Vocabria

6 ADVERSE REACTIONS The following adverse reactions are described below and in other sections of the labeling: • Hypersensitivity reactions [see Warnings and Precautions ( 5.2 )] • Hepatotoxicity [see Warnings and Precautions ( 5.3 )] • Depressive disorders [see Warnings and Precautions ( 5.4 )] • In HIV-1–infected patients, the most common adverse reactions observed in at least 3 subjects receiving VOCABRIA were fatigue, headache, diarrhea, nausea, dizziness, abnormal dreams, anxiety, insomnia, abdominal discomfort, abdominal distension, and asthenia. ( 6.1 ) • In HIV-1–uninfected individuals receiving VOCABRIA, the most common adverse reactions reported in ≥1% were headache, diarrhea, nausea, dizziness, upper respiratory tract infection, somnolence, fatigue, abnormal dreams, and abdominal pain. ( 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. See full prescribing information for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) for additional safety information. Since VOCABRIA is taken in combination with EDURANT tablets, the prescribing information for EDURANT (rilpivirine) should be consulted for relevant information on rilpivirine. Adverse Reactions of VOCABRIA in Clinical Trials for the Treatment of HIV-1 Infection Clinical Trials Experience in Adults: The safety assessment of VOCABRIA for oral lead-in therapy prior to therapy with CABENUVA is based on the analysis of 48-week data from virologically suppressed subjects with HIV-1 infection in 3 international, multicenter, open-label trials, where 590 of 1,182 subjects received oral lead-in within the pivotal trials FLAIR and ATLAS (pooled analysis) and 655 of 1,045 subjects received oral lead-in within ATLAS-2M [see Clinical Studies ( 14.1 )] . Adverse reactions were reported following exposure to VOCABRIA tablets and EDURANT tablets administered in combination as oral lead-in therapy (median time exposure: 5.3 weeks). Adverse reactions included those attributable to the oral formulation of cabotegravir and rilpivirine administered as a combination regimen. Refer to the prescribing information for EDURANT for other adverse reactions associated with oral rilpivirine. The most common adverse reactions during the oral lead-in period in the pooled analyses of FLAIR and ATLAS at Week 48 were headache, nausea, abnormal dreams, anxiety, and insomnia, all of which occurred in at least 3 subjects with an incidence ≤1%. The most common adverse reactions during the oral lead-in period for ATLAS-2M were fatigue, diarrhea, headache, nausea, dizziness, abdominal discomfort, abdominal distension, insomnia, and asthenia, all of which occurred in at least 3 subjects across both arms, with an incidence ≤2%. During the oral lead-in period for FLAIR and ATLAS, 6 (1%) subjects discontinued due to adverse events, including asthenia, myalgia, depression suicidal, and headache. During the oral lead-in period for ATLAS-2M, 4 (<1%) subjects discontinued due to adverse events, including asthenia, skin lesion, fatigue, transaminases increased, and depression. In the extension phase of the FLAIR study at Week 124, the overall safety profile was consistent with that observed at Week 48 and when injection therapy with CABENUVA was initiated directly without the oral lead-in phase. Clinical Trial Experience in Adolescents: Based on data from the Week 16 analysis of the MOCHA study in 8 adolescents (aged 12 to younger than 18 years and weighing ≥35 kg) receiving background antiretroviral therapy, the safety profile during the oral lead-in period in adolescents was consistent with the safety profile established with cabotegravir in adults. Adverse Reactions of VOCABRIA in Clinical Trials for HIV-1 PrEP Clinical Trial Experience in Adults: In trial HPTN 083, adverse reactions were reported while participants were on blinded study product following exposure to VOCABRIA tablets as oral lead-in for HIV-1 PrEP (median time exposure: 4.1 weeks). The most common adverse reactions reported at ≥1% during the oral lead-in period were diarrhea (4% and 4%), nausea (3% and 5%), dizziness (2% and 2%), headache (2% and 2%), fatigue (1% and 2%), and abnormal dreams (1% and 2%) for VOCABRIA and TRUVADA (emtricitabine and tenofovir disoproxil fumarate), respectively. During the oral lead-in period, 24 (1%) participants receiving VOCABRIA discontinued due to adverse events, including increased alanine aminotransferase, increased aspartate aminotransferase, suicide attempt, and dizziness, which were observed in ≥2 participants. In Trial HPTN 084, adverse reactions were reported while participants were on blinded study product following exposure to VOCABRIA tablets as oral lead-in for HIV-1 PrEP (median time exposure: 4.1 weeks). The most common adverse reactions reported at ≥1% during the oral lead-in period were headache (6% and 7%), nausea (3% and 7%), dizziness (3% and 4%), diarrhea (2% and 4%), upper respiratory tract infection (2% and 2%), somnolence (2% and 1%), fatigue (1% and 2%), abdominal pain (1% and 1%), vomiting (<1% and 3%), decreased appetite (<1% and 2%), and pruritus (<1% and 1%) for VOCABRIA and TRUVADA, respectively. During the oral lead-in period, 4 (<1%) participants receiving VOCABRIA discontinued due to adverse events of increased alanine aminotransferase (n = 3) and sleep disorders (n = 1). Clinical Trials Experience in Adolescents: In adolescents receiving VOCABRIA for HIV-1 PrEP, the safety data were comparable to the safety data reported in adults receiving VOCABRIA 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 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 (5.2)] .

4 CONTRAINDICATIONS Treatment of HIV-1 Infection VOCABRIA is contraindicated in patients: • with previous hypersensitivity reaction to cabotegravir [see Warnings and Precautions ( 5.2 )] . • 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 loss of virologic response [see Drug Interactions ( 7.2 , 7.3 ), Clinical Pharmacology ( 12.3 )] : o Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin o Antimycobacterials: Rifampin, rifapentine Prior to initiation of VOCABRIA, note that use of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) with rifabutin is contraindicated. Since VOCABRIA is taken in combination with EDURANT tablets, the prescribing information for EDURANT should be consulted for additional contraindications. HIV-1 Pre-Exposure Prophylaxis VOCABRIA is contraindicated in individuals: • with unknown or positive HIV-1 status [see Warnings and Precautions ( 5.1 )] . • with previous hypersensitivity reaction to cabotegravir [see Warnings and Precautions ( 5.2 )] . • receiving the following coadministered drugs for which significant decreases in cabotegravir plasma concentrations may occur due to UGT1A1 enzyme induction, which may result in loss of efficacy [see Drug Interactions ( 7.2 , 7.3 ), Clinical Pharmacology ( 12.3 )] : o Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin o Antimycobacterials: Rifampin, rifapentine • Previous hypersensitivity reaction to cabotegravir. ( 4 ) • Coadministration with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, and rifapentine. ( 4 ) • Positive HIV-1 status for HIV-1 PrEP. ( 4 )

11 DESCRIPTION VOCABRIA contains cabotegravir, as cabotegravir sodium, an HIV integrase strand transfer inhibitor (INSTI). The chemical name of cabotegravir sodium is sodium ( 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 16 F 2 N 3 NaO 5 and the molecular weight is 427.34 g/mol. It has the following structural formula: Cabotegravir sodium is a white to almost white crystalline solid that is slightly soluble in water. Each immediate-release film-coated tablet of VOCABRIA for oral administration contains 30 mg of cabotegravir (equivalent to 31.62 mg cabotegravir sodium) and the inactive ingredients: hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablet film-coating contains hypromellose, polyethylene glycol, and titanium dioxide. Cabotegravir sodium chemical structure

