Juluca

1 INDICATIONS AND USAGE JULUCA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of JULUCA. JULUCA, a two-drug combination of dolutegravir, an HIV-1 integrase strand transfer inhibitor (INSTI), and rilpivirine, an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI), is indicated as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of JULUCA. ( 1 )

2 DOSAGE AND ADMINISTRATION • One tablet taken orally once daily with a meal. ( 2.1 ) • Rifabutin coadministration: Take an additional 25-mg tablet of rilpivirine with JULUCA once daily with a meal for the duration of the rifabutin coadministration. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of JULUCA is one tablet taken orally once daily with a meal [see Clinical Pharmacology ( 12.3 )] . One tablet of JULUCA contains 50 mg of dolutegravir and 25 mg of rilpivirine. 2.2 Recommended Dosage with Rifabutin Coadministration If JULUCA is coadministered with rifabutin, take an additional 25-mg tablet of rilpivirine with JULUCA once daily with a meal for the duration of the rifabutin coadministration [see Drug Interactions ( 7.4 )] .

4 CONTRAINDICATIONS JULUCA is contraindicated in patients: • with previous hypersensitivity reaction to dolutegravir or rilpivirine [see Warnings and Precautions ( 5.1 )] . • receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events [see Drug Interactions ( 7 )] . • receiving other coadministered drugs in Table 1 that significantly decrease rilpivirine plasma concentrations [see Drug Interactions ( 7 ), Clinical Pharmacology ( 12.3 )] . Table 1. Drugs That Are Contraindicated with JULUCA Drug Class Contraindicated Drugs in Class Clinical Comment Antiarrhythmic Dofetilide Potential for serious and/or life-threatening events due to the potential for increased dofetilide plasma concentrations. Anticonvulsants Carbamazepine Oxcarbazepine Phenobarbital Phenytoin Potential for significant decreases in rilpivirine plasma concentrations due to cytochrome P450 (CYP)3A enzyme induction, which may result in loss of virologic response. Antimycobacterials Rifampin Rifapentine Glucocorticoid (systemic) Dexamethasone (more than a single-dose treatment) Herbal Products St John’s wort ( Hypericum perforatum ) Proton Pump Inhibitors e.g., Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole Potential for significant decreases in rilpivirine plasma concentrations due to gastric pH increase, which may result in loss of virologic response. • Previous hypersensitivity reaction to dolutegravir or rilpivirine. ( 4 ) • Coadministration with dofetilide. ( 4 ) • Coadministration with drugs where significant decreases in rilpivirine plasma concentrations may occur, which may result in loss of virologic response. ( 4 )

5 WARNINGS AND PRECAUTIONS • Severe skin and hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury, have been reported with the individual components. Discontinue JULUCA immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, as a delay in stopping treatment may result in a life-threatening reaction. ( 5.1 ) • Hepatotoxicity has been reported in patients receiving a dolutegravir- or rilpivirine-containing regimen. Monitoring for hepatotoxicity is recommended. ( 5.2 ) • Depressive disorders have been reported with the use of rilpivirine- or dolutegravir-containing regimens. Immediate medical evaluation is recommended for severe depressive symptoms. ( 5.3 , 6.1 ) 5.1 Skin and Hypersensitivity Reactions Hypersensitivity reactions have been reported with dolutegravir and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. These events were reported in less than 1% of subjects receiving dolutegravir in Phase 3 clinical trials. Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase 3 clinical trials of rilpivirine, treatment-related rashes with at least Grade 2 severity were reported in 3% of subjects. No Grade 4 rash was reported [see Adverse Reactions ( 6.2 )] . Discontinue JULUCA immediately if signs or symptoms of severe skin or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, mucosal involvement [oral blisters or lesions], conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including laboratory parameters with liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with JULUCA after the onset of hypersensitivity may result in a life-threatening reaction [see Contraindications ( 4 )] . 5.2 Hepatotoxicity Hepatic adverse events have been reported in patients receiving a dolutegravir- or rilpivirine-containing regimen [see Adverse Reactions ( 6.1 )] . Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations. Additionally, in some patients receiving dolutegravir-containing regimens, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries and hepatitis, have also been reported in patients receiving a dolutegravir- or rilpivirine-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to acute liver failure has been reported with dolutegravir-containing products, including liver transplant with TRIUMEQ (abacavir, dolutegravir, and lamivudine). Monitoring for hepatotoxicity is recommended. 5.3 Depressive Disorders Depressive disorders (including depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, and suicidal ideation) have been reported with rilpivirine [see Adverse Reactions ( 6.1 )] . For information regarding depressive disorders reported in patients taking dolutegravir, [see Adverse Reactions ( 6.1 )] . Promptly evaluate patients with severe depressive symptoms to assess whether the symptoms are related to JULUCA and to determine whether the risks of continued therapy outweigh the benefits. 5.4 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of JULUCA and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications ( 4 ), Drug Interactions ( 7.4 )] : • Loss of therapeutic effect of JULUCA and possible development of resistance. • Possible clinically significant adverse reactions from greater exposures of concomitant drugs. In healthy subjects, 75 mg once daily of rilpivirine (3 times the dose in JULUCA) and 300 mg once daily (12 times the dose in JULUCA) have been shown to prolong the QTc interval of the electrocardiogram [see Drug Interactions ( 7.3 ), Clinical Pharmacology ( 12.2 )] . Consider alternatives to JULUCA when coadministered with a drug with a known risk of Torsade de Pointes. See Table 4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with JULUCA; review concomitant medications during therapy with JULUCA; and monitor for the adverse reactions associated with the concomitant drugs.

7 DRUG INTERACTIONS • Because JULUCA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. ( 7.1 ) • Refer to the full prescribing information for important drug interactions with JULUCA. ( 4 , 5.4 , 7 ) • Drugs that induce or inhibit cytochrome P450 (CYP)3A4 or uridine diphosphate glucuronosyltransferase (UGT)1A1 may affect the plasma concentrations of the components of JULUCA. ( 7.3 ) • Drugs that increase gastric pH or containing polyvalent cations may decrease plasma concentrations of the components of JULUCA. ( 4 , 7.3 , 7.4 ) • Consider alternatives to prescribing JULUCA with drugs with a known risk of Torsade de Pointes. ( 7.3 ) 7.1 Concomitant Use with Other Antiretroviral Medicines Because JULUCA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended [see Indications and Usage ( 1 )] . Information regarding potential drug-drug interactions with other antiretroviral medications is not provided [see Contraindications ( 4 ), Warnings and Precautions ( 5.4 ), Clinical Pharmacology ( 12.3 )] . 7.2 Potential for JULUCA to Affect Other Drugs Dolutegravir, a component of JULUCA, inhibits the renal organic cation transporters (OCT)2 and multidrug and toxin extrusion transporter (MATE)1, thus it may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 such as dofetilide, dalfampridine, and metformin [see Contraindications ( 4 ), Drug Interactions ( 7.4 )] . 7.3 Potential for Other Drugs to Affect the Components of JULUCA Dolutegravir Dolutegravir is metabolized by uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1 with some contribution from cytochrome P450 (CYP)3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp) in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of dolutegravir [see Drug Interactions ( 7.4 )] . Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations. Coadministration of dolutegravir with polyvalent cation-containing products may lead to decreased absorption of dolutegravir [see Drug Interactions ( 7.4 )] . Rilpivirine Rilpivirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of rilpivirine. Coadministration of JULUCA and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs [see Contraindications ( 4 ), Drug Interactions ( 7.4 )] . Coadministration of JULUCA and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of JULUCA with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs [see Contraindications ( 4 ), Drug Interactions ( 7.4 ), Clinical Pharmacology ( 12.3 )] . QT-Prolonging Drugs: In healthy subjects, 75 mg once daily of rilpivirine (3 times the dose in JULUCA) and 300 mg once daily (12 times the dose in JULUCA) have been shown to prolong the QTc interval of the electrocardiogram [see Clinical Pharmacology ( 12.2 )] . Consider alternatives to JULUCA when coadministered with a drug with a known risk of Torsade de Pointes. 