Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate

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# Black Box Warning

# Overview
Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is a combination of two nucleoside analog reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor that is FDA approved for the treatment of HIV-1 infection. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include headache, dizziness, drowsiness, hyperlipoproteinemia, insomnia, abnormal dreams, skin rash, diarrhea, vomiting, nausea, abdominal pain, gastroenteritis, infection, weakness, otitis media, cough, rhinitis, and fever.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is indicated as a complete regimen for the treatment of HIV-1 infection in patients 12 years of age and older as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies per mL; or to replace a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) for at least six months with no history of treatment failure and no known substitutions associated with resistance to the individual components of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
Dosing Information
- The recommended dosage of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is one tablet taken orally once daily with a meal in adults with body weight greater than or equal to 35 kg and a creatinine clearance greater than or equal to 30 mL per minute.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is a 3-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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is one tablet taken orally once daily with a meal in the following patient population:
Pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg and a creatinine clearance greater than or equal to 30 mL per minute.
- Pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg and a creatinine clearance greater than or equal to 30 mL per minute.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate in pediatric patients.

# Contraindications
Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is contraindicated when coadministered with the following drugs, as significant decreases in RPV plasma concentrations may occur due to cytochrome P450 (CYP) 3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate or to the class of NNRTIs.
- the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
- the antimycobacterials rifampin and rifapentine
- proton pump inhibitors, such as dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
- the glucocorticoid systemic dexamethasone (more than a single dose)
- St. John's wort (Hypericum perforatum)

# Warnings
- Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV
Patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy. Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is not approved for the treatment of chronic HBV infection, and the safety and efficacy of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate have not been established in patients coinfected with HIV-1 and HBV.
Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing FTC and/or TDF, and may occur with discontinuation of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
Patients coinfected with HIV-1 and HBV who discontinue emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of antihepatitis 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.
- Patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy. Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is not approved for the treatment of chronic HBV infection, and the safety and efficacy of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate have not been established in patients coinfected with HIV-1 and HBV.
- Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing FTC and/or TDF, and may occur with discontinuation of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
- Patients coinfected with HIV-1 and HBV who discontinue emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of antihepatitis 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.
- 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 subjects. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy. Discontinue emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate 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.
- 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 subjects. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy. Discontinue emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate 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.
- Loss of Virologic Response Due to Drug Interactions
The concomitant use of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate and other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate and possible development of resistance due to reduced exposure of RPV.
Consider the potential for drug interactions prior to and during emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate therapy; review concomitant medications during emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate therapy; and monitor for the adverse reactions associated with the concomitant drugs.
- The concomitant use of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate and other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate and possible development of resistance due to reduced exposure of RPV.
- Consider the potential for drug interactions prior to and during emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate therapy; review concomitant medications during emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate therapy; and monitor for the adverse reactions associated with the concomitant drugs.
- Prolongation of QTc Interval with Higher Than Recommended Dosages
In healthy subjects, higher than recommended doses of RPV (75 mg once daily and 300 mg once daily  3 and 12 times the recommended dosages, respectively) have been shown to prolong the QTc interval of the electrocardiogram. Consider alternatives to emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsades de Pointes.
- In healthy subjects, higher than recommended doses of RPV (75 mg once daily and 300 mg once daily  3 and 12 times the recommended dosages, respectively) have been shown to prolong the QTc interval of the electrocardiogram. Consider alternatives to emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsades de Pointes.
- 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate, and to determine whether the risks of continued therapy outweigh the benefits.
In Phase 3 trials of RPV in adult subjects (N=1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among RPV-treated subjects (n=686) was 9%. Most events were mild or moderate in severity. In RPV-treated subjects, 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 subjects, respectively.
During the Phase 2 trial in RPV-treated pediatric subjects 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 Grade 3 and 4 depressive disorders (regardless of causality) was 6% (2/36). None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 subject.
- 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate, and to determine whether the risks of continued therapy outweigh the benefits.
In Phase 3 trials of RPV in adult subjects (N=1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among RPV-treated subjects (n=686) was 9%. Most events were mild or moderate in severity. In RPV-treated subjects, 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 subjects, respectively.
During the Phase 2 trial in RPV-treated pediatric subjects 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 Grade 3 and 4 depressive disorders (regardless of causality) was 6% (2/36). None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 subject.
- In Phase 3 trials of RPV in adult subjects (N=1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among RPV-treated subjects (n=686) was 9%. Most events were mild or moderate in severity. In RPV-treated subjects, 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 subjects, respectively.