2 DOSAGE AND ADMINISTRATION • One tablet of VOCABRIA 30 mg taken orally once daily in combination with 1 tablet of EDURANT 25 mg taken orally once daily with a meal: • for approximately 1 month if oral lead-in is used for HIV-1 treatment. ( 2.1 ) • for up to 2 months to replace up to 2 consecutive missed monthly injections of CABENUVA ( 2.2 ) Refer to 2.1 for dosing recommendations for missed injections. ( 2.1 ) • HIV-1 Screening: Screen all individuals for HIV-1 infection prior to initiating VOCABRIA and APRETUDE for HIV-1 PrEP and at least once every 3 months while taking APRETUDE. ( 2.2 ) • One tablet of VOCABRIA 30 mg taken orally once daily for approximately 1 month if oral lead-in is used for HIV-1 PrEP. Refer to 2.2 for dosing recommendations for missed injections. ( 2.2 ) 2.1 Treatment of HIV-1 Infection in Adults and Adolescents 12 Years of Age and Older and Weighing at Least 35 kg Oral Lead-in Dosing to Assess Tolerability of Cabotegravir Consult the prescribing information for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) before initiating VOCABRIA to ensure therapy with CABENUVA is appropriate. See full prescribing information for CABENUVA. Oral lead-in may be used to assess the tolerability of cabotegravir prior to the initiation of CABENUVA. The recommended oral lead-in daily dose is one 30-mg tablet of VOCABRIA with one 25-mg tablet of EDURANT for approximately 1 month (at least 28 days). The last oral dose should be taken on the same day injections with CABENUVA are started. Take VOCABRIA once daily with EDURANT at approximately the same time each day with a meal [see Clinical Pharmacology ( 12.3 )] . Because VOCABRIA is indicated in combination with EDURANT tablets, the prescribing information for EDURANT should also be consulted. Recommended Oral Dosing to Replace Planned Missed Injections of CABENUVA Planned Missed Injections for Patients on the Monthly Dosing Schedule: If a patient plans to miss a monthly scheduled injection of CABENUVA by more than 7 days, take daily oral therapy for up to 2 months to replace missed injection visits. For oral therapy with VOCABRIA and EDURANT, the recommended oral daily dose is one 30‑mg tablet of VOCABRIA and one 25-mg tablet of EDURANT. Take VOCABRIA with EDURANT at approximately the same time each day with a meal. The first dose of oral therapy should be taken 1 month (+/-7 days) after the last injection dose of CABENUVA and continued until the day injection dosing is restarted. For oral therapy with VOCABRIA and EDURANT of durations greater than 2 months, an alternative oral regimen is recommended. See full prescribing information for CABENUVA to resume monthly injection dosing. Planned Missed Injections for Patients on the Every-2-Month Dosing Schedule: If a patient plans to miss a scheduled every-2-month injection of CABENUVA by more than 7 days, take daily oral therapy for up to 2 months to replace 1 missed scheduled every-2-month injection. For oral therapy with VOCABRIA and EDURANT of durations greater than 2 months, the recommended oral daily dose is one 30-mg tablet of VOCABRIA and one 25-mg tablet of EDURANT. Take VOCABRIA with EDURANT at approximately the same time each day with a meal. The first dose of oral therapy should be taken approximately 2 months after the last injection dose of CABENUVA and continued until the day injection dosing is restarted. For oral therapy with VOCABRIA and EDURANT of durations greater than 2 months, an alternative oral regimen is recommended. See full prescribing information for CABENUVA to resume every-2-month injection dosing. 2.2 HIV-1 Pre-Exposure Prophylaxis in Adults and Adolescents Weighing at Least 35 kg HIV-1 Screening for Individuals for HIV-1 PrEP Individuals must be tested for HIV-1 infection prior to initiating VOCABRIA and APRETUDE for HIV-1 PrEP, 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 VOCABRIA or APRETUDE administration [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . Oral Lead-in Dosing to Assess Tolerability of Cabotegravir for HIV-1 PrEP Consult the prescribing information for APRETUDE before initiating VOCABRIA to ensure use of APRETUDE is appropriate. See full prescribing information for APRETUDE. Oral lead-in may be used to assess the tolerability of cabotegravir prior to the initiation of APRETUDE. The recommended oral daily dose is one 30-mg tablet of VOCABRIA for approximately 1 month (at least 28 days). Following oral lead-in, start initiation injection of APRETUDE on the last day of oral lead-in or within 3 days. Oral Dosing to Replace a Planned Missed Injection of APRETUDE (One Every-2-Month Injection) If an individual plans to miss a scheduled injection of APRETUDE by more than 7 days, take daily oral VOCABRIA to replace one every 2-month injection visit. The recommended oral daily dose is one 30-mg tablet of VOCABRIA. The first dose of oral VOCABRIA should be taken approximately 2 months after the last injection dose of APRETUDE. Restart injection with APRETUDE on the day oral dosing completes or within 3 days. See full prescribing information for APRETUDE to resume every-2-month injection dosing.

1 INDICATIONS AND USAGE HIV-1 Treatment: VOCABRIA is an HIV-1 integrase strand transfer inhibitor (INSTI) indicated in combination with EDURANT (rilpivirine) for short-term treatment of HIV-1 infection in adults and adolescents 12 years of age and older and weighing at least 35 kg who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine. ( 1.1 ) HIV-1 Pre-Exposure Prophylaxis: VOCABRIA is indicated in at-risk adults and adolescents weighing at least 35 kg for short-term pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Individuals must have a negative HIV-1 test prior to initiating VOCABRIA for HIV-1 PrEP. ( 1.2 ) VOCABRIA may be used as: • oral lead-in to assess the tolerability of cabotegravir prior to administration of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) for HIV-1 treatment or APRETUDE (cabotegravir extended-release injectable suspension) for HIV-1 PrEP. ( 1.1 , 1.2 ) • oral therapy for patients who will miss planned injection dosing with CABENUVA for HIV-1 treatment or APRETUDE for HIV-1 PrEP. ( 1.1 , 1.2 ) 1.1 Treatment of HIV-1 Infection VOCABRIA is indicated in combination with EDURANT (rilpivirine) tablets for short-term treatment of HIV-1 infection in adults and adolescents 12 years of age and older and weighing at least 35 kg who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine, for use as [see Microbiology ( 12.4 ), Clinical Studies ( 14.1 )] : • oral lead-in to assess the tolerability of cabotegravir prior to administration of cabotegravir extended-release injectable suspension, a component of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension). • oral therapy for patients who will miss planned injection dosing with CABENUVA. 1.2 HIV-1 Pre-Exposure Prophylaxis VOCABRIA is indicated in at-risk adults and adolescents weighing at least 35 kg for short-term pre exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Individuals must have a negative HIV-1 test prior to initiating VOCABRIA for HIV-1 PrEP. VOCABRIA may be used as [see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), Clinical Studies ( 14.2 )] : • oral lead-in to assess the tolerability of cabotegravir prior to administration of APRETUDE (cabotegravir extended-release injectable suspension). • oral PrEP for patients who will miss planned injection dosing with APRETUDE.