7.4 Established and Other Potentially Significant Drug Interactions Information regarding potential drug interactions with dolutegravir and rilpivirine are provided in Table 4 . These recommendations are based on either drug interaction trials of individual components or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy [see Contraindications ( 4 ), Warnings and Precautions ( 5.4 ), Clinical Pharmacology ( 12.3 )] . Table 4. Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interactions a ↑ = Increase, ↓ = Decrease, ↔ = No change. a This table is not all inclusive. b See Clinical Pharmacology ( 12.3 ) for magnitude of interaction. Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment Antacids (e.g., aluminum or magnesium hydroxide, calcium carbonate) ↓Rilpivirine Administer JULUCA 4 hours before or 6 hours after taking antacids. Antiarrhythmic: Dofetilide ↑Dofetilide Coadministration is contraindicated with JULUCA [see Contraindications ( 4 )] . Anticonvulsants: Carbamazepine Oxcarbazepine Phenobarbital Phenytoin ↓Dolutegravir ↓Rilpivirine Coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations [see Contraindications ( 4 )] . Antidiabetic: Metformin b ↑Metformin Refer to the prescribing information for metformin for assessing the benefit and risk of concomitant use of JULUCA and metformin. Antimycobacterials: Rifampin Rifapentine ↓Dolutegravir ↓Rilpivirine Coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations [see Contraindications ( 4 )] . Antimycobacterial: Rifabutin b ↔Dolutegravir ↔Rifabutin ↓Rilpivirine An additional rilpivirine 25-mg tablet should be taken with JULUCA once daily with a meal when rifabutin is coadministered. Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment) ↓Rilpivirine Coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations [see Contraindications ( 4 )] . H 2 -receptor antagonists: Famotidine Cimetidine Nizatidine Ranitidine ↔Dolutegravir ↓Rilpivirine JULUCA should only be administered at least 4 hours before or 12 hours after taking H 2 -receptor antagonists. Herbal product: St John’s wort ( Hypericum perforatum ) ↓Dolutegravir ↓Rilpivirine Coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations [see Contraindications ( 4 )] . Macrolide or ketolide antibiotics: Clarithromycin Erythromycin Telithromycin ↔Dolutegravir ↑Rilpivirine Where possible, consider alternatives, such as azithromycin. Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing products b or laxatives Sucralfate Buffered medications ↓Dolutegravir Administer JULUCA 4 hours before or 6 hours after taking products containing polyvalent cations. Narcotic analgesic: Methadone b ↔Dolutegravir ↓Methadone ↔Rilpivirine No dose adjustments are required when starting coadministration of methadone with JULUCA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. Oral calcium and iron supplements , including multivitamins containing calcium or iron b (non-antacid) ↓Dolutegravir Administer JULUCA and supplements containing calcium or iron together with a meal or take JULUCA 4 hours before or 6 hours after taking these supplements. Potassium channel blocker: Dalfampridine ↑Dalfampridine Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dalfampridine concurrently with JULUCA should be considered against the risk of seizures in these patients. Proton pump inhibitors: e.g., Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole ↓Rilpivirine Coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations [see Contraindications ( 4 )] .

6 ADVERSE REACTIONS The following adverse reactions are described below and in other sections of the labeling: • Skin and hypersensitivity reactions [see Warnings and Precautions ( 5.1 )]. • Hepatotoxicity [see Warnings and Precautions ( 5.2 )]. • Depressive disorders [see Warnings and Precautions ( 5.3 )]. The most common adverse reactions (all grades) observed in at least 2% of subjects were diarrhea, headache, and nausea. ( 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 the rates observed in practice. The safety assessment of JULUCA is based on the pooled primary Week 48 analyses of data from 2 identical, international, multicenter, open-label trials, SWORD-1 and SWORD-2, including additional follow up through Week 148. A total of 1,024 adult HIV-1-infected subjects who were on a stable suppressive antiretroviral regimen (containing 2 nucleoside reverse transcriptase inhibitors [NRTIs] plus either an integrase strand transfer inhibitor [INSTI], a non-nucleoside reverse transcriptase inhibitor [NNRTI], or a protease inhibitor [PI]) for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or rilpivirine, were randomized and received treatment. Subjects were randomized 1:1 to continue their current antiretroviral regimen or be switched to dolutegravir plus rilpivirine administered once daily. Subjects originally assigned to continue