Apretude Drug Information

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 . 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.

• 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. 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. Injection Site Reactions HPTN 083 HPTN 084 APRETUDE (n = 1,740) TRUVADA a (n = 724) APRETUDE (n = 578) TRUVADA a (n = 166) Pain/tenderness 98% 95% 90% 87% Nodules 15% 2% 14% 2% Induration 15% <1% 12% 2% Swelling 12% 1% 18% 3% Bruising 4% 4% 1% 0 Erythema 4% 2% 5% 2% Pruritus 3% 3% 6% 11% Warmth 3% 1% <1% 0 Anesthesia 1% 2% 1% 2% Abscess <1% 0 2% 3% Discoloration <1% 0 1% 0 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. 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 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. Laboratory Abnormalities: Grade 3 or 4 post-baseline maximum toxicity laboratory abnormalities for HPTN 083 or HPTN 084 are summarized in Table 6 . Table 6. Laboratory Abnormalities (Grades 3 to 4) in ≥1% of Participants in Either HPTN 083 or HPTN 084 ALT = Alanine transaminase, ULN = upper limit of normal, AST = Aspartate aminotransferase. Laboratory Parameter 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) ALT (≥5.0 x ULN) 2% 2% <1% 1% AST (≥5.0 x ULN) 3% 3% <1% <1% Creatine phosphokinase (≥10.0 x ULN) 15% 14% 2% 2% Lipase (≥3.0 x ULN) 3% 3% <1% <1% Creatinine (>1.8 x ULN) or increase to ≥1.5 x baseline) 3% 3% 5% 4% Serum Lipids: Changes from baseline to Month 15 in total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and total cholesterol to HDL ratio in HPTN 083 and HPTN 084 are presented in Table 7 . Table 7. Fasting Lipid Values, Median Change from Baseline a at Week 57, Reported in HPTN 083 and HPTN 084 a Nearly 60% of participants with baseline data available had Week 57 data available in both arms of both trials. Within each trial, baseline values were comparable among participants receiving APRETUDE and TRUVADA. HPTN 083 HPTN 084 APRETUDE TRUVADA APRETUDE TRUVADA Total cholesterol (mg/dL) +1.0 -10.0 +0.2 -3.9 LDL cholesterol (mg/dL) +1.0 -6.0 -1.1 -5.0 HDL cholesterol (mg/dL) -0.2 -3.0 -0.8 -2.6 Triglycerides (mg/dL) +2.7 0.0 +3.1 +0.7 Total cholesterol: HDL cholesterol ratio +0.1 +0.0 +0.1 +0.1 Clinical Trials Experience in Adolescents 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 [see Use in Specific Populations ( 8.4 )]. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of APRETUDE or cabotegravir-containing regimens. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders Hypersensitivity reactions (including angioedema and urticaria) [see Warnings and Precautions ( 5.4 )] . Skin and Subcutaneous Tissue Disorders Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) [see Warnings and Precautions ( 5.4 )] .

• 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 )] .

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 . 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 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 . 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. The safety, efficacy, and pharmacokinetics of APRETUDE in pediatric participants younger than 12 years of age or weighing <35 kg have not been established.

• 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 )

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 .