10 OVERDOSAGE There is no known specific treatment for overdose with VOCABRIA. If overdose occurs, monitor the patient and apply standard supportive treatment as required as well as observation of the clinical status of the individual. As cabotegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

7 DRUG INTERACTIONS • Refer to the full prescribing information for important drug interactions with VOCABRIA. ( 4 , 5.5 , 7 ) • VOCABRIA in combination with EDURANT is a complete regimen for HIV-1 treatment. Coadministration with other antiretroviral medications for PrEP is not recommended. ( 7.1 ) • Drugs that induce uridine diphosphate glucuronosyltransferase (UGT)1A1 may decrease the plasma concentrations of cabotegravir. ( 4 , 7.2 , 7.3 ) 7.1 Concomitant Use with Other Antiretroviral Medicines VOCABRIA in combination with EDURANT (rilpivirine) is a complete regimen for the treatment of HIV-1 infection. Refer to the prescribing information for EDURANT for relevant information on rilpivirine. Coadministration of VOCABRIA with other antiretroviral medications for PrEP is not recommended [see Drug Interactions ( 7.4 ), Clinical Pharmacology ( 12.3 )] . Prior to initiating dosing with VOCABRIA, the prescribing information for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) or APRETUDE should be consulted to ensure use of CABENUVA or APRETUDE will be appropriate for either the treatment of HIV-1 infection or HIV-1 PrEP, respectively. 7.2 Potential for Other Drugs to Affect VOCABRIA Cabotegravir is primarily metabolized by UGT1A1 with some contribution from UGT1A9. Drugs that are strong inducers of UGT1A1 or UGT1A9 are expected to decrease cabotegravir plasma concentrations and may result in loss of efficacy; therefore, coadministration of VOCABRIA with these drugs is contraindicated [see Contraindications ( 4 )] . Coadministration of oral cabotegravir with polyvalent cation-containing products may lead to decreased absorption of cabotegravir [see Drug Interactions ( 7.3 )] . 7.3 Established and Other Potentially Significant Drug Interactions Information regarding potential drug interactions with cabotegravir are provided in Table 1 . These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of the interaction and potential for loss of efficacy [see Contraindications ( 4 ), Warnings and Precautions ( 5.5 ), Clinical Pharmacology ( 12.3 )] . Table 1 includes potentially significant interactions but is not all inclusive. Refer to the prescribing information for EDURANT (rilpivirine) for established or potentially significant interactions that should be considered during concomitant administration of VOCABRIA and EDURANT for HIV-1 treatment. Table 1. Drug Interactions with VOCABRIA ↓ = Decrease. a Rifabutin can be coadministered with cabotegravir; however, it is contraindicated with CABENUVA for HIV-1 treatment. Dosage modification is recommended with APRETUDE for HIV-1 PrEP. Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment Antacids containing polyvalent cations (e.g., aluminum or magnesium hydroxide, calcium carbonate) ↓Cabotegravir Administer antacid products at least 2 hours before or 4 hours after taking VOCABRIA. Anticonvulsants: Carbamazepine Oxcarbazepine Phenobarbital Phenytoin ↓Cabotegravir Coadministration is contraindicated with VOCABRIA due to potential for loss of efficacy and development of resistance [see Contraindications ( 4 )] . Antimycobacterials a : Rifampin Rifapentine ↓Cabotegravir Antimycobacterial: Rifabutin ↓Cabotegravir Dose modification is not required for VOCABRIA. Dose modification is recommended for APRETUDE for HIV-1 PrEP. Coadministration is contraindicated with CABENUVA for HIV-1 treatment. 7.4 Drugs without Clinically Significant Interactions with Cabotegravir Based on drug interaction study results, the following drugs can be coadministered with cabotegravir without a dose adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, rifabutin, and rilpivirine [see Clinical Pharmacology ( 12.3 )] . Prior to initiating oral therapy, note that use of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) with rifabutin is contraindicated for the treatment of HIV-1 infection. Dosage modification is recommended when APRETUDE is used with rifabutin for HIV-1 PrEP.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Cabotegravir is an HIV-1 antiretroviral drug [see Microbiology ( 12.4 )] . 12.2 Pharmacodynamics Cardiac Electrophysiology At a dose of cabotegravir 150 mg orally every 12 hours (10 times the recommended total daily oral lead-in dosage of VOCABRIA), the QT interval is not prolonged to any clinically relevant extent. Administration of 3 doses of cabotegravir 150 mg orally every 12 hours resulted in a geometric mean C max approximately 2.8-fold above the geometric mean steady-state C max associated with the recommended 30-mg dose of oral cabotegravir. For additional QT information related to the injectable formulations of cabotegravir and rilpivirine (CABENUVA), the injectable formulation of cabotegravir (APRETUDE), and the oral formulation of rilpivirine (EDURANT), refer to the prescribing information for CABENUVA, APRETUDE, and EDURANT. 12.3 Pharmacokinetics Absorption, Distribution, and Elimination The pharmacokinetic properties of cabotegravir are provided in Table 2 . The multiple-dose pharmacokinetic parameters are provided in Table 3 . Table 2. Pharmacokinetic Properties of Cabotegravir CSF = Cerebrospinal fluid. a Geometric mean ratio (fed/fasted) in pharmacokinetic parameters and 90% confidence interval. High‑calorie/high-fat meal = 870 kcal, 53% fat. b Dosing in mass balance studies: single-dose oral administration of [ 14 C] cabotegravir. Absorption T max (h), median 3 Effect of high-fat meal (relative to fasting): 1.14 AUC (0-inf) ratio a (1.02, 1.28) 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 (h), mean 41 Metabolism Metabolic pathways UGT1A1 UGT1A9 (minor) Excretion Major route of elimination Metabolism % of dose excreted as total 14 C (unchanged drug) in urine b 27 (0) % of dose excreted as total 14 C (unchanged drug) in feces b 59 (47) Table 3. Multiple-Dose Pharmacokinetic Parameters of Oral Cabotegravir in Adults a Pharmacokinetic parameter values were based on individual post-hoc estimates from the final population pharmacokinetic model for subjects receiving 30 mg of oral cabotegravir once daily in FLAIR and ATLAS trials. b tau is dosing interval: 24 hours for oral cabotegravir. Parameter Geometric Mean (5 th , 95 th Percentile) a C max (mcg/mL) 8.0 (5.3, 11.9) AUC (0-tau) (mcg•h/mL) b 145 (93.5, 224) C tau (mcg/mL) b 4.6 (2.8, 7.5) Specific Populations No clinically significant differences in the pharmacokinetics of cabotegravir were observed based on age, sex, race/ethnicity, body mass index, or UGT1A1 polymorphisms. The effect of hepatitis B and C virus co-infection on the pharmacokinetics of cabotegravir is unknown. Renal Impairment: No clinically significant differences in the pharmacokinetics of cabotegravir are expected with mild, moderate, or severe