their current antiretroviral regimen and who remained virologically suppressed at Week 48 switched to dolutegravir plus rilpivirine at Week 52. In the pooled analyses, the proportion of subjects who discontinued treatment due to an adverse event through Week 48 was 4% in subjects receiving dolutegravir plus rilpivirine once daily and less than 1% in subjects who remained on their current antiretroviral regimen. The most common adverse events leading to discontinuation through Week 48 were psychiatric disorders: 2% of subjects receiving dolutegravir plus rilpivirine and less than 1% on the current antiretroviral regimen. In the pooled analyses, the proportion of subjects receiving dolutegravir plus rilpivirine who discontinued treatment due to an adverse event through Week 148 was 8%. The most common adverse reactions (ARs) (all grades) reported in at least 2% of subjects in the Week 48 pooled analyses from SWORD-1 and SWORD-2 are provided in Table 2 . Table 2. Adverse Reactions (Grades 1 to 4) Reported in at Least 2% of Virologically Suppressed Subjects with HIV-1 Infection in SWORD-1 and SWORD-2 Trials (Week 48 Pooled Analyses) Adverse Reaction Dolutegravir plus Rilpivirine (n = 513) Current Antiretroviral Regimen (n = 511) Diarrhea 2% <1% Headache 2% 0 In the Week 148 pooled analyses, the only adverse reaction (all grades) occurring in at least 2% of subjects who received dolutegravir plus rilpivirine and that was not observed during the Week 48 analyses was nausea (2%). Less Common Adverse Reactions The following ARs occurred in less than 2% of subjects receiving dolutegravir plus rilpivirine or are from studies described in the prescribing information of the individual components, TIVICAY (dolutegravir) and EDURANT (rilpivirine). Some events have been included because of their seriousness and assessment of potential causal relationship. General Disorders: Fatigue. Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, nausea, upper abdominal pain, vomiting. Hepatobiliary Disorders: Cholecystitis, cholelithiasis, hepatitis. Immune System Disorders: Immune reconstitution syndrome. Metabolism and Nutrition Disorders: Decreased appetite. Musculoskeletal Disorders: Myositis. Nervous System Disorders: Dizziness, somnolence. Psychiatric Disorders: Depressive disorders including depressed mood; depression; suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. Other reported psychiatric adverse reactions include anxiety, insomnia, sleep disorders, and abnormal dreams. Renal and Urinary Disorders: Glomerulonephritis membranous, glomerulonephritis mesangioproliferative, nephrolithiasis, renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus, rash. Laboratory Abnormalities Selected laboratory abnormalities with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects in the Week 48 pooled analysis are presented in Table 3 . Table 3. Selected Laboratory Abnormalities (Grades 2 and 3 to 4; Week 48 Pooled Analyses) in SWORD-1 and SWORD-2 Trials ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ULN = Upper limit of normal. Laboratory Parameter Preferred Term Dolutegravir plus Rilpivirine (n = 513) Current Antiretroviral Regimen (n = 511) ALT Grade 2 (>2.5-5.0 x ULN) 2% <1% Grade 3 to 4 (>5.0 x ULN) <1% <1% AST Grade 2 (>2.5-5.0 x ULN) <1% 2% Grade 3 to 4 (>5.0 x ULN) <1% <1% Total Bilirubin Grade 2 (1.6-2.5 x ULN) 2% 4% Grade 3 to 4 (>2.5 x ULN) 0 3% Creatine kinase Grade 2 (6.0-9.9 x ULN) <1% <1% Grade 3 to 4 (≥10.0 x ULN) 1% 2% Hyperglycemia Grade 2 (126-250 mg/dL) 4% 5% Grade 3 to 4 (>250 mg/dL) <1% <1% Lipase Grade 2 (>1.5-3.0 x ULN) 5% 5% Grade 3 to 4 (>3.0 x ULN) 2% 2% In the Week 148 pooled analyses, there were no additional selected laboratory abnormalities with dolutegravir plus rilpivirine compared with those shown in Table 3 . Changes in Serum Creatinine: Dolutegravir and rilpivirine have been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology ( 12.2 )] . Increases in serum creatinine occurred within the first 4 weeks of treatment with dolutegravir plus rilpivirine and remained stable through 148 weeks. Mean changes from baseline of 0.093 mg/dL (range: -0.30 to 0.58 mg/dL) and 0.112 mg/dL (range: -0.24 to 0.81 mg/dL) were observed after 48 and 148 weeks of treatment with dolutegravir plus rilpivirine, respectively. These changes are not considered to be clinically relevant. Serum Lipids: At 48 weeks, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and total cholesterol to HDL ratio were similar between the treatment arms, with no further notable changes beyond Week 48. Bone Mineral Density Effects Mean bone mineral density (BMD) increased from baseline to Week 48 in subjects who switched from an antiretroviral treatment (ART) regimen