity [see Warnings and Precautions ( 5.5 )]
• Depressive disorders [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (all grades) observed in at least 1% of participants 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. ( 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 APRETUDE is based on the analysis of data from 2 international, multicenter, double-blind trials, HPTN 083 and HPTN 084 [see Clinical Studies ( 14.1 )] . Adverse reactions were reported while on blinded study product following exposure to APRETUDE extended-release injectable suspension and oral cabotegravir tablets as oral lead-in. The median time on blinded study product in HPTN 083 was 65 weeks and 2 days (range: 1 day to 156 weeks and 1 day), with a total exposure on cabotegravir of 3,231 person‑years. The median time on blinded study product in HPTN 084 was 64 weeks and 1 day (range: 1 day to 153 weeks and 1 day), with a total exposure on cabotegravir of 2,009 person‑years. The most common adverse reactions regardless of severity reported in at least 1% of participants in HPTN 083 or HPTN 084 are presented in Table 4 . In HPTN 083, 6% of participants in the group receiving APRETUDE intramuscular injection every 2 months and 4% of participants receiving oral TRUVADA [emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF)] once daily discontinued due to adverse events (all causality). Non-injection-site–associated adverse events leading to discontinuation and occurring in ≥1% of participants were increased alanine aminotransferase with APRETUDE and TRUVADA. In HPTN 084, 1% of participants receiving APRETUDE and 1% of participants receiving TRUVADA discontinued due to adverse events. The most commonly reported adverse event (all causality) leading to discontinuation was increased alanine aminotransferase (<1%) with APRETUDE and TRUVADA. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trials. Table 4. Adverse Drug Reactions a (All Grades) Reported in at Least 1% of Participants Receiving APRETUDE in Either HPTN 083 or HPTN 084 a Adverse reactions defined as “treatment-related” as assessed by the investigator, with exception of injection site reactions, where all injection site reactions were reported regardless of causality. b Participants who received injection: HPTN 083, APRETUDE (n = 2,117) and TRUVADA (n = 2,081); HPTN 084, APRETUDE (n = 1,519) and TRUVADA (n = 1,516). c Pyrexia includes pyrexia, feeling hot, chills, influenza-like illness. d Fatigue includes fatigue, malaise. e Sleep disorders includes insomnia, abnormal dreams. f Abdominal pain includes abdominal pain, upper abdominal pain. g Rash includes rash, erythema, pruritis, macular, papular, maculopapular. Adverse Reactions HPTN 083 HPTN 084 APRETUDE Every 2 Months (n = 2,281) TRUVADA Once Daily (n = 2,285) APRETUDE Every 2 Months (n = 1,614) TRUVADA Once Daily (n = 1,610) Injection site reactions b 82% 35% 38% 11% Diarrhea 4% 5% 4% 4% Headache 4% 3% 12% 13% Pyrexia c 4% <1% <1% <1% Fatigue d 4% 2% 3% 3% Sleep disorders e 3% 3% 1% 1% Nausea 3% 5% 4% 8% Dizziness 2% 3% 4% 6% Flatulence 1% 1% <1% <1% Abdominal pain f 1% 1% 2% 2% Vomiting <1% 1% 2% 5% Myalgia <1% <1% 2% 1% Rash g <1% <1% 2% 1% Decreased appetite <1% <1% 2% 4% Somnolence <1% <1% 2% 2% Back pain <1% <1% 1% <1% Upper respiratory tract infection 0 <1% 4% 4% 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 commonly reported ISRs (all causality and grades) in at least 1% of participants who received APRETUDE and experienced at least one ISR from HPTN 083 are presented in Table 5 . 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.
