Odefsey: Package Insert / Prescribing Info

Limitations of Use:

• More rilpivirine-treated participants with no antiretroviral treatment history with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥ 50 copies/mL) compared to rilpivirine-treated participants with HIV-1 RNA less than or equal to 100,000 copies/mL [see Clinical Studies (14.2,14.3)].

2.1 Testing Prior to Initiation and During Treatment with ODEFSEY

Prior to or when initiating ODEFSEY, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1)].

Prior to or when initiating ODEFSEY, and during treatment with ODEFSEY, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.5)].

2.2 Recommended Dosage in Adult and Pediatric Patients Weighing at Least 25 kg

ODEFSEY is a three-drug fixed dose combination product containing 200 mg of emtricitabine (FTC), 25 mg of rilpivirine (RPV), and 25 mg of tenofovir alafenamide (TAF). The recommended dosage of ODEFSEY is one tablet taken orally once daily with a meal in adults and pediatric patients with body weight at least 25 kg and creatinine clearance greater than or equal to 30 mL per minute [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.3 Recommended Dosage During Pregnancy

For pregnant patients who are already on ODEFSEY prior to pregnancy and are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet of ODEFSEY taken once daily may be continued. Lower exposures of rilpivirine, a component of ODEFSEY, were observed during pregnancy, therefore viral load should be monitored closely [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].

2.4 Not Recommended in Patients with Severe Renal Impairment

ODEFSEY is not recommended in patients with:

• severe renal impairment (estimated creatinine clearance of 15 to below 30 mL per minute); or
• end stage renal disease (ESRD; estimated creatinine clearance below 15 mL per minute) who are not receiving chronic hemodialysis [see Dosage and Administration (2.2), Warnings and Precautions (5.5), and Use in Specific Populations (8.6)].

5.1 Severe Acute Exacerbation of Hepatitis B in Patients with HIV-1 and HBV

Test patients with HIV-1 for the presence of hepatitis B virus (HBV) before or when initiating antiretroviral therapy [see Dosage and Administration (2.1)].

Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients with HIV-1 and HBV who have discontinued products containing FTC and/or TDF, and may occur with discontinuation of ODEFSEY. Patients with HIV-1 and HBV who discontinue ODEFSEY should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with ODEFSEY. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

5.2 Skin and Hypersensitivity Reactions

Severe skin and hypersensitivity reactions, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported during postmarketing experience with RPV-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunction, including elevations in hepatic serum biochemistries. During Phase 3 clinical trials of RPV, treatment-related rashes with at least Grade 2 severity were reported in 1% of participants. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy [see Adverse Reactions (6.2)].

Discontinue ODEFSEY immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis, or eosinophilia. Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated.

5.3 Hepatotoxicity

Hepatic adverse events have been reported in patients receiving an RPV-containing regimen. Patients with underlying hepatitis B or C virus infection, or marked elevations in liver-associated tests prior to treatment, may be at increased risk for worsening or development of liver-associated test elevations with use of ODEFSEY. A few cases of hepatic toxicity have been reported in adult patients receiving an RPV-containing regimen who had no preexisting hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with ODEFSEY is recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in liver-associated tests prior to treatment initiation. Liver-associated test monitoring should also be considered for patients without preexisting hepatic dysfunction or other risk factors.

5.4 Depressive Disorders

Depressive disorders (including depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with RPV. Promptly evaluate patients with severe depressive symptoms to assess whether the symptoms are related to ODEFSEY, and to determine whether the risks of continued therapy outweigh the benefits.

In Phase 3 trials of RPV in adult participants (N=1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among RPV-treated participants (n=686) was 9%. Most events were mild or moderate in severity. In RPV-treated participants, the incidence of Grades 3 and 4 depressive disorders (regardless of causality) was 1%, the incidence of discontinuation due to depressive disorders was 1%, and suicidal ideation and suicide attempt was reported in 4 and 2 participants, respectively.

During the Phase 2 trial in RPV-treated pediatric participants 12 to less than 18 years of age (N=36), the incidence of depressive disorders (regardless of causality, severity) was 19% (7/36) through 48 weeks. Most events were mild or moderate in severity. The incidence of Grades 3 and 4 depressive disorders (regardless of causality) was 6% (2/36). None of the participants discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 participant.