renal impairment. Cabotegravir has not been studied in patients 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 cisgender men and transgender women (+/-hormone use). Therefore, no dose adjustment is necessary based on gender. Geriatric Patients: 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 )] . Pediatric Patients: Population pharmacokinetic analyses revealed no clinically relevant differences in exposure between HIV-1–infected adolescents (weighing ≥35 kg) and HIV-1–infected and uninfected adult participants from the cabotegravir development program; therefore, no dosage adjustment is needed for adolescents weighing ≥35 kg ( Table 4 ). Table 4. Predicted Pharmacokinetic Parameters following Once-Daily Oral Cabotegravir in Adolescents Aged 12 to Younger than 18 Years (≥35 kg) a Pharmacokinetic parameter values were based on population pharmacokinetic model simulations in a virtual HIV-1–infected adolescent population weighing 35 to 156 kg. b tau is dosing interval: 24 hours for oral administration. Parameter Geometric Mean (5 th , 95 th Percentile) a C max (mcg/mL) 14.4 (8.02, 25.5) AUC (0-tau) (mcg•h/mL) b 193 (106, 346) C tau (mcg/mL) b 5.79 (2.48,12.6) 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. The effects of coadministered drugs on the exposure of cabotegravir are summarized in Table 5 , and the effects of cabotegravir on the exposure of coadministered drugs are summarized in Table 6 . Table 5. Effect of Coadministered Drugs on the Pharmacokinetics of Cabotegravir 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) n = Maximum number of subjects with data, CI = Confidence Interval. Table 6. Effect of Cabotegravir on the Pharmacokinetics of Coadministered Drugs 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) n = Maximum number of subjects with data, CI = Confidence Interval, NA = Not available. 12.4 Microbiology Mechanism of Action Cabotegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration that is essential for the HIV replication cycle. The mean 50% inhibitory concentration (IC 50 ) value of cabotegravir in a strand transfer assay using purified recombinant HIV-1 integrase was 3.0 nM. Antiviral Activity in Cell Culture Cabotegravir exhibited antiviral activity against laboratory strains of HIV-1 (subtype B, n = 4) with mean 50 percent effective concentration (EC 50 ) values of 0.22 to 1.7 nM in peripheral blood mononuclear cells (PBMCs) and 293 cells. Cabotegravir demonstrated antiviral activity in PBMCs against a panel of 24 HIV-1 clinical isolates (3 in each of group M subtypes A, B, C, D, E, F, and G and 3 in group O) with a median EC 50 value of 0.19 nM (range: 0.02 to 1.06 nM, n = 24). The median EC 50 value against subtype B clinical isolates was 0.05 nM (range: 0.02 to 0.50 nM, n = 3). Against clinical HIV-2 isolates, the median EC 50 value was 0.12 nM (range: 0.10 to 0.14 nM, n = 3). In cell culture, cabotegravir was not antagonistic in combination with the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine, or the nucleoside reverse transcriptase inhibitors (NRTIs) emtricitabine (FTC), lamivudine (3TC), or tenofovir disoproxil fumarate (TDF). Resistance Cell Culture: Cabotegravir-resistant viruses were selected during passage of HIV-1 strain IIIB in MT-2 cells in the presence of cabotegravir. Amino acid substitutions in integrase that emerged and conferred decreased susceptibility to cabotegravir included Q146L (fold change: 1.3 to 4.6), S153Y (fold change: 2.8 to 8.4), and I162M (fold change: 2.8). The integrase substitution T124A also emerged alone (fold change: 1.1 to 7.4 in cabotegravir susceptibility), in combination with S153Y (fold change: 3.6 to 6.6 in cabotegravir susceptibility) or I162M (2.8-fold change in cabotegravir susceptibility). Cell culture passage of virus harboring integrase substitutions Q148H, Q148K, or Q148R selected for additional substitutions (C56S, V72I, L74M, V75A, T122N, E138K, G140S, G149A, and M154I), with substituted viruses having reduced susceptibility to cabotegravir of 2.0- to 410-fold change. The combinations of E138K+Q148K and V72I+E138K+Q148K conferred the greatest reductions of 53- to 260-fold change and 410-fold change, respectively. Clinical Trials: Treatment of HIV-1 Infection: In the pooled Phase 3 FLAIR (Week 124) and ATLAS (Week 96) analysis, there were 8 confirmed virologic failures (2 consecutive HIV-1 RNA ≥200 copies/mL) on cabotegravir plus rilpivirine (8/591, 1.4%) and 8 confirmed virologic failures on current antiretroviral regimen (8/591, 1.4%). Of the 8 confirmed virologic failures in the cabotegravir plus rilpivirine arm, 7 (88%) had treatment-emergent NNRTI resistance-associated substitutions K101E, V106V/A, V108I, E138A, E138G, E138K, H221H/L, or M230L in reverse transcriptase, and 6 of them showed reduced phenotypic susceptibility to rilpivirine (range: 2- to 27-fold). One additional subject in the ATLAS Extension Switch on cabotegravir plus rilpivirine had emergent NNRTI resistance substitution E138A at Week 80 with HIV-1 RNA >50 copies/mL and <200 copies/mL. Additionally, 5 of the 8 (63%) cabotegravir plus rilpivirine confirmed virologic failures had treatment-emergent INSTI resistance-associated substitutions and reduced phenotypic susceptibility to cabotegravir: Q148R (n = 2; 5- and 9-fold decreased susceptibility to cabotegravir), G140R (n = 1; 7-fold decreased susceptibility to cabotegravir), N155H (n = 1; 3-fold decreased susceptibility to cabotegravir), or N155H+R263K (n = 1; 9-fold decreased susceptibility to cabotegravir). There was another confirmed virologic failure subject at Week 112 in FLAIR who had switched to cabotegravir plus rilpivirine direct to injection at Week 100; there were no INSTI resistance-associated substitutions detected at failure. In comparison, in the current antiretroviral regimen arm with 8 confirmed virologic failures, 2 of 7 (29%) who had post‑baseline resistance data had treatment-emergent resistance substitutions and phenotypic resistance to their antiretroviral drugs; both had treatment-emergent NRTI substitutions, M184V or I, which conferred resistance to emtricitabine or lamivudine in their regimen, and one of them also had the treatment-emergent NNRTI resistance substitution G190S, which conferred resistance to efavirenz in their regimen. In the ATLAS-2M trial, there were 11 confirmed virologic failures (2 consecutive HIV-1 RNA ≥200 copies/mL) through Week 48: 9 subjects (1.7%) in the every-2-month treatment arm and 2 subjects (0.4%) in the monthly treatment arm. Of note, 8 of the 11 (73%) subjects met confirmed virologic failure criteria at or before the Week 24 injection visit. Four of the 9 confirmed virologic failure subjects in the every-2-month arm transitioned from the oral current antiretroviral regimen arm of ATLAS into this trial. In the every-2-month treatment arm, 8 of 9 (89%) confirmed virologic failure subjects had NNRTI resistance-associated substitutions (E138E/K+V179V/I, K101E+E138A, A98G+K103N, E138K, V179I+Y188L+P225H, Y188L, K103N+E138A, or