Drug interactions
• Refer to the full prescribing information for important drug interactions with APRETUDE. ( 4 , 5.7 , 7 )
• Drugs that induce uridine diphosphate glucuronosyltransferase (UGT)1A1 may significantly decrease plasma concentrations of cabotegravir. ( 4 , 7.2 , 7.3 ) 7.1 Use of Other Antiretroviral Drugs after Discontinuation of APRETUDE Residual concentrations of cabotegravir may remain in the systemic circulation of individuals 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 APRETUDE [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7.4 ), Clinical Pharmacology ( 12.3 )] . 7.2 Potential for Other Drugs to Affect APRETUDE Cabotegravir is primarily metabolized by UGT1A1 with some contribution from UGT1A9. Drugs that are strong inducers of UGT1A1 or 1A9 are expected to decrease cabotegravir plasma concentrations; therefore, coadministration of APRETUDE with these drugs is contraindicated [see Contraindications ( 4 )] . 7.3 Established and Other Potentially Significant Drug Interactions Information regarding potential drug interactions with cabotegravir is provided in Table 8 . These recommendations are based on either drug interaction trials following oral administration of cabotegravir or predicted interactions due to the expected magnitude of the interaction [see Contraindications ( 4 ), Warnings and Precautions ( 5.7 ), Clinical Pharmacology ( 12.3 )] . Table 8 includes potentially significant interactions but is not all inclusive. Table 8. Drug Interactions with APRETUDE ↑ = Increase, ↓ = Decrease, ↔ = No change. Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment Anticonvulsants: Carbamazepine Oxcarbazepine Phenobarbital Phenytoin ↓Cabotegravir Coadministration is contraindicated with APRETUDE due to potential for significant decreases in plasma concentration of APRETUDE. Antimycobacterials: Rifampin Rifapentine ↓Cabotegravir Antimycobacterial: Rifabutin ↓Cabotegravir When rifabutin is started before or concomitantly with the first initiation injection of APRETUDE, the recommended dosing of APRETUDE is one 600-mg (3-mL) injection, followed 2 weeks later by a second 600‑mg (3-mL) initiation injection and monthly thereafter while on rifabutin. When rifabutin is started at the time of the second initiation injection or later, the recommended dosing schedule of APRETUDE is 600‑mg (3 mL) monthly while on rifabutin. After stopping rifabutin, the recommended dosing schedule of APRETUDE is 600-mg (3 mL) every 2 months. 7.4 Drugs without Clinically Significant Interactions with Cabotegravir Based on drug interaction study results, the following drugs can be coadministered with cabotegravir (non-antiretrovirals) 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 )] .
Use in specific populations
• Lactation: Assess the benefit-risk of using APRETUDE to the infant while breastfeeding due to the potential for adverse reactions and residual concentrations in the systemic circulation for up to 12 months or longer after discontinuation. ( 8.2 )
• Pediatrics: Not recommended in individuals weighing <35 kg. ( 8.4 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to APRETUDE during pregnancy. Healthcare providers are encouraged to register individuals by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary There are insufficient human data on the use of APRETUDE during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. Discuss the benefit-risk of using APRETUDE with individuals of childbearing potential or during pregnancy. Cabotegravir use in pregnant individuals has not been evaluated. APRETUDE should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus. The APR has been established to monitor for birth defects following prenatal exposure to antiretrovirals. The rate of miscarriage is not reported in the APR. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (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) . Clinical Considerations Cabotegravir is detected in systemic circulation for up to 12 months or longer after discontinuing injections of APRETUDE; therefore, consideration should be given to the potential for fetal exposure during pregnancy [see Warnings and Precautions ( 5.3 )] . Data Animal Data: 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. 8.2 Lactation Risk Summary There are no data on the presence of cabotegravir in human milk. Cabotegravir is present in animal milk (see Data) . When a drug is present in animal milk, it is likely that the drug will be present in human milk. It is not known if cabotegravir affects human milk production, or has effects on the breastfed infant. If cabotegravir is present in human milk, residual exposures may remain for 12 months or longer after the last injections have been administered [see Warnings and Precautions ( 5.3 )] . Cabotegravir concentrations may be detectable in systemic circulation for up to 12 months or longer after discontinuing injections of APRETUDE. Breastfeeding should only be considered if the expected benefit justifies the potential risk to the infant, including the potential risk for adverse reaction in the breastfed child, along with the risk of HIV-1 acquisition due to nonadherence and subsequent vertical transmission to the child. Breastfeeding is not recommended if acute HIV-1 infection is suspected to avoid the risk of postnatal transmission of HIV-1 infection. Data Animal lactation studies with cabotegravir have not been conducted. However, cabotegravir was detected in the plasma of nursing pups on Lactation Day 10 in the rat pre- and postnatal development study.
Pregnancy
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to APRETUDE during pregnancy. Healthcare providers are encouraged to register individuals by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary There are insufficient human data on the use of APRETUDE during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. Discuss the benefit-risk of using APRETUDE with individuals of childbearing potential or during pregnancy. Cabotegravir use in pregnant individuals has not been evaluated. APRETUDE should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus. The APR has been established to monitor for birth defects following prenatal exposure to antiretrovirals. The rate of miscarriage is not reported in the APR. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (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) . Clinical Considerations Cabotegravir is detected in systemic circulation for up to 12 months or longer after discontinuing injections of APRETUDE; therefore, consideration should be given to the potential for fetal exposure during pregnancy [see Warnings and Precautions ( 5.3 )] . Data Animal Data: 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.