- During the Phase 2 trial in RPV-treated pediatric subjects 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 Grade 3 and 4 depressive disorders (regardless of causality) was 6% (2/36). None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 subject.
- Hepatotoxicity
Hepatic adverse events have been reported in patients receiving an RPV-containing regimen. Patients with underlying hepatitis B or C, 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. A few cases of hepatic toxicity have been reported in adult patients receiving a 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate 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.
- Hepatic adverse events have been reported in patients receiving an RPV-containing regimen. Patients with underlying hepatitis B or C, 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. A few cases of hepatic toxicity have been reported in adult patients receiving a 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate 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.
- Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including FTC and RPV, both components of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections , which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barre syndrome) 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.
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including FTC and RPV, both components of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections , which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barre syndrome) 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.
- New Onset or Worsening Renal Impairment
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of FTC+TAF with EVG+COBI, there have been no cases of Fanconi syndrome or proximal renal tubulopathy (PRT). In clinical trials of FTC+TAF with EVG+COBI in treatment-naive subjects and in virally suppressed subjects switched to FTC+TAF with EVG+COBI with eGFRs greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with FTC+TAF with EVG+COBI. In a study of virally suppressed subjects with baseline eGFRs between 30 and 69 mL per minute treated with FTC+TAF with EVG+COBI for a median duration of 43 weeks, FTC+TAF with EVG+COBI was permanently discontinued due to worsening renal function in two of 80 (3%) subjects with a baseline eGFR between 30 and 50 mL per minute. Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is not recommended in patients with estimated creatinine clearance below 30 mL per minute because data in this population are insufficient.
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.
Estimated creatinine clearance, urine glucose and urine protein should be assessed before initiating emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate therapy and should be monitored during therapy in all patients. Serum phosphorus should be monitored in patients with chronic kidney disease because these patients are at greater risk of developing Fanconi syndrome on tenofovir prodrugs. Discontinue emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.
- Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of FTC+TAF with EVG+COBI, there have been no cases of Fanconi syndrome or proximal renal tubulopathy (PRT). In clinical trials of FTC+TAF with EVG+COBI in treatment-naive subjects and in virally suppressed subjects switched to FTC+TAF with EVG+COBI with eGFRs greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with FTC+TAF with EVG+COBI. In a study of virally suppressed subjects with baseline eGFRs between 30 and 69 mL per minute treated with FTC+TAF with EVG+COBI for a median duration of 43 weeks, FTC+TAF with EVG+COBI was permanently discontinued due to worsening renal function in two of 80 (3%) subjects with a baseline eGFR between 30 and 50 mL per minute. Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is not recommended in patients with estimated creatinine clearance below 30 mL per minute because data in this population are insufficient.
- 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.
- Estimated creatinine clearance, urine glucose and urine protein should be assessed before initiating emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate therapy and should be monitored during therapy in all patients. Serum phosphorus should be monitored in patients with chronic kidney disease because these patients are at greater risk of developing Fanconi syndrome on tenofovir prodrugs. Discontinue emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.
- 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate 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).
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate 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).
- Bone Loss and Mineralization Defects
Decrease in Bone mineral density (BMD)
In animal toxicology studies and human clinical trials, TAF and tenofovir have been associated with decreases in BMD and increases in biochemical markers of bone metabolism suggestive of increased bone turnover. In clinical trials in HIV-1 infected treatment-naive adults, a significant decline in BMD was observed in 15% of subjects treated with FTC+TAF with EVG+COBI. The long-term clinical significance of these changes has not been established.
Assessment of BMD should be considered for adults and pediatric patients treated with emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Calcium and vitamin D supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.
Mineralization Defects:
Cases of osteomalacia associated with proximal renal tubulopathy (PRT), manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of TDF-containing products. Hypophosphatemia and osteomalacia secondary to PRT have occurred in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing TDF. While not observed in clinical studies of FTC+TAF with EVG+COBI, the risk of osteomalacia with emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is not known.
- Decrease in Bone mineral density (BMD)
In animal toxicology studies and human clinical trials, TAF and tenofovir have been associated with decreases in BMD and increases in biochemical markers of bone metabolism suggestive of increased bone turnover. In clinical trials in HIV-1 infected treatment-naive adults, a significant decline in BMD was observed in 15% of subjects treated with FTC+TAF with EVG+COBI. The long-term clinical significance of these changes has not been established.
Assessment of BMD should be considered for adults and pediatric patients treated with emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Calcium and vitamin D supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.