5.5 New Onset or Worsening Renal Impairment

Postmarketing case of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with TAF-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events [see Adverse Reactions (6.1, 6.2)]. ODEFSEY is not recommended in patients with estimated creatinine clearance of 15 to below 30 mL per minute, or in patients with estimated creatinine clearance below 15 mL per minute who are not receiving chronic hemodialysis.

Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents, including nonsteroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.

Prior to or when initiating ODEFSEY, and during treatment with ODEFSEY, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue ODEFSEY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

5.6 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of ODEFSEY and other drugs may result in potentially significant drug interactions, some of which may lead to [see Contraindications (4), and Drug Interactions (7)]:

• Loss of therapeutic effect of ODEFSEY and possible development of resistance due to reduced exposure of RPV.

In healthy participants, higher than recommended doses of RPV (75 mg once daily and 300 mg once daily – 3 and 12 times the recommended dosages in ODEFSEY, respectively) have been shown to prolong the QTc interval of the electrocardiogram. Consider alternatives to ODEFSEY when coadministered with a drug that is known to have a risk of Torsade de Pointes [see Drug Interactions (7.2) and Clinical Pharmacology (12.2)].

See Table 3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Contraindications (4) and Drug Interactions (7)]. Consider the potential for drug interactions prior to and during ODEFSEY therapy and review concomitant medications during ODEFSEY therapy.

5.7 Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of ODEFSEY, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with ODEFSEY should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

5.8 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including FTC and RPV, both components of ODEFSEY. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

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 (or a drug given in various combinations with other concomitant therapy) cannot be directly compared to rates in the clinical trials of another drug (or drug given in the same or different combination therapy) and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postmarketing experience in patients receiving RPV or TAF-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.

7.1 Not Recommended with Other Antiretroviral Medications

Because ODEFSEY is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.

7.2 Drugs Inducing or Inhibiting CYP3A Enzymes

RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of RPV [see Clinical Pharmacology (12.3)]. Coadministration of RPV and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs [see Contraindications (4), Warnings and Precautions (5.6), and Table 4].

Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV and possible adverse events.

7.3 Drugs Inducing or Inhibiting P-glycoprotein

TAF, a component of ODEFSEY, is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp and BCRP activity may lead to changes in TAF absorption (see Table 4). Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF, which may lead to loss of therapeutic effect of ODEFSEY and development of resistance. Coadministration of ODEFSEY with other drugs that inhibit P-gp and BCRP may increase the absorption and plasma concentration of TAF.

7.4 Drugs Increasing Gastric pH

Coadministration of RPV with drugs that increase gastric pH may decrease plasma concentrations of RPV and lead to loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Use of RPV with proton pump inhibitors is contraindicated and use of RPV with H2-receptor antagonists requires staggered administration [see Contraindications (4) and Table 4].

7.5 QT Prolonging Drugs

There is limited information available on the potential for a pharmacodynamic interaction between RPV and drugs that prolong the QTc interval. In a study of healthy participants, higher than recommended doses of RPV, 75 mg once daily and 300 mg once daily (3 times and 12 times recommended daily dose in ODEFSEY) prolonged the QTc interval [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.2)]. Consider alternative medications to ODEFSEY in patients taking a drug with a known risk of Torsade de Pointes.

7.6 Drugs Affecting Renal Function

Because FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of ODEFSEY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of FTC, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.5)].

7.7 Significant Drug Interactions

Table 4 provides a listing of established or potentially clinically significant drug interactions with recommended steps to prevent or manage the drug interaction (the table is not all inclusive). The drug interactions described are based on studies conducted with either ODEFSEY, the components of ODEFSEY (FTC, RPV and TAF) as individual agents, or are predicted drug interactions that may occur with ODEFSEY [see Clinical Pharmacology (12.3), Tables 9–12]. For list of contraindicated drugs, [see Contraindications (4)].