Pediatric use
8.4 Pediatric Use The safety and effectiveness of APRETUDE for HIV-1 PrEP in adolescents weighing at least 35 kg who are at risk for HIV-1 acquisition 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 adults with HIV-1 who were administered CABENUVA, and in adolescent participants with HIV-1 who were administered separate components of CABENUVA in addition to their current antiretroviral therapy [see Dosage and Administration ( 2.5 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.1 )] . APRETUDE for HIV-1 PrEP was evaluated in 2 open-label multicenter clinical trials, HPTN 083-01 and HPTN 084-01, in adolescent individuals 12 to less than 18 years of age weighing at least 35 kg who are at risk for HIV-1 acquisition. Sixty-four adolescents were enrolled. Of these, 62 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 [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 )]. The safety, efficacy, and pharmacokinetics of APRETUDE in pediatric participants younger than 12 years of age or weighing <35 kg have not been established.
Geriatric use
8.5 Geriatric Use No dose adjustment is required in elderly individuals. There are limited data available on the use of APRETUDE in individuals aged 65 years and older. In general, caution should be exercised in administration of APRETUDE in elderly individuals, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy [see Clinical Pharmacology ( 12.3 )] .
Overdosage
There is no known specific treatment for overdose with APRETUDE. If overdose occurs, monitor the individual and apply standard supportive treatment as required as well as observation of the clinical status of the individual. As APRETUDE is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis. Consider the prolonged exposure to APRETUDE following an injection when assessing treatment needs and recovery [see Warnings and Precautions ( 5.5 )] .
Description
11 DESCRIPTION APRETUDE contains cabotegravir extended-release injectable suspension, an HIV INSTI. The chemical name of cabotegravir is ( 3S,11aR )-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide. The empirical formula is C 19 H 17 F 2 N 3 O 5 and the molecular weight is 405.35 g/mol. It has the following structural formula: Cabotegravir extended-release injectable suspension is a white to light pink free-flowing suspension for intramuscular injection in a sterile single-dose vial. Each vial contains 3 mL of the following: cabotegravir 200 mg/mL and the inactive ingredients mannitol (35 mg/mL), polyethylene glycol (PEG) 3350 (20 mg/mL), polysorbate 20 (20 mg/mL), and Water for Injection. The vial stoppers are not made with natural rubber latex. Cabotegravir chemical structure
Mechanism of action
12.1 Mechanism of Action Cabotegravir is an HIV-1 antiretroviral drug [see Microbiology ( 12.4 )] in a long-acting formulation.
How supplied
How Supplied APRETUDE is supplied in a kit containing one 600-mg/3-mL single-dose (200-mg/mL) vial of cabotegravir extended-release injectable suspension, 1 syringe, 1 vial adapter, and 1 needle for intramuscular injection (23 gauge, 1½ inch) (NDC 49702-264-23). The vial stopper is not made with natural rubber latex. Storage and Handling Store APRETUDE at 2°C to 25°C (36°F to 77°F) in the original carton until ready to use. Exposure up to 30°C permitted. Do not freeze. Do not mix with any other product or diluent. If the pack has been stored in the refrigerator, the vial should be brought to room temperature prior to administration (not to exceed 30°C [86°F]). Once the suspension has been drawn into the syringe, the injection should be administered as soon as possible, but may remain in the syringe for up to 2 hours. The filled syringes should not be placed in the refrigerator. If the medicine remains in the syringe for more than 2 hours, the filled syringe and needle must be discarded [see Dosage and Administration ( 2.7 )] .
Patient information
Advise the individual to read the FDA-approved patient labeling (Patient Information). Important Information for Individuals without HIV-1 Taking APRETUDE for HIV-1 Pre ‑ Exposure Prophylaxis Advise individuals without HIV-1 about the following [see Warnings and Precautions ( 5.1 )] :
• APRETUDE should be used for PrEP as part of an overall HIV-1 infection prevention strategy, including adherence to the administration schedule and safer sex practices, including condoms, to reduce the risk of STIs.
• APRETUDE is not always effective in preventing HIV-1 acquisition [see Clinical Studies ( 14.1 )] . The time from initiation of APRETUDE for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown.
• Counsel individuals on the use of other prevention measures (e.g., knowledge of partner HIV-1 status, testing for STIs condom use). Inform individuals about and support their efforts in reducing sexual risk behavior.
• APRETUDE should be used to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV-1 negative [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . HIV-1 resistance substitutions may emerge in individuals with undiagnosed HIV-1 infection who are taking only APRETUDE, because APRETUDE alone does not constitute a complete regimen for HIV-1 treatment; therefore, care should be taken to minimize the risk of initiating or continuing APRETUDE before confirming the individual is HIV-1 negative.
• If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection.
• When using APRETUDE for HIV-1 PrEP, HIV-1 testing should be repeated prior to each injection of APRETUDE, and upon diagnosis of any other STIs.