containing tenofovir disoproxil fumarate (TDF) to dolutegravir plus rilpivirine (1.34% total hip and 1.46% lumbar spine) compared with those who continued on treatment with a TDF-containing antiretroviral regimen (0.05% total hip and 0.15% lumbar spine) in a dual-energy X-ray absorptiometry (DXA) substudy. BMD declines of 5% or greater at the lumbar spine were experienced by 2% of subjects receiving JULUCA and 5% of subjects who continued their TDF-containing regimen. In subjects who received dolutegravir plus rilpivirine from study start and were continuing JULUCA at Week 148, mean BMD increases from baseline were 0.98% (total hip) and 0.53% (lumbar spine). The long-term clinical significance of these BMD changes is not known. Fractures (excluding fingers and toes) were reported in 3 (0.6%) subjects who switched to dolutegravir plus rilpivirine and 9 (1.8%) subjects who continued their current antiretroviral regimen through 48 weeks. Adrenal Function In the pooled Phase 3 trials results analysis of rilpivirine, at Week 96, there was an overall mean change from baseline in basal cortisol of -0.69 (-1.12, 0.27) micrograms/dL in the rilpivirine group and of -0.02 (-0.48, 0.44) micrograms/dL in the efavirenz group. The clinical significance of the higher abnormal rate of 250 micrograms ACTH stimulation tests in the rilpivirine group is not known. Refer to the EDURANT (rilpivirine) Prescribing Information for additional information. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving a dolutegravir- or rilpivirine-containing regimen. 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. Blood and Lymphatic Systems Sideroblastic anemia. Hepatobiliary Disorders Acute liver failure, hepatotoxicity. Investigations Weight increased. Musculoskeletal Disorders Arthralgia, myalgia. Renal and Genitourinary Disorders Nephrotic syndrome. Skin and Subcutaneous Tissue Disorders Severe skin and hypersensitivity reactions, including DRESS .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to JULUCA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Data from two, ongoing birth outcome surveillance studies in Botswana and Eswatini which together include over 14,000 individuals evaluated during pregnancy show similar prevalence of neural tube defects among infants born to individuals taking dolutegravir at the time of conception compared to those born to individuals taking non-dolutegravir-containing regimens at conception or infants born to HIV-negative individuals (see Data). There are insufficient human data on the use of JULUCA during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. However, available human data from the APR with the individual components of JULUCA do not indicate an increased risk of birth defects (see Data) . The background risk for major birth defects for the indicated population is unknown. In the U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. In animal reproduction studies, no evidence of adverse developmental outcomes (including neural tube defects) was observed with the components of JULUCA at systemic exposures (AUC) to dolutegravir less than (rabbits) and 38 times (rats) and exposures to rilpivirine 15 (rats) and 70 (rabbits) times the exposure at the recommended human dose (RHD) of JULUCA (see Data) . Data Human Data: Dolutegravir: Observational studies: The first interim analysis from an ongoing birth outcome surveillance study in Botswana identified an association between dolutegravir and an increased risk of neural tube defects when dolutegravir was administered at the time of conception and in early pregnancy. A subsequent analysis was conducted based on a larger cohort from the birth outcome surveillance study in Botswana and included over 9,460 individuals exposed to dolutegravir at conception, 23,664 individuals exposed to non-dolutegravir-containing regimens, and 170,723 HIV-negative pregnant individuals. The prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.11% (95% CI: 0.05-0.19%). The observed prevalence rate did not differ significantly from that of infants delivered to individuals taking non-dolutegravir-containing regimens (0.11%, 95% CI: 0.07-0.16%), or to HIV-negative individuals (0.06%, 95% CI: 0.05-0.08%). The Eswatini birth outcome surveillance study includes 9,743 individuals exposed to dolutegravir at conception, 1,838 individuals exposed to non-dolutegravir-containing regimens, and 32,259 HIV-negative pregnant individuals. The prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.08% (95% CI: 0.04-0.16%). The observed prevalence rate did not differ significantly from that of infants delivered to individuals taking non-dolutegravir-containing regimens (0.22%, 95% CI: 0.06-0.56%) or to HIV-negative