Cabotegravir

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 )

2 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. 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 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 cabotegravir (or alternative oral PrEP regimen) should be taken approximately 2 months after the last injection dose of APRETUDE. Restart injection with APRETUDE on the day oral cabotegravir dosing completes or within 3 days, thereafter, as recommended in Table 3 . For oral PrEP durations greater than 2 months, an alternative regimen to oral cabotegravir 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 [see Warnings and Precautions ( 5.1 )] . If the injection dosing schedule will be continued, see Table 3 for dosing recommendations. Table 3. Injection Dosing Recommendations after Missed Injections Time since Last Injection Recommendation If second injection is missed and time since first injection is: Less than or equal to 2 months Administer 600-mg (3-mL) gluteal intramuscular injection of APRETUDE as soon as possible, then continue to follow the every-2-month injection dosing schedule. Greater than 2 months Restart with 600-mg (3-mL) gluteal intramuscular injection of APRETUDE, followed by a second 600-mg (3-mL) initiation injection dose 1 month later. Then continue to follow the every-2-month injection dosing schedule thereafter. If third or subsequent injection is missed and time since prior injection is: Less than or equal to 3 months Administer 600-mg (3-mL) intramuscular injection of APRETUDE as soon as possible, then continue with the every-2-month injection dosing schedule. Greater than 3 months Restart with 600-mg (3-mL) gluteal intramuscular injection of APRETUDE, followed by the second 600-mg (3-mL) initiation injection dose 1 month later. Then continue with the every-2-month injection dosing schedule thereafter. 2.7 Administration Instructions Refer to the Instructions for Use for complete administration instructions with illustrations. Carefully follow these instructions and ensure that the vial adaptor is used correctly when preparing the suspension for injection to avoid leakage. APRETUDE is a suspension for gluteal intramuscular injection that does not need further dilution or reconstitution. The ventrogluteal site is recommended for injection. A dorsogluteal approach (upper outer quadrant) is acceptable, if preferred by the healthcare professional. Do not administer by any other route or anatomical site. Consider the body mass index (BMI) of the individual to ensure that the needle length is sufficient to reach the gluteus muscle. Longer needle lengths (not included in the dosing kit) may be required for individuals with higher BMI (e.g., >30 kg/m 2 ) to ensure that the injection is administered intramuscularly as opposed to subcutaneously. 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]). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The APRETUDE vial has a brown tint to the glass that may limit visual inspection. Discard the vial if the medicine exhibits particulate matter or discoloration. Shake the vial vigorously so that the suspension looks uniform before injecting. Small air bubbles are expected and acceptable. 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 syringe 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 How Supplied/Storage and Handling ( 16 )].

6 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. 6.1 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 )] .

12.3 Pharmacokinetics Absorption, Distribution, and Elimination The pharmacokinetic properties of cabotegravir are provided in Table 9 . The multiple-dose pharmacokinetic parameters are provided in Table 10 . For the pharmacokinetic properties of oral cabotegravir, refer to the full prescribing information for VOCABRIA (cabotegravir). Table 9. Pharmacokinetic Properties of Cabotegravir CSF = Cerebrospinal fluid. a When taken orally with a high-fat meal versus fasted, the AUC (0-inf) (geometric mean ratio [90% CI] of cabotegravir are 1.14 [1.02, 1.28]). b The clinical relevance of CSF-to-plasma concentration ratios is unknown. Concentrations were measured at steady-state 1 week after intramuscular administration of cabotegravir extended-release injectable suspensions given monthly or every 2 months. c Elimination half-life driven by slow absorption