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 )
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 )
5.1Comprehensive 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 )] .
5.2Potential 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.
5.3Long-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 )] .
5.4Hypersensitivity Reactions Serious
or severe hypersensitivity reactions have been reported with cabotegravir and include Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) [see Adverse Reactions ( 6.2 )] . Administration of cabotegravir oral lead-in dosing was used in clinical studies to help identify participants who may be at risk of a hypersensitivity reaction. Remain vigilant and discontinue APRETUDE if a hypersensitivity reaction is suspected [see Dosage and Administration ( 2.4 ), Contraindications ( 4 ), Adverse Reactions ( 6 )] .
Discontinue APRETUDE 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 APRETUDE [see Warnings and Precautions ( 5.3 )] .
5.5Hepatotoxicity
Hepatotoxicity has been reported in a limited number of individuals receiving cabotegravir with or without known pre-existing hepatic disease or identifiable risk factors [see Adverse Reactions ( 6.1 )] . Clinical and laboratory monitoring should be considered and APRETUDE should be discontinued if hepatotoxicity is suspected and individuals managed as clinically indicated. For information regarding the long-acting properties of APRETUDE [see Warnings and Precautions ( 5.3 )] .
5.6Depressive Disorders
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 )] . Promptly evaluate individuals with depressive symptoms to assess whether the symptoms are related to APRETUDE and to determine whether the risks of continued therapy outweigh the be
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
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 )
7.1Use 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 )] .
7.2Potential 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 )] .
7.3Established 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.
7.4Drugs 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 )] .
Pregnancy and breastfeeding
8.1Pregnancy 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.
Adverse reactions
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.
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect rates observed in practice. Clinical Trials Experience in Adults The safety assessment of 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. The proportion of participants reporting ISRs at each visit and the severity of the ISRs generally 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 084 are presented in Table 5 . Table 5. Injection Site Reactions (All Grades) Reported in at Least 1% of Participants Who Experienced at Least One Injection Site Reaction (All Causality) with APRETUDE in Either HPTN 083 or HPTN 084 a Placebo injectable suspension: intralipid 20% fat emulsion.
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. Less Common Adverse Reactions: The following select adverse reactions (regardless of severity) occurred in <1% of participants receiving APRETUDE in HPTN 083 or HPTN 084.
Hepatobiliary Disorders: Hepatotoxicity. Investigations: Weight increase (see below). Psychiatric Disorders: Depression; suicidal ideation, and suicide attempt (these events were observed primarily in participants with a pre‑existing history of depression or other psychiatric illness). Weight Increase: At the
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
CABOTEGRAVIR 600MG/3ML (200MG/ML)
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application NDA215499.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