• If an HIV-1 test indicates possible HIV-1 infection, or if symptoms consistent with acute HIV-1 infection develop following an exposure event, additional HIV testing to determine HIV status is needed. If an individual has confirmed HIV-1 infection, then the individual must be transitioned to a complete HIV-1 treatment regimen.
• Some individuals, such as adolescents, may benefit from frequent visits and counseling to support adherence. Potential Risk of Resistance with APRETUDE Advise individuals there is a potential risk of developing resistance to APRETUDE if HIV-1 is acquired either before or while taking APRETUDE or following discontinuation of APRETUDE [see Warnings and Precautions ( 5.2 )] . To minimize this, it is essential that individuals are clinically reassessed for risk of HIV-1 acquisition and tested frequently to confirm HIV-1 negative status. Advise individuals who are confirmed to have with HIV-1 infection to consult with their healthcare professional, as HIV-1 treatment must be initiated [see Warnings and Precautions ( 5.2 )] . Inform individuals that alternative forms of PrEP should be considered following discontinuation of APRETUDE for those at continuing risk of HIV-1 acquisition and initiated within 2 months of the final injection of APRETUDE [see Warnings and Precautions ( 5.2 )] . Long-Acting Properties of APRETUDE Advise individuals that APRETUDE is an extended-release injectable that may be systemically present for 12 months or longer and consideration should be taken regarding the prolonged release characteristics when APRETUDE is discontinued [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 )] . Adherence to APRETUDE Counsel individuals about the importance of continued medication adherence and scheduled visits to help reduce the risk of acquiring HIV-1 infection and development of resistance [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 )] . Hypersensitivity Reactions Advise individuals to immediately contact their healthcare provider if they develop a rash. Instruct individuals to immediately stop taking APRETUDE and seek medical attention if they develop a rash associated with any of the following symptoms as it may be a sign of a more serious reaction such as Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN): fever; generally ill feeling; extreme tiredness; muscle or joint aches; blisters; oral blisters or lesions; eye inflammation; facial swelling; swelling of the eyes, lips, tongue, or mouth; difficulty breathing; and/or signs and symptoms of liver problems (e.g., yellowing of the skin or whites of the eyes; dark or tea‑colored urine; pale-colored stools or bowel movements; nausea; vomiting; loss of appetite; or pain, aching, or sensitivity on the right side below the ribs). Advise individuals that if hypersensitivity occurs, they will be closely monitored, laboratory tests will be ordered, and appropriate therapy will be initiated [see Warnings and Precautions ( 5.4 )] . Hepatotoxicity Inform individuals that hepatotoxicity has been reported with cabotegravir [see Warnings and Precautions ( 5.5 ), Adverse Reactions ( 6.1 )] . Inform individuals that clinical and laboratory monitoring should be considered and APRETUDE should be discontinued if hepatoxicity is confirmed [see Warnings and Precautions ( 5.5 )] . Depressive Disorders Inform individuals that depressive disorders (including depression, depressed mood, major depression, persistent depressive disorder, suicidal ideation, suicide attempt) have been reported with APRETUDE [see Adverse Reactions ( 6.1 )] . Advise individuals to seek prompt medical evaluation if they experience depressive symptoms [see Warnings and Precautions ( 5.6 )] . Drug Interactions Inform individuals that APRETUDE may interact with other drugs and may reduce exposure of APRETUDE; therefore, advise individuals to report to their healthcare provider the use of any other prescription or nonprescription medication [see Contraindications ( 4 ), Warnings and Precautions ( 5.7 ), Drug Interactions ( 7.2 , 7.3 )] .
Label text from the FDA structured product label by ViiV Healthcare Company (revised Apr 11, 2025). Long sections are shortened; the complete label is on DailyMed.
Apretude NDC products (2)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 49702-264 | Kit | ViiV Healthcare Company | NDA |
| 49702-280 | Kit | ViiV Healthcare Company | NDA |
Frequently asked questions
What is Apretude used for?
1 INDICATIONS AND USAGE APRETUDE is indicated for pre‑exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in adults and adolescents weighing at least 35 kg who are at risk for HIV-1 acquisition. 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 [see Dosage and…
What are the side effects of Apretude?
The following adverse reactions are described below and in other sections of the labeling: • Hypersensitivity reactions [see Warnings and Precautions ( 5.4 )] • Hepatotoxicity [see Warnings and Precautions ( 5.5 )] • Depressive disorders [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (all grades) observed in at least 1% of participants receiving APRETUDE were injection… See the full label for the complete list.
Who makes Apretude?
Apretude is listed by 1 labeler in the FDA NDC directory, including ViiV Healthcare Company.