- In animal toxicology studies and human clinical trials, TAF and tenofovir have been associated with decreases in BMD and increases in biochemical markers of bone metabolism suggestive of increased bone turnover. In clinical trials in HIV-1 infected treatment-naive adults, a significant decline in BMD was observed in 15% of subjects treated with FTC+TAF with EVG+COBI. The long-term clinical significance of these changes has not been established.
- Assessment of BMD should be considered for adults and pediatric patients treated with emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Calcium and vitamin D supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.
- Mineralization Defects:
Cases of osteomalacia associated with proximal renal tubulopathy (PRT), manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of TDF-containing products. Hypophosphatemia and osteomalacia secondary to PRT have occurred in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing TDF. While not observed in clinical studies of FTC+TAF with EVG+COBI, the risk of osteomalacia with emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is not known.
- Cases of osteomalacia associated with proximal renal tubulopathy (PRT), manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of TDF-containing products. Hypophosphatemia and osteomalacia secondary to PRT have occurred in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing TDF. While not observed in clinical studies of FTC+TAF with EVG+COBI, the risk of osteomalacia with emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is not known.

# Adverse Reactions

## 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.
- Adverse Reactions in Clinical Trials of RPV-Containing Regimens in Adult Subjects with HIV-1 Infection
In pooled 96-week trials of antiretroviral treatment-naive HIV-1 infected adult subjects, the most common adverse reactions in subjects treated with RPV+FTC/TDF (N=550) (incidence greater than or equal to 2%, Grades 24) were headache, depressive disorders, and insomnia. The proportion of subjects who discontinued treatment with RPV+FTC/TDF due to adverse reactions, regardless of severity, was 2%. The most common adverse reactions that led to discontinuation in this treatment group were psychiatric disorders (1.6%) and rash (0.2%). Although the safety profile was similar in virologically-suppressed adults with HIV-1 infection who were switched to RPV and other antiretroviral drugs, the frequency of adverse events increased by 20% (N=317).
- In pooled 96-week trials of antiretroviral treatment-naive HIV-1 infected adult subjects, the most common adverse reactions in subjects treated with RPV+FTC/TDF (N=550) (incidence greater than or equal to 2%, Grades 24) were headache, depressive disorders, and insomnia. The proportion of subjects who discontinued treatment with RPV+FTC/TDF due to adverse reactions, regardless of severity, was 2%. The most common adverse reactions that led to discontinuation in this treatment group were psychiatric disorders (1.6%) and rash (0.2%). Although the safety profile was similar in virologically-suppressed adults with HIV-1 infection who were switched to RPV and other antiretroviral drugs, the frequency of adverse events increased by 20% (N=317).
- Adverse Reactions in Clinical Trials of FTC+TAF with EVG+COBI in Adult Subjects with HIV-1 Infection
In pooled 48-week trials of antiretroviral treatment-naive HIV-1 infected adult subjects, the most common adverse reaction in subjects treated with FTC+TAF with EVG+COBI (N=866) (incidence greater than or equal to 10%, all grades) was nausea (10%). In this treatment group, 0.9% of subjects discontinued FTC+TAF with EVG+COBI due to adverse event. The safety profile was similar in virologically-suppressed adults with HIV-1 infection who were switched to FTC+TAF with EVG+COBI (N=799). Antiretroviral treatment-naive adult subjects treated with FTC+TAF with EVG+COBI experienced mean increases of 30 mg/dL of total cholesterol, 15 mg/dL of LDL cholesterol, 7 mg/dL of HDL cholesterol and 29 mg/dL of triglycerides after 48 weeks of use.
Renal Laboratory Tests
In two 48-week trials in antiretroviral treatment-naive HIV-1 infected adults treated with FTC+TAF with EVG+COBI (N=866) with a median baseline eGFR of 115 mL per minute, mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48. Median urine protein-to-creatinine ratio (UPCR) was 44 mg per gram at baseline and at Week 48. In a 48-week trial in virologically-suppressed TDF-treated adults who switched to FTC+TAF with EVG+COBI (N=959) with a mean baseline eGFR of 112 mL per minute, mean serum creatinine was similar to baseline and median UPCR was 61 mg per gram at baseline and 46 mg per gram at Week 48. In a 24-week trial in adults with renal impairment (baseline eGFR 30 to 69 mL per minute) who received FTC+TAF with EVG+COBI (N=248), mean serum creatinine was 1.5 mg per dL at both baseline and Week 24. Median UPCR was 161 mg per gram at baseline and 93 mg per gram at Week 24.