rate from the intramuscular injection site. d Dosing in mass balance studies: single-dose oral administration of [ 14 C] cabotegravir. Absorption a T max (days), median 7 Distribution % Bound to human plasma proteins >99.8 Blood-to-plasma ratio 0.52 CSF-to-plasma concentration ratio (median [range]) b 0.003 (0.002 to 0.004) Elimination t 1/2 (weeks), mean c 5.6 to 11.5 Metabolism Metabolic pathways UGT1A1 UGT1A9 (minor) Excretion Major route of elimination Metabolism % of dose excreted as total 14 C (unchanged drug) in urine d 27 (0) % of dose excreted as total 14 C (unchanged drug) in feces d 59 (47) Table 10. Pharmacokinetic Parameters following Once-Daily Oral Cabotegravir and following Initiation and Every-2-Month Continuation Intramuscular Injections of APRETUDE IM = Intramuscular. a Pharmacokinetic parameter values were based on individual post-hoc estimates from cabotegravir population pharmacokinetic models for patients in Phase 3 treatment studies of HIV treatment. b tau is dosing interval: 24 hours for oral administration, 1 month for the initial injection, and 2 months for every 2 months for intramuscular injections of extended-release injectable suspension. c Oral lead-in pharmacokinetic parameter values represent steady state. d Initial injection C max values primarily reflect oral dosing because the initial injection was administered on the same day as the last oral dose; however, AUC (0-tau) and the C tau values reflect the initial injection. When administered without oral lead-in to recipients with HIV-1 (n = 110), the observed cabotegravir geometric mean (5th, 95th percentile) C max (1-week post‑initial injection) was 1.89 mcg/mL (0.438, 5.69) and C tau was 1.43 mcg/mL (0.403, 3.90). e Pharmacokinetic parameter values represent steady state. Dosing Phase Dosage Regimen Geometric Mean (5 th , 95 th Percentile) a AUC (0-tau) b (mcg•h/mL) C max (mcg/mL) C tau b (mcg/mL) Oral lead-in c 30 mg 145 8.0 4.6 once daily (93.5, 224) (5.3, 11.9) (2.8, 7.5) Initial injection d 600 mg IM 1,591 8.0 1.5 initial dose (714; 3,245) (5.3, 11.9) (0.65, 2.9) Every-2-month injection e 600 mg IM 3,764 4.0 1.6 every 2 months (2,431; 5,857) (2.3, 6.8) (0.8, 3.0) Specific Populations No clinically significant differences in the pharmacokinetics of cabotegravir were observed based on age, sex, race/ethnicity, BMI, or UGT1A1 polymorphisms. There are no data available for the use of cabotegravir in participants with hepatitis B virus and hepatitis C virus co-infection in PrEP studies. Renal Impairment: With oral cabotegravir, no clinically significant differences in the pharmacokinetics of cabotegravir are expected in individuals with mild, moderate, or severe renal impairment. Cabotegravir has not been studied in participants with end-stage renal disease not on dialysis. As cabotegravir is >99% protein bound, dialysis is not expected to alter exposures of cabotegravir [see Use in Specific Populations ( 8.6 )] . Hepatic Impairment: No clinically significant differences in the pharmacokinetics of cabotegravir are expected in mild to moderate (Child-Pugh A or B) hepatic impairment. The effect of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of cabotegravir has not been studied [see Use in Specific Populations ( 8.7 )] . Gender: Population pharmacokinetic analyses revealed no clinically relevant effect of gender on the exposure of cabotegravir. In addition, no clinically relevant differences in plasma cabotegravir concentrations were observed in PrEP studies by gender, including in cisgender men and transgender women (+/- hormone use). Therefore, no dose adjustment is necessary based on gender. Geriatrics: No dose adjustment is required in elderly individuals. There are limited data available on the use of cabotegravir in individuals aged 65 years and older. In general, caution should be exercised in administration of cabotegravir in elderly individuals, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy [see Use in Specific Populations ( 8.5 )] . Pediatrics: Population pharmacokinetic analyses revealed no clinically relevant differences in exposure between adolescent participants and adult participants with and without HIV-1 from the cabotegravir development program; therefore, no dosage adjustment is needed for adolescents weighing ≥35 kg ( Table 11 ). Table 11. Pharmacokinetic Parameters following Once-Daily