K101E) at virologic failure. Decreases in rilpivirine susceptibility for these 8 subject isolates ranged from 2- to 30-fold. Six of the 8 subjects with NNRTI resistance-associated substitutions also had INSTI resistance-associated substitutions (L74I+Q148Q/R+N155N/H (n = 2), L74I+T97A+N155H, L74I+N155H, N155H, or L74I+Q148R) at failure with cabotegravir fold changes ranging from 1- to 9-fold. The INSTI polymorphism L74I was detected at baseline in 5 of the virologic failure subjects by a HIV-1 proviral DNA assay. In the monthly treatment arm, both of the confirmed virologic failure subjects had NNRTI resistance-associated substitutions (K101E+M230L or Y188F+G190Q) at virologic failure with decreased susceptibility to rilpivirine of 17- and >119.2-fold, respectively. Both subjects also had INSTI resistance-associated substitutions (N155N/H or Q148R+E138E/K) at failure with decreased susceptibility to cabotegravir of 2- and 5-fold, respectively. Neither subject had the L74I integrase polymorphism at baseline. Genotypic Baseline Factors Associated with Virologic Failure An increased risk of cabotegravir plus rilpivirine confirmed virologic failure is associated with baseline virological factors: HIV-1 subtype A1, the presence of baseline integrase L74I polymorphism, and archived NNRTI resistance-associated substitutions. Association of Subtype A1 and Baseline L74I Polymorphism in Integrase with Cabotegravir plus Rilpivirine Virologic Failure Eight of the 18 (44%) cabotegravir plus rilpivirine confirmed virologic failures in FLAIR, ATLAS, and ATLAS-2M had HIV-1 subtype A1 with 7 of the 8 subtype A1 failures having the integrase polymorphism L74I detected at baseline and failure timepoints ( Table 7 ). There was no detectable phenotypic resistance to cabotegravir conferred by the presence of L74I at baseline. Subtype A1 is uncommon in the U.S. The presence of the integrase polymorphism L74I in subtype B commonly seen in the U.S. was not associated with virologic failure. In contrast to FLAIR and ATLAS, where all virologic failures were subtype A, A1, or AG, subtypes of the cabotegravir plus rilpivirine virologic failures in ATLAS-2M included A (n = 1), A1 (n = 3), B (n = 4), C (n = 2), and complex/A1 (n = 1). Association of Archived Baseline NNRTI Substitutions with Cabotegravir plus Rilpivirine Virologic Failure The presence of archived NNRTI resistance-associated substitutions at baseline detected using an exploratory HIV-1 proviral DNA assay was associated with a higher virologic failure rate in the every-2-month arm of ATLAS-2M and in the cabotegravir plus rilpivirine arm (monthly) of ATLAS compared to without archived NNRTI resistance-associated substitutions (Table 7). However, in clinical practice, it is unlikely baseline resistance testing will be performed on virologically suppressed patients (HIV-1 RNA <50 copies/mL). Thus, in patients with an incomplete or uncertain NNRTI treatment history, consideration should be given before starting cabotegravir plus rilpivirine treatment. Table 7. Rate of Confirmed Virologic Failure in FLAIR, ATLAS, and ATLAS-2M: Baseline a Analysis (Subtype Al, Presence of lntegrase Polymorphism L74I, and Presence of Archived NNRTI Resistance-Associated Substitutions NNRTI = Non-Nucleoside Reverse Transcriptase Inhibitor, CAB+RPV = Cabotegravir + Rilpivirine, CAR = Current Antiretroviral Regimen, RAS = resistance-associated substitutions, NA = Not available. a Baseline and/or Screening result used. b Per Standard Monogram Nomenclature Reports. Based on June 2020 Los Alamos National Library panel, the majority of HIV-1 subtype A1 was reclassified as HIV-1 subtype A6. c L74I and L74L/I mixture. d Baseline/Screening NNRTI substitutions at L100, K101, K103, V106, V108, E138, V179, Y181, Y188, G190, H221, P225, M230. FLAIR CAB+RPV N = 283 FLAIR CAR N = 283 ATLAS CAB+RPV N = 308 ATLAS CAR N = 308 ATLAS ‑ 2M Q4W N = 523 ATLAS ‑ 2M Q8W N = 522 Total confirmed virologic failures 5 4 3 4 2 9 Subtype A1 b 4/8 (50%) 1/4 (25%) 1/17 (6%) 0/21 (0%) 0/30 (0%) 4/31 (13%) +L74I c 4/5 (80%) 1/3 (33%) 1/16 (6%) 0/19 (0%) 2/28 (0%) 3/26 (12%) -L74I 0/3 (0%) 0/1 (0%) 0/1 (0%) 0/2 (0%) 0/2 (0%) 1/5 (20%) Other subtypes 2/268 (0.7%) 3/272 (1%) 2/240 (0.8%) 4/252 (1.6%) 2/409 (0.5%) 5/415 (1.2%) +L74I c 0/49 (0%) 1/43 (2.3%) 1/29 (3%) 1/39 (2.6%) 0/42 (0%) 2/48 (4%) -L74I 0/219 (2.5%) 2/229 (0.9%) 1/211 (0.5%) 3/213 (1.4%) 2/367 (0.5%) 3/367 (0.8%) Missing data 7 7 51 35 84 76 With NNRTI RAS d NA NA 3/78 (4%) 2/83 (2%) 1/128 (0.8%) 7/117 (6%) Without NNRTI RAS NA NA 0/179 (0%) 2/190 (1%) 1/310 (0.3%) 2/327 (0.6%) Missing data NA NA 51 35 84 76 HIV-1 PrEP: There were 12 incident infections and 4 prevalent infections among subjects receiving cabotegravir injection for HIV-1 PrEP in HPTN 083. Genotypic data were generated for viruses from 13 of these 16 subjects (4 subjects with prevalent infections and 9 subjects with incident infections) and phenotypic data were generated for 3 of these viruses. INSTI resistance-associated substitutions were detected in 5 viruses from subjects who achieved target plasma concentrations of cabotegravir (≥0.65 mcg/mL [1.6 μM]) and included R263K (2-fold less susceptible to cabotegravir), E138A+Q148R (6-fold less susceptible to cabotegravir), E138K+Q148K, G140A+Q148R (13-fold less susceptible to cabotegravir), and L74I+E138E/K+G140G/S+Q148R+E157Q. There were 3 incident infections and 1 prevalent infection among subjects receiving cabotegravir injection for HIV-1 PrEP in HPTN 084. All 3 incident infections occurred during periods with cabotegravir exposures below the target concentration. No variants expressing INSTI resistance-associated substitutions were detected. Cross-Resistance Cross-resistance has been observed among INSTIs. Cabotegravir had reduced susceptibility (>5-fold change) to recombinant HIV-1 strain NL432 viruses harboring the following integrase amino acid substitutions: G118R, Q148K, Q148R, T66K+L74M, E92Q+N155H, E138A+Q148R, E138K+Q148K/R, G140C+Q148R, G140S+Q148H/K/R, Y143H+N155H, and Q148R+N155H (range: 5.1- to 81-fold). The substitutions E138K+Q148K and Q148R+N155H conferred the greatest reductions in susceptibility of 81- and 61-fold, respectively. Cabotegravir was active against viruses harboring the NNRTI substitutions K103N or Y188L, or the NRTI substitutions M184V, D67N/K70R/T215Y, or V75I/F77L/F116Y/Q151M. Virologic failure isolates from cabotegravir plus rilpivirine treatment in FLAIR, ATLAS, and ATLAS-2M exhibited cross-resistance to INSTIs and NNRTIs. All confirmed virologic isolates with genotypic evidence of cabotegravir resistance had cross-resistance to elvitegravir and raltegravir but retained phenotypic susceptibility to dolutegravir and when tested bictegravir. Viruses harboring E138A+Q148R or G140A+Q148R with reduced susceptibility to cabotegravir were isolated from subjects using cabotegravir injection for HIV-1 PrEP in HPTN 083. These viruses remained susceptible to bictegravir and dolutegravir but had cross-resistance to elvitegravir and raltegravir.

