APRETUDE

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

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 )

• 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 )].

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 )

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 )] .