individuals (0.08%, 95% CI: 0.06-0.12%). The observed prevalence of neural tube defects in infants delivered to individuals taking non-dolutegravir-containing regimens had a wide confidence interval due to low sample size. Limitations of these birth outcome surveillance studies include insufficient data to determine if baseline characteristics were balanced between the study groups or to assess other factors such as the use of folic acid during the preconception or first trimester periods. Antiretroviral Pregnancy Registry: Based on prospective reports to the APR, of 1,377 exposures to dolutegravir during pregnancy resulting in live births (including 874 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 2.2% to 4.7%) following first-trimester exposure to dolutegravir-containing regimens and 5.0% (95% CI: 3.2% to 7.3%) following second-/third-trimester exposure to dolutegravir-containing regimens. In the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background birth defect rate was 2.7%. Dolutegravir has been shown to cross the placenta. In a clinical trial in Uganda and South Africa in women during the last trimester of pregnancy receiving dolutegravir 50 mg once daily, the ratio of median dolutegravir concentration in fetal umbilical cord to that in maternal peripheral plasma was 1.21 (range 0.51 to 2.11) (n = 15). Rilpivirine: Based on prospective reports to the APR of over 870 exposures to rilpivirine-containing regimens during pregnancy resulting in live births (including over 660 exposed during the first trimester and over 210 exposed in the second/third trimester), there was no significant difference between the overall risk of birth defects for rilpivirine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 2.1% (95% CI: 1.1% to 3.5%) and 0.9% (95% CI: 0.1% to 3.4%) following first and second/third trimester exposure, respectively, to rilpivirine-containing regimens. Rilpivirine in combination with a background regimen was evaluated in a clinical trial of 19 HIV-1–infected pregnant subjects during the second and third trimesters and postpartum. Each of the subjects were on a rilpivirine-based regimen at the time of enrollment. Twelve subjects completed the trial through the postpartum period (6 to 12 weeks after delivery) and pregnancy outcomes are missing for 6 subjects. The exposure (C 0h and AUC) of total rilpivirine was approximately 30% to 40% lower during pregnancy compared with postpartum (6 to 12 weeks). The protein binding of rilpivirine was similar (>99%) during the second trimester, third trimester, and the postpartum period [see Clinical Pharmacology ( 12.3 )] . One subject discontinued the trial following fetal death at 25 weeks’ gestation due to suspected premature rupture of membranes. Among the 12 subjects who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was preserved in 10 subjects (83.3%) through the third trimester visit and in 9 subjects (75%) through the 6- to 12-week postpartum visit. Virologic outcomes during the third trimester visit were missing for 2 subjects who were withdrawn (one subject was nonadherent to the study drug and one subject withdrew consent). Among the 10 infants with HIV test results available, born to 10 HIV-1–infected pregnant subjects, all had negative test results for HIV-1 at the time of delivery and up to 16 weeks postpartum. All 10 infants received antiretroviral prophylactic treatment with zidovudine. Rilpivirine was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of rilpivirine in HIV-1–infected adults. Animal Data: Dolutegravir: Dolutegravir was administered orally at up to 1,000 mg/kg daily to pregnant rats and rabbits on Gestation Days 6 to 17 and 6 to 18, respectively, and to rats on Gestation Day 6 to Lactation/Post-partum Day 20. No adverse effects on embryo-fetal (rats and rabbits) development were observed at up to the highest dose tested. During organogenesis, systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans, and in rats were approximately 38 times the exposure in humans (50 mg once daily). In the rat pre/post-natal development study, decreased body weight of the developing offspring was observed during lactation at a maternally toxic dose (approximately 32 times the human exposure with 50 mg once daily). Rilpivirine: Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg/kg/d) and rabbits (5, 10, or 20 mg/kg/day) through organogenesis (on Gestation Days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans at the recommended dose of 25 mg once daily. In a pre/postnatal development study with rilpivirine, where rats were administered up to 400 mg/kg/day through lactation, no significant adverse effects directly related to drug were noted in the offspring.