7.8 Drugs Without Clinically Significant Interactions with ODEFSEY

Based on drug interaction studies conducted with the fixed dose combination or components of ODEFSEY, no clinically significant drug interactions have been observed when ODEFSEY is combined with the following drugs: acetaminophen, atorvastatin, chlorzoxazone, digoxin, ethinyl estradiol, ledipasvir, metformin, midazolam, norethindrone, norgestimate, sildenafil, simeprevir, sofosbuvir, velpatasvir, and voxilaprevir.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The efficacy and safety of ODEFSEY as a complete regimen for the treatment of HIV-1 was established in pediatric patients 6 years of age and older with body weight greater than or equal to 25 kg [see Dosage and Administration (2.2)]. No pediatric clinical trials were conducted with ODEFSEY. Use of ODEFSEY in this age group is supported by adequate and well-controlled studies of RPV+FTC+TDF in adults with HIV-1 infection, adequate and well-controlled studies of FTC+TAF with EVG+COBI in adults with HIV-1, and by the following pediatric studies conducted using the components of ODEFSEY [see Clinical Studies (14)]:

• 48-week open-label trials of antiretroviral treatment-naïve pediatric participants with HIV-1 aged 12 to less than 18 years and weighing at least 32 kg (N=36) and aged 6 to less than 12 years weighing at least 17 kg (N=18) treated with RPV and other antiretrovirals. The safety and efficacy of RPV administered with other antiretrovirals were similar to that in antiretroviral treatment-naïve adults with HIV-1 on this regimen [see Adverse Reactions (6.1) and Clinical Studies (14)].
• 48-week open-label trial of 26 virologically-suppressed pediatric participants with HIV-1 aged less than 12 years old and weighing at least 16 kg (N=26) treated with RPV and other antiretrovirals. The safety and efficacy of RPV administered with other antiretrovirals were similar to that in virologically-suppressed adults with HIV-1 on this regimen [see Adverse Reactions (6.1)]
• 48-week open-label trials of antiretroviral treatment-naïve pediatric participants with HIV-1 aged 12 to less than 18 years and weighing at least 35 kg (N=50) and virologically-suppressed pediatric participants between the ages of 6 to less than 12 years weighing at least 25 kg (N=52) treated with FTC+TAF with EVG+COBI. The safety and efficacy of FTC+TAF with EVG+COBI were similar to that in adults with HIV-1 on this regimen, with the exception of a decrease from baseline in CD4+ cell counts in participants 6 to less than 12 years of age weighing at least 25 kg [see Adverse Reactions (6.1) and Clinical Studies (14)].

Because it is a fixed-dose combination tablet, the dose of ODEFSEY cannot be adjusted for patients of lower age and weight. The safety and efficacy of ODEFSEY have not been established in pediatric patients weighing less than 25 kg [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

8.5 Geriatric Use

In clinical trials, 80 of the 97 participants enrolled aged 65 years and over received FTC+TAF with EVG+COBI. No differences in safety or efficacy have been observed between elderly participants and those between 12 and less than 65 years of age. Clinical trials of RPV did not include sufficient numbers of participants aged 65 years and over to determine whether they respond differently from younger participants [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

No dosage adjustment of ODEFSEY is recommended in patients with estimated creatinine clearance greater than or equal to 30 mL per minute. ODEFSEY should be used with caution in adults patients with ESRD (estimated creatinine clearance below 15mL per minute) who are receiving chronic hemodialysis and increased monitoring is recommended for RPV-related adverse effects in patients with ESRD, as RPV concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. On days of hemodialysis, administer the daily dose of ODEFSEY after completion of hemodialysis treatment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

ODEFSEY is not recommended in patients with severe renal impairment (estimated creatinine clearance of 15 to below 30 mL per minute), or in patients with ESRD who are not receiving chronic hemodialysis, as the safety of ODEFSEY has not been established in these populations [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dosage adjustment of ODEFSEY is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. ODEFSEY has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].

Emtricitabine (FTC): Hemodialysis treatment removes approximately 30% of the FTC dose over a 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether FTC can be removed by peritoneal dialysis.

Rilpivirine (RPV): Human experience of overdose with RPV is limited. There is no specific antidote for overdose with RPV. Since RPV is highly bound to plasma protein, dialysis is unlikely to result in significant removal of RPV.

Tenofovir Alafenamide (TAF): Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.

Emtricitabine: The chemical name of FTC is 4-amino-5-fluoro-1-(2R-hydroxymethyl-1,3-oxathiolan-5S-yl)-(1H)-pyrimidin-2-one. FTC is the (-)enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position.

FTC has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24 and has the following structural formula:

FTC is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25 °C.