12.1 Mechanism of Action Cabotegravir is an HIV-1 antiretroviral drug [see Microbiology ( 12.4 )] .

12.2 Pharmacodynamics Cardiac Electrophysiology At a dose of cabotegravir 150 mg orally every 12 hours (10 times the recommended total daily oral lead-in dosage of VOCABRIA), the QT interval is not prolonged to any clinically relevant extent. Administration of 3 doses of cabotegravir 150 mg orally every 12 hours resulted in a geometric mean C max approximately 2.8-fold above the geometric mean steady-state C max associated with the recommended 30-mg dose of oral cabotegravir. For additional QT information related to the injectable formulations of cabotegravir and rilpivirine (CABENUVA), the injectable formulation of cabotegravir (APRETUDE), and the oral formulation of rilpivirine (EDURANT), refer to the prescribing information for CABENUVA, APRETUDE, and EDURANT.

12.3 Pharmacokinetics Absorption, Distribution, and Elimination The pharmacokinetic properties of cabotegravir are provided in Table 2 . The multiple-dose pharmacokinetic parameters are provided in Table 3 . Table 2. Pharmacokinetic Properties of Cabotegravir CSF = Cerebrospinal fluid. a Geometric mean ratio (fed/fasted) in pharmacokinetic parameters and 90% confidence interval. High‑calorie/high-fat meal = 870 kcal, 53% fat. b Dosing in mass balance studies: single-dose oral administration of [ 14 C] cabotegravir. Absorption T max (h), median 3 Effect of high-fat meal (relative to fasting): 1.14 AUC (0-inf) ratio a (1.02, 1.28) 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 (h), mean 41 Metabolism Metabolic pathways UGT1A1 UGT1A9 (minor) Excretion Major route of elimination Metabolism % of dose excreted as total 14 C (unchanged drug) in urine b 27 (0) % of dose excreted as total 14 C (unchanged drug) in feces b 59 (47) Table 3. Multiple-Dose Pharmacokinetic Parameters of Oral Cabotegravir in Adults a Pharmacokinetic parameter values were based on individual post-hoc estimates from the final population pharmacokinetic model for subjects receiving 30 mg of oral cabotegravir once daily in FLAIR and ATLAS trials. b tau is dosing interval: 24 hours for oral cabotegravir. Parameter Geometric Mean (5 th , 95 th Percentile) a C max (mcg/mL) 8.0 (5.3, 11.9) AUC (0-tau) (mcg•h/mL) b 145 (93.5, 224) C tau (mcg/mL) b 4.6 (2.8, 7.5) Specific Populations No clinically significant differences in the pharmacokinetics of cabotegravir were observed based on age, sex, race/ethnicity, body mass index, or UGT1A1 polymorphisms. The effect of hepatitis B and C virus co-infection on the pharmacokinetics of cabotegravir is unknown. Renal Impairment: No clinically significant differences in the pharmacokinetics of cabotegravir are expected with mild, moderate, or severe renal impairment. Cabotegravir has not been studied in patients 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 cisgender men and transgender women (+/-hormone use). Therefore, no dose adjustment is necessary based on gender. Geriatric Patients: 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 )] . Pediatric Patients: Population pharmacokinetic analyses revealed no clinically relevant differences in exposure between HIV-1–infected adolescents (weighing ≥35 kg) and HIV-1–infected and uninfected adult participants from the cabotegravir development program; therefore, no dosage adjustment is needed for adolescents weighing ≥35 kg ( Table 4 ). Table 4. Predicted Pharmacokinetic Parameters following Once-Daily Oral Cabotegravir in Adolescents Aged 12 to Younger than 18 Years (≥35 kg) a Pharmacokinetic parameter values were based on population pharmacokinetic model simulations in a virtual HIV-1–infected adolescent population weighing 35 to 156 kg. b tau is dosing interval: 24 hours for oral administration. Parameter Geometric Mean (5 th , 95 th Percentile) a C max (mcg/mL) 14.4 (8.02, 25.5) AUC (0-tau) (mcg•h/mL) b 193 (106, 346) C tau (mcg/mL) b 5.79 (2.48,12.6) 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. The effects of coadministered drugs on the exposure of cabotegravir are summarized in Table 5 , and the effects of cabotegravir on the exposure of coadministered drugs are summarized in Table 6 . Table 5. Effect of Coadministered Drugs on the Pharmacokinetics of Cabotegravir 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) n = Maximum number of subjects with data, CI = Confidence Interval. Table 6. Effect of Cabotegravir on the Pharmacokinetics of Coadministered Drugs 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) n = Maximum number of subjects with data, CI = Confidence Interval, NA = Not available.

20230227

5

3 DOSAGE FORMS AND STRENGTHS Tablets: 30 mg. Tablets: 30 mg ( 3 )

Vocabria cabotegravir sodium CABOTEGRAVIR SODIUM CABOTEGRAVIR HYPROMELLOSE, UNSPECIFIED LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE SODIUM STARCH GLYCOLATE TYPE A CORN POLYETHYLENE GLYCOL, UNSPECIFIED TITANIUM DIOXIDE SV;CTV

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Two-year carcinogenicity studies in mice and rats were conducted with cabotegravir. In mice, no drug-related increases in tumor incidence were observed at cabotegravir exposures (AUC) up to approximately 8 times (males) and 7 times (females) higher than those in humans at the RHD. In rats, no drug-related increases in tumor incidence were observed at cabotegravir exposures up to approximately 26 times higher than those in humans at the RHD. Mutagenesis Cabotegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay. Impairment of Fertility In rats, no effects on fertility were observed at cabotegravir exposures (AUC) >20 times (male) and 28 times (female) the exposure in humans at the RHD.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Two-year carcinogenicity studies in mice and rats were conducted with cabotegravir. In mice, no drug-related increases in tumor incidence were observed at cabotegravir exposures (AUC) up to approximately 8 times (males) and 7 times (females) higher than those in humans at the RHD. In rats, no drug-related increases in tumor incidence were observed at cabotegravir exposures up to approximately 26 times higher than those in humans at the RHD. Mutagenesis Cabotegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay. Impairment of Fertility In rats, no effects on fertility were observed at cabotegravir exposures (AUC) >20 times (male) and 28 times (female) the exposure in humans at the RHD.

NDA212887

Vocabria

cabotegravir sodium

49702-248

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL NDC 49702-248-13 VOCABRIA (cabotegravir) Tablets 30 mg Rx Only Note to pharmacist: Do not cover ALERT box with pharmacy label. ALERT: Find out about medicines that should NOT be taken with VOCABRIA. 30 tablets Each tablet contains 30 mg of cabotegravir equivalent to 31.62 mg of cabotegravir sodium This package is child-resistant. Keep out of reach of children. Store below 30°C (86°F). Do not accept if membrane seal under cap is missing or broken. See prescribing information for dosage information. Mfd for: ViiV Healthcare RTP, NC 27709 by: GlaxoSmithKline RTP, NC 27709 Made in Singapore 62000000039717 Rev.11/20 Vocabria tablet 30 mg 30 count label

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Important Information for Uninfected Individuals Taking VOCABRIA for HIV-1 PrEP Advise HIV-1–uninfected individuals about the following [see Warnings and Precautions ( 5.1 )] : • VOCABRIA should be used for PrEP as part of an overall HIV-1 infection prevention strategy, including adherence to the dosing schedule and safer sex practices, including condoms, to reduce the risk of STIs. • VOCABRIA is not always effective in preventing HIV-1 acquisition [see Clinical Studies ( 14.2 )] . The time from initiation of VOCABRIA for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown. • Counsel individuals on the use of other prevention measures (e.g., knowledge of partner HIV-1 status, testing for STIs condom use). Inform individuals about and support their efforts in reducing sexual risk behavior. • VOCABRIA should be used to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV-1 negative [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . HIV-1 resistance substitutions may emerge in individuals with undiagnosed HIV-1 infection who are taking only VOCABRIA, because VOCABRIA alone does not constitute a complete regimen for HIV-1 treatment; therefore, care should be taken to minimize the risk of initiating or continuing VOCABRIA before confirming the individual is HIV-1 negative. • If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection. • 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. Hypersensitivity Reactions Advise patients to immediately contact their healthcare provider if they develop a rash. Instruct patients to immediately stop taking VOCABRIA and seek medical attention if they develop a rash associated with any of the following symptoms: fever; generally ill feeling; extreme tiredness; muscle or joint aches; blisters; oral blisters or lesions; eye inflammation; facial swelling; swelling of the eyes, lips, tongue, or mouth; difficulty breathing; and/or signs and symptoms of liver problems (e.g., yellowing of the skin or whites of the eyes; dark or tea-colored urine; pale-colored stools or bowel movements; nausea; vomiting; loss of appetite; or pain, aching, or sensitivity on the right side below the ribs). Advise patients that if hypersensitivity occurs, they will be closely monitored, laboratory tests will be ordered, and appropriate therapy will be initiated [see Warnings and Precautions ( 5.2 )] . Hepatotoxicity Inform patients that hepatotoxicity has been reported with cabotegravir [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.1 )] . Inform patients that monitoring for liver transaminases is recommended when VOCABRIA is used for HIV-1 treatment. Inform individuals that clinical and laboratory monitoring should be considered and APRETUDE should be discontinued if hepatoxicity is confirmed when VOCABRIA is used for HIV-1 PrEP [see Warnings and Precautions ( 5.3 )] . Depressive Disorders Inform patients that depressive disorders (including depressed mood, depression, mood altered, mood swings) have been reported with VOCABRIA for treatment of HIV-1. Inform patients that depressive disorders (including depression, depressed mood, persistent depressive disorder and suicide attempt) have been reported with VOCABRIA for HIV-1 PrEP. Promptly evaluate patients with severe depressive symptoms to assess whether the symptoms are related to VOCABRIA and to determine whether the risks of continued therapy outweigh the benefits [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.1 )] . Drug Interactions Inform patients that VOCABRIA may interact with other drugs and may reduce exposure of VOCABRIA; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products [see Contraindications ( 4 ), Warnings and Precautions ( 5.5 ), Drug Interactions ( 7.2 , 7.3 )] . Dosage and Administration Inform patients that it is important to take VOCABRIA once daily on a regular dosing schedule with a meal at the same time as EDURANT for HIV-1 treatment and to avoid missing doses, as this can result in development of resistance . Instruct patients that if they miss a dose of VOCABRIA to take it as soon as they remember [see Dosage and Administration ( 2.1 ), Clinical Pharmacology ( 12.3 )] . Pregnancy Registry Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to VOCABRIA during pregnancy [see Use in Specific Populations ( 8.1 )] . Lactation Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations ( 8.2 )] . Inform individuals it is recommended that women taking VOCABRIA for HIV-1 PrEP breastfeed only if the expected benefit justifies the potential risk to the infant. Trademarks are owned by or licensed to the ViiV Healthcare group of companies. The other brands listed are trademarks owned by or licensed to their respective owners and are not trademarks owned by or licensed to the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products. Manufactured for: ViiV Healthcare Durham, NC 27701 by: GlaxoSmithKline Durham, NC 27701 ©2023 ViiV Healthcare group of companies or its licensor. VCB:7PI