Oral Cabotegravir and following Initiation and Every-2-Month Continuation Intramuscular Injections of APRETUDE in Adolescent Participants Aged 12 to Younger than 18 Years (≥35 kg) IM = intramuscular. a Pharmacokinetic parameter values were based on individual post-hoc estimates from population pharmacokinetic models in both adolescents with HIV-1 (n = 147) weighing 35.2 to 98.5 kg and adolescents without HIV-1 (n = 62) weighing 39.9 to 167 kg. b tau is dosing interval: 24 hours for oral administration, 1 month for the initial injection, and 2 months for every 2 months for intramuscular injections of extended-release injectable suspension. c Oral lead-in pharmacokinetic parameter values represent steady state. d Initial injection C max values primarily reflect oral dosing because the initial injection was administered on the same day as the last oral dose; however, the AUC (0-tau) and C tau values reflect the initial injection. e Pharmacokinetic parameter values represent steady state. Dosing Phase Dosage Regimen Geometric Mean (5 th , 95 th Percentile) a AUC (0-tau) b (mcg•h/mL) C max (mcg/mL) C tau b (mcg/mL) Oral lead-in c 30 mg 203 10.7 6.43 once daily (136, 320) (7.36, 16.6) (4.15, 10.5) Initial injection d 600 mg IM 2,085 10.8 1.88 initial dose (1,056; 4,259) (7.42, 16.6) (0.801, 3.71) Every-2-month injection e 600 mg IM 5,184 5.10 2.54 every 2 months (3,511; 7,677) (3.06, 8.24) (1.25, 4.19) Drug Interaction Studies Cabotegravir is not a clinically relevant inhibitor of the following enzymes and transporters: cytochrome P450 (CYP)1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4; UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B15, and 2B17; P-glycoprotein (P‑gp); breast cancer resistance protein (BCRP); bile salt export pump (BSEP); organic cation transporter (OCT)1, OCT2; organic anion transporter polypeptide (OATP)1B1, OATP1B3; multidrug and toxin extrusion transporter (MATE) 1, MATE 2-K; and multidrug resistance protein (MRP)2 or MRP4. In vitro, cabotegravir inhibited renal OAT1 (IC 50 = 0.81 microM) and OAT3 (IC 50 = 0.41 microM). Based on physiologically based pharmacokinetic (PBPK) modeling, cabotegravir may increase the AUC of OAT1/3 substrates up to approximately 80%. In vitro, cabotegravir did not induce CYP1A2, CYP2B6, or CYP3A4. ‎ Simulations using PBPK modeling show that no clinically significant interaction is expected during coadministration of cabotegravir with drugs that inhibit UGT1A1. In vitro, cabotegravir was not a substrate of OATP1B1, OATP1B3, OATP2B1, or OCT1. Cabotegravir is a substrate of P-gp and BCRP in vitro; however, because of its high permeability, no alteration in cabotegravir absorption is expected with coadministration of P-gp or BCRP inhibitors. Drug interaction studies were not conducted with injectable cabotegravir. Drug interaction studies with oral cabotegravir are summarized in Tables 12 and 13 . Table 12. Effect of Coadministered Drugs on the Pharmacokinetics of Cabotegravir n = Maximum number of participants with data, CI = Confidence Interval. Coadministered Drug(s) and Dose(s) Dose of Cabotegravir n Geometric Mean Ratio (90% CI) of Cabotegravir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00 C max AUC C tau or C 24 Etravirine 30 mg 12 1.04 1.01 1.00 200 mg twice daily once daily (0.99, 1.09) (0.96, 1.06) (0.94, 1.06) Rifabutin 30 mg 12 0.83 0.77 0.74 300 mg once daily once daily (0.76, 0.90) (0.74, 0.83) (0.70, 0.78) Rifampin 30-mg 15 0.94 0.41 0.50 600 mg once daily single dose (0.87, 1.02) (0.36, 0.46) (0.44, 0.57) Rilpivirine 30 mg 11 1.05 1.12 1.14 25 mg once daily once daily (0.96, 1.15) (1.05, 1.19) (1.04, 1.24) Table 13. Effect of Cabotegravir on the Pharmacokinetics of Coadministered Drugs n = Maximum number of participants with data, CI = Confidence Interval; NA = Not available. Coadministered Drug(s) and Dose(s) Dose of Cabotegravir n Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Cabotegravir No Effect = 1.00 C max AUC C tau or C 24 Ethinyl estradiol 30 mg 19 0.92 1.02 1.00 0.03 mg once daily once daily (0.83, 1.03) (0.97, 1.08) (0.92, 1.10) Levonorgestrel 30 mg 19 1.05 1.12 1.07 0.15 mg once daily once daily (0.96, 1.15) (1.07, 1.18) (1.01, 1.15) Midazolam 30 mg 12 1.09 1.10 NA 3 mg once daily (0.94, 1.26) (0.95, 1.26) Rilpivirine 30 mg 11 0.96 0.99 0.92 25 mg once daily once daily (0.85, 1.09) (0.89, 1.09) (0.79, 1.07)