Rilpivirine: The chemical name of rilpivirine hydrochloride drug substance is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C22H18N6 ∙ HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula:

Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range.

Tenofovir Alafenamide: The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1).

Tenofovir alafenamide fumarate has an empirical formula of C21H29O5N6P∙½(C4H4O4) and a formula weight of 534.50 and has the following structural formula:

Tenofovir alafenamide fumarate is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20 °C.

12.1 Mechanism of Action

ODEFSEY is a fixed dose combination of antiretroviral drugs emtricitabine, rilpivirine, and tenofovir alafenamide [see Microbiology (12.4)].

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Minimal to slight infiltration of mononuclear cells in the posterior uvea was observed in dogs with similar severity after three- and nine-month administration of TAF; reversibility was seen after a three-month recovery period. No eye toxicity was observed in the dog at systemic exposures of 5 (TAF) and 15 (tenofovir) times the exposure seen in humans at the recommended daily TAF dose in ODEFSEY.

14.1 Clinical Trial Results in HIV-1 Virologically-Suppressed Subjects Who Switched to ODEFSEY

In Trial 1216, the efficacy and safety of switching from emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) to ODEFSEY were evaluated in a randomized, double-blind study of virologically-suppressed adults with HIV-1. Participants were suppressed (HIV-1 RNA <50 copies/mL) on their baseline regimen of FTC/RPV/TDF for at least 6 months and had no documented resistance mutations to FTC, TAF, or RPV prior to study entry. Participants were randomized in a 1:1 ratio to either switch to ODEFSEY (N=316) once daily or stay on FTC/RPV/TDF (N=314) once daily. Participants had a mean age of 45 years (range: 23–72), 90% were male, 75% were White, and 19% were Black. The mean baseline CD4+ cell count was 709 cells/mm3 (range: 104–2527).

In Trial 1160, the efficacy and safety of switching from efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) to ODEFSEY were evaluated in a randomized, double-blind study of virologically-suppressed adults with HIV-1. Participants were stably suppressed (HIV-1 RNA <50 copies/mL) on their baseline regimen of EFV/FTC/TDF for at least 6 months and had no documented resistance mutations to FTC, TAF, or RPV prior to study entry. Participants were randomized in a 1:1 ratio to either switch to ODEFSEY (N=438) once daily or stay on EFV/FTC/TDF (N=437) once daily. Participants had a mean age of 48 years (range: 19–76), 87% were male, 67% were White, and 27% were Black. The mean baseline CD4+ cell count was 700 cells/mm3 (range: 140–1862).

Treatment outcomes of Trials 1216 and 1160 are presented in Table 13.

14.2 Clinical Trial Results for Adult Participants with no Antiretroviral Treatment History and Adults with Renal Impairment for Components of ODEFSEY

The efficacy of RPV, FTC, and TAF in the treatment of HIV-1 infection in adults as initial therapy in those with no antiretroviral treatment history [see Indications and Usage (1)] was established in trials of:

• RPV+FTC/TDF in adults with HIV-1 as initial therapy in those with no antiretroviral treatment history (n=550). The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 77% at Week 96. The virologic response rate at 96 weeks was 83% in participants with baseline HIV-1 RNA less than or equal to 100,000 copies per mL and 71% in participants with baseline HIV-1 RNA greater than 100,000 copies per mL. Further, the virologic response rate at 96 weeks among participants with baseline CD4+ cell counts less than 200 and greater than or equal to 200 cells/mm3 were 68% and 82%, respectively.
• FTC+TAF with EVG+COBI in adults with HIV-1 as initial therapy in those with no antiretroviral treatment history (n=866). The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 92% at Week 48.

In the clinical trial of 248 adults with HIV-1 and estimated creatinine clearance greater than 30 mL per minute but less than 70 mL per minute, 95% (235/248) of the combined populations of treatment-naïve (N=6) begun on FTC+TAF with EVG+COBI and those previously virologically-suppressed on other regimens (N=242) and switched to FTC+TAF with EVG +COBI had HIV-1 RNA levels less than 50 copies per mL at Week 24.