14 CLINICAL STUDIES 14.1 Clinical Trials in Adults for Treatment of HIV-1 Infection The use of VOCABRIA in combination with EDURANT as an oral lead-in and in patients who miss planned injections with CABENUVA was evaluated in 3 Phase 3 randomized, multicenter, active-controlled, parallel-arm, open-label, non-inferiority trials (Trial 201584: FLAIR [NCT02938520], Trial 201585: ATLAS [NCT02951052], and Trial 207966: ATLAS‑2M [NCT03299049]) in subjects who were virologically suppressed (HIV-1 RNA <50 copies/mL). Please refer to the CABENUVA prescribing information for additional information. In the FLAIR study during the Extension Phase (Week 100 to Week 124), the efficacy of CABENUVA was evaluated in subjects who switched (at Week 100) from their current antiretroviral regimen to CABENUVA, with and without an oral lead-in phase. A total of 121 subjects chose to start the treatment with oral lead-in and 111 subjects chose direct to injection. Subjects were not randomized during the Extension Phase. At Week 124, the proportion of subjects with HIV-1 RNA ≥50 copies/mL was 0.8% and 0.9% for the oral lead-in and direct to injection groups, respectively. The rates of virologic suppression (HIV-1 RNA <50 copies/mL) were similar in both the oral lead-in (93%) and direct to injection (99%) groups. 14.2 Clinical Trials in Adults for HIV-1 Pre-Exposure Prophylaxis The use of VOCABRIA as an oral lead-in and in participants who miss planned injections with APRETUDE to reduce the risk of acquiring HIV-1 infection were evaluated in 2 randomized, double-blind, controlled, multinational trials, Trial 201738 (HPTN 083 [NCT02720094]) in HIV-1–uninfected men and transgender women who have sex with men and have evidence of high-risk behavior for HIV-1 infection and Trial 201739 (HPTN 084 [NCT03164564]) in HIV-1–uninfected cisgender women at risk of acquiring HIV-1. Please refer to the APRETUDE prescribing information for additional information.

8.5 Geriatric Use Clinical trials of VOCABRIA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in administration of VOCABRIA in elderly patients, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy [see Clinical Pharmacology ( 12.3 )] .

8.4 Pediatric Use Treatment of HIV-1 Infection The safety and effectiveness of VOCABRIA have been established in adolescents aged 12 to younger than 18 years and weighing at least 35 kg, which is supported by the following: • Trials in adults [see Clinical Studies ( 14.1 )] • MOCHA (NCT03497676) trial in adolescents MOCHA Trial The safety, tolerability, and pharmacokinetics of oral and injectable cabotegravir and oral and injectable rilpivirine are being assessed in an ongoing Phase 1/2 multicenter, open-label, non-comparative study, MOCHA (IMPAACT 2017). Data are available from the Week 16 interim analysis from MOCHA. The primary objective at Week 16 was to confirm the use of the adult dose, through the evaluation of safety and pharmacokinetics, for oral and injectable cabotegravir and injectable rilpivirine in 23 HIV-1–infected virologically suppressed adolescents (aged 12 to younger than 18 years and weighing at least 35 kg) receiving background antiretroviral therapy. A total of 8 HIV-1–infected pediatric participants 12 years of age and older and weighing at least 35 kg and receiving background antiretroviral therapy received oral cabotegravir. The safety of VOCABRIA in adolescents is expected to be similar to adults, as there was no clinically significant difference in drug exposure [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 )] . Please refer to the CABENUVA prescribing information for additional information. The safety, efficacy, and pharmacokinetics of VOCABRIA have not been established in pediatric patients younger than 12 years of age or weighing <35 kg. HIV-1 Pre-Exposure Prophylaxis The safety and effectiveness of VOCABRIA for HIV-1 PrEP in at-risk adolescents weighing at least 35 kg is supported by data from 2 adequate and well-controlled trials of VOCABRIA for HIV-1 PrEP in adults with additional safety and pharmacokinetic data from studies in HIV-1–infected adults who were administered CABENUVA and in HIV-1–infected pediatric subjects who were administered separate components of CABENUVA in addition to their current antiretroviral therapy [see Dosage and Administration ( 2.2 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.2 )] . APRETUDE for HIV-1 PrEP is being evaluated in 2 open-label multicenter clinical trials in adolescent individuals. Fifty-nine adolescents have been enrolled. Of these, 54 adolescent participants received one or more injections after receiving VOCABRIA. In adolescents receiving VOCABRIA and 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 schedule [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 )]. The safety, efficacy, and pharmacokinetics of VOCABRIA in pediatric participants younger than 12 years of age or weighing <35 kg have not been established.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VOCABRIA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary There are insufficient human data on the use of VOCABRIA during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. While there are insufficient human data to assess the risk of neural tube defects (NTDs) with exposure to VOCABRIA during pregnancy, NTDs were associated with dolutegravir, another integrase inhibitor. Discuss the benefit-risk of using VOCABRIA with individuals of childbearing potential or during pregnancy. 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 risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in a United States (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 women 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) . Data Human Data: Data from a birth outcome surveillance study in Botswana showed that dolutegravir, another integrase inhibitor, was associated with increased risk of NTDs when administered at the time of conception and in early pregnancy. Data from clinical trials are insufficient to address this risk with cabotegravir. Animal Data: Cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from 15 days before cohabitation, during cohabitation, and from Gestation Days 0 to 17. There were no effects on fetal viability when fetuses were delivered by caesarean, although a minor decrease in fetal body weight was observed at 1,000 mg/kg/day (>28 times the exposure in humans at the RHD). No drug-related fetal toxicities were observed at 5 mg/kg/day (approximately 13 times the exposure in humans at the RHD), and no drug-related fetal malformations were observed at any dose. Cabotegravir was administered orally to pregnant rabbits at 0, 30, 500, or 2,000 mg/kg/day from Gestation Days 7 to 19. No drug-related fetal toxicities were observed at 2,000 mg/kg/day (approximately 0.7 times the exposure in humans at the RHD). In a rat pre- and postnatal development study, cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from Gestation Day 6 to Lactation Day 21. A delay in the onset of parturition and increases in the number of stillbirths and neonatal deaths by Lactation Day 4 were observed at 1,000 mg/kg/day (>28 times the exposure in humans at the RHD); there were no alterations to growth and development of surviving offspring. In a cross-fostering study, similar incidences of stillbirths and early postnatal deaths were observed when rat pups born to cabotegravir-treated mothers were nursed from birth by control mothers. There was no effect on neonatal survival of control pups nursed from birth by cabotegravir-treated mothers. A lower dose of 5 mg/kg/day (13 times the exposure at the RHD) was not associated with delayed parturition or neonatal mortality in rats. Studies in pregnant rats showed that cabotegravir crosses the placenta and can be detected in fetal tissue.

8 USE IN SPECIFIC POPULATIONS • Lactation: Breastfeeding is not recommended in HIV-1–infected mothers due to the potential for HIV-1 transmission. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VOCABRIA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary There are insufficient human data on the use of VOCABRIA during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. While there are insufficient human data to assess the risk of neural tube defects (NTDs) with exposure to VOCABRIA during pregnancy, NTDs were associated with dolutegravir, another integrase inhibitor. Discuss the benefit-risk of using VOCABRIA with individuals of childbearing potential or during pregnancy. 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 risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in a United States (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 women 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) . Data Human Data: Data from a birth outcome surveillance study in Botswana showed that dolutegravir, another integrase inhibitor, was associated with increased risk of NTDs when administered at the time of conception and in early pregnancy. Data from clinical trials are insufficient to address this risk with cabotegravir. Animal Data: Cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from 15 days before cohabitation, during cohabitation, and from Gestation Days 0 to 17. There were no effects on fetal viability when fetuses were delivered by caesarean, although a minor decrease in fetal body weight was observed at 1,000 mg/kg/day (>28 times the exposure in humans at the RHD). No drug-related fetal toxicities were observed at 5 mg/kg/day (approximately 13 times the exposure in humans at the RHD), and no drug-related fetal malformations were observed at any dose. Cabotegravir was administered orally to pregnant rabbits at 0, 30, 500, or 2,000 mg/kg/day from Gestation Days 7 to 19. No drug-related fetal toxicities were observed at 2,000 mg/kg/day (approximately 0.7 times the exposure in humans at the RHD). In a rat pre- and postnatal development study, cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from Gestation Day 6 to Lactation Day 21. A delay in the onset of parturition and increases in the number of stillbirths and neonatal deaths by Lactation Day 4 were observed at 1,000 mg/kg/day (>28 times the exposure in humans at the RHD); there were no alterations to growth and development of surviving offspring. In a cross-fostering study, similar incidences of stillbirths and early postnatal deaths were observed when rat pups born to cabotegravir-treated mothers were nursed from birth by control mothers. There was no effect on neonatal survival of control pups nursed from birth by cabotegravir-treated mothers. A lower dose of 5 mg/kg/day (13 times the exposure at the RHD) was not associated with delayed parturition or neonatal mortality in rats. Studies in pregnant rats showed that cabotegravir crosses the placenta and can be detected in fetal tissue. 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommends that HIV‑1–infected mothers in the U.S. not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. It is not known if cabotegravir is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, cabotegravir was present in milk (see Data) . Because of the potential for (1) HIV‑1 transmission (in HIV-1–negative infants), (2) developing viral resistance (in HIV-1–positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct HIV-1–infected mothers not to breastfeed if they are receiving VOCABRIA for the treatment of HIV-1 infection. For uninfected mothers receiving VOCABRIA for HIV-1 PrEP, assess the benefit-risk of using VOCABRIA to the infant while breastfeeding. Data Animal Data: Animal lactation studies with cabotegravir have not been conducted. However, cabotegravir was detected in the plasma of nursing pups on Lactation Day 10 in the rat pre- and postnatal development study. 8.4 Pediatric Use Treatment of HIV-1 Infection The safety and effectiveness of VOCABRIA have been established in adolescents aged 12 to younger than 18 years and weighing at least 35 kg, which is supported by the following: • Trials in adults [see Clinical Studies ( 14.1 )] • MOCHA (NCT03497676) trial in adolescents MOCHA Trial The safety, tolerability, and pharmacokinetics of oral and injectable cabotegravir and oral and injectable rilpivirine are being assessed in an ongoing Phase 1/2 multicenter, open-label, non-comparative study, MOCHA (IMPAACT 2017). Data are available from the Week 16 interim analysis from MOCHA. The primary objective at Week 16 was to confirm the use of the adult dose, through the evaluation of safety and pharmacokinetics, for oral and injectable cabotegravir and injectable rilpivirine in 23 HIV-1–infected virologically suppressed adolescents (aged 12 to younger than 18 years and weighing at least 35 kg) receiving background antiretroviral therapy. A total of 8 HIV-1–infected pediatric participants 12 years of age and older and weighing at least 35 kg and receiving background antiretroviral therapy received oral cabotegravir. The safety of VOCABRIA in adolescents is expected to be similar to adults, as there was no clinically significant difference in drug exposure [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 )] . Please refer to the CABENUVA prescribing information for additional information. The safety, efficacy, and pharmacokinetics of VOCABRIA have not been established in pediatric patients younger than 12 years of age or weighing <35 kg. HIV-1 Pre-Exposure Prophylaxis The safety and effectiveness of VOCABRIA for HIV-1 PrEP in at-risk adolescents weighing at least 35 kg is supported by data from 2 adequate and well-controlled trials of VOCABRIA for HIV-1 PrEP in adults with additional safety and pharmacokinetic data from studies in HIV-1–infected adults who were administered CABENUVA and in HIV-1–infected pediatric subjects who were administered separate components of CABENUVA in addition to their current antiretroviral therapy [see Dosage and Administration ( 2.2 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.2 )] . APRETUDE for HIV-1 PrEP is being evaluated in 2 open-label multicenter clinical trials in adolescent individuals. Fifty-nine adolescents have been enrolled. Of these, 54 adolescent participants received one or more injections after receiving VOCABRIA. In adolescents receiving VOCABRIA and 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 schedule [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 )]. The safety, efficacy, and pharmacokinetics of VOCABRIA in pediatric participants younger than 12 years of age or weighing <35 kg have not been established. 8.5 Geriatric Use Clinical trials of VOCABRIA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in administration of VOCABRIA in elderly patients, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy [see Clinical Pharmacology ( 12.3 )] . 8.6 Renal Impairment No dosage adjustment of VOCABRIA is necessary for patients with mild to moderate (creatinine clearance equal to 30 mL/min to <90 mL/min) or severe renal impairment (creatinine clearance <30 mL/min) [see Clinical Pharmacology ( 12.3 )] . The effect of end-stage renal disease (creatinine clearance <15 mL/min) on the pharmacokinetics of cabotegravir is unknown. As cabotegravir is >99% protein bound, dialysis is not expected to alter exposures of cabotegravir. Since VOCABRIA is taken in combination with EDURANT for the treatment of HIV-1 infection, the prescribing information for EDURANT should be consulted for additional recommendations in patients with severe impairment or end-stage renal disease. 8.7 Hepatic Impairment No dosage adjustment of VOCABRIA is necessary for patients with mild or moderate hepatic impairment (Child-Pugh A or B). The effect of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of cabotegravir is unknown [see Clinical Pharmacology ( 12.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING Each VOCABRIA tablet contains 30 mg of cabotegravir and is a white, oval, film-coated, biconvex tablet debossed with “SV CTV” on one side. Bottle of 30 tablets with child-resistant closure NDC 49702-248-13. Store below 30°C (86°F).