14.3 Clinical Trial Results for Pediatric Participants Aged 6 to Less than 18 Years Old for Components of ODEFSEY

The efficacy of RPV, FTC, and TAF in the treatment of HIV-1 infection in pediatric patients aged 6 to less than 18 years old and greater than 25 kg as initial therapy in those with no antiretroviral treatment history and to replace a stable antiretroviral regimen in those who are virologically-suppressed [see Indications and Usage (1)] was established in trials of pediatric participants with HIV-1 aged 6 to less than 18 years with:

• RPV in combination with other antiretroviral agents in 36 treatment-naïve adolescents with HIV-1 weighing at least 32 kg. The majority of participants (24/36) received RPV in combination with FTC and TDF. Of these 24 participants, 20 had a baseline HIV-1 RNA less than or equal to 100,000 copies per mL. The virologic response rate in these 20 participants (i.e., HIV-1 RNA less than 50 copies per mL) was 80% (16/20) at 48 weeks.
• RPV in combination with other antiretroviral agents (two NRTIs) in 18 treatment-naïve pediatric participants with HIV-1 weighing at least 17 kg (median [range]: 25 kg [17–51 kg]). The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 72% (13/18) at 48 weeks.
• RPV in combination with other antiretrovirals in 26 virologically-suppressed pediatric participants with HIV-1 less than 12 years old weighing at least 16 kg (N=26) at 48-week.
• FTC+TAF with EVG+COBI in 50 treatment-naïve adolescents with HIV-1 aged 12 to less than 18 years weighing at least 35 kg. The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 92% (46/50) at 48 weeks.
• FTC+TAF with EVG+COBI in 52 virologically-suppressed pediatric participants with HIV-1 aged 6 to less than 12 years weighing at least 25 kg. The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 98% (51/52) at 48 weeks.

Store below 30°C (86°F).

• Keep container tightly closed.
• Dispense only in original container.

Post-treatment Acute Exacerbation of Hepatitis B in Patients with HBV Coinfection

Severe acute exacerbations of hepatitis B have been reported in patients with HBV and HIV-1 who have discontinued products containing FTC and/or TDF, and may likewise occur with discontinuation of ODEFSEY [see Warnings and Precautions (5.1)]. Advise the patient to not discontinue ODEFSEY without first informing their healthcare provider.

Severe Skin Reactions and Hypersensitivity

Inform patients that skin reactions ranging from mild to severe, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported with RPV-containing products. Instruct patients to immediately stop taking ODEFSEY and seek medical attention if they develop a rash associated with any of the following symptoms: fever, blisters, mucosal involvement, eye inflammation (conjunctivitis), severe allergic reaction causing swelling of the face, eyes, lips, mouth, tongue or throat which may lead to difficulty swallowing or breathing, and any signs and symptoms of liver problems, as they may be a sign of a more serious reaction. Patients should understand that if severe rash occurs, they will be closely monitored, laboratory tests will be performed and appropriate therapy will be initiated [see Warnings and Precautions (5.2)].

Hepatotoxicity

Inform patients that hepatotoxicity has been reported with RPV, therefore, it is important to inform the healthcare professional if patients have underlying hepatitis B or C or elevations in liver-associated tests prior to treatment [see Dosage and Administration (2.1) and Warnings and Precautions (5.3)].

Depressive Disorders

Inform patients that depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with RPV. Inform patients to seek immediate medical evaluation if they experience depressive symptoms [see Warnings and Precautions (5.4)].

New Onset or Worsening Renal Impairment

Advise patients to avoid taking ODEFSEY with concurrent or recent use of nephrotoxic agents. Postmarketing cases of renal impairment, including acute renal failure, have been reported [see Warnings and Precautions (5.5)].

Drug Interactions

ODEFSEY may interact with many drugs and is not recommended to be coadministered with numerous drugs. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort [see Contraindications (4), Warnings and Precautions (5.6) and Drug Interactions (7)].

Lactic Acidosis and Severe Hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to ODEFSEY. Advise patients to stop taking ODEFSEY if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.7)].

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.8)].

Missed Dosage

Inform patients that it is important to take ODEFSEY on a regular dosing schedule with a meal and to avoid missing doses, as it can result in development of resistance [see Dosage and Administration (2.2)].

Pregnancy Registry

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to ODEFSEY during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Instruct patients with HIV-1 that the potential risks of breastfeeding include: (1) HIV-1 transmission to infants without HIV-1, (2) developing viral resistance in infants with HIV-1, and (3) adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)].