Bone Mineral Density Effects
In the pooled analysis of two 48-week trials of antiretroviral treatment-naive HIV-1 infected adult subjects, bone mineral density (BMD) from baseline to Week 48 was assessed by dual-energy X-ray absorptiometry (DXA). Mean BMD decreased from baseline to Week 48 by 1.30% with FTC+TAF with EVG+COBI at the lumbar spine and -0.66% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 10% of FTC+TAF with EVG+COBI subjects. BMD declines of 7% or greater at the femoral neck were experienced by 7% of FTC+TAF with EVG+COBI subjects. The long-term clinical significance of these BMD changes is not known. Fractures (excluding fingers and toes) were reported in 7 (0.8%) subjects in the FTC+TAF with EVG+COBI group.
In 799 virologically-suppressed TDF-treated adult subjects that switched to FTC+TAF with EVG+COBI, at Week 48 mean BMD increased (1.86% lumbar spine, 1.95% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 1% of FTC+TAF with EVG+COBI subjects. BMD declines of 7% or greater at the femoral neck were experienced by 1% of FTC+TAF with EVG+COBI subjects.
- In pooled 48-week trials of antiretroviral treatment-naive HIV-1 infected adult subjects, the most common adverse reaction in subjects treated with FTC+TAF with EVG+COBI (N=866) (incidence greater than or equal to 10%, all grades) was nausea (10%). In this treatment group, 0.9% of subjects discontinued FTC+TAF with EVG+COBI due to adverse event. The safety profile was similar in virologically-suppressed adults with HIV-1 infection who were switched to FTC+TAF with EVG+COBI (N=799). Antiretroviral treatment-naive adult subjects treated with FTC+TAF with EVG+COBI experienced mean increases of 30 mg/dL of total cholesterol, 15 mg/dL of LDL cholesterol, 7 mg/dL of HDL cholesterol and 29 mg/dL of triglycerides after 48 weeks of use.
- Renal Laboratory Tests
In two 48-week trials in antiretroviral treatment-naive HIV-1 infected adults treated with FTC+TAF with EVG+COBI (N=866) with a median baseline eGFR of 115 mL per minute, mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48. Median urine protein-to-creatinine ratio (UPCR) was 44 mg per gram at baseline and at Week 48. In a 48-week trial in virologically-suppressed TDF-treated adults who switched to FTC+TAF with EVG+COBI (N=959) with a mean baseline eGFR of 112 mL per minute, mean serum creatinine was similar to baseline and median UPCR was 61 mg per gram at baseline and 46 mg per gram at Week 48. In a 24-week trial in adults with renal impairment (baseline eGFR 30 to 69 mL per minute) who received FTC+TAF with EVG+COBI (N=248), mean serum creatinine was 1.5 mg per dL at both baseline and Week 24. Median UPCR was 161 mg per gram at baseline and 93 mg per gram at Week 24.
- In two 48-week trials in antiretroviral treatment-naive HIV-1 infected adults treated with FTC+TAF with EVG+COBI (N=866) with a median baseline eGFR of 115 mL per minute, mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48. Median urine protein-to-creatinine ratio (UPCR) was 44 mg per gram at baseline and at Week 48. In a 48-week trial in virologically-suppressed TDF-treated adults who switched to FTC+TAF with EVG+COBI (N=959) with a mean baseline eGFR of 112 mL per minute, mean serum creatinine was similar to baseline and median UPCR was 61 mg per gram at baseline and 46 mg per gram at Week 48. In a 24-week trial in adults with renal impairment (baseline eGFR 30 to 69 mL per minute) who received FTC+TAF with EVG+COBI (N=248), mean serum creatinine was 1.5 mg per dL at both baseline and Week 24. Median UPCR was 161 mg per gram at baseline and 93 mg per gram at Week 24.
- Bone Mineral Density Effects
In the pooled analysis of two 48-week trials of antiretroviral treatment-naive HIV-1 infected adult subjects, bone mineral density (BMD) from baseline to Week 48 was assessed by dual-energy X-ray absorptiometry (DXA). Mean BMD decreased from baseline to Week 48 by 1.30% with FTC+TAF with EVG+COBI at the lumbar spine and -0.66% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 10% of FTC+TAF with EVG+COBI subjects. BMD declines of 7% or greater at the femoral neck were experienced by 7% of FTC+TAF with EVG+COBI subjects. The long-term clinical significance of these BMD changes is not known. Fractures (excluding fingers and toes) were reported in 7 (0.8%) subjects in the FTC+TAF with EVG+COBI group.
In 799 virologically-suppressed TDF-treated adult subjects that switched to FTC+TAF with EVG+COBI, at Week 48 mean BMD increased (1.86% lumbar spine, 1.95% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 1% of FTC+TAF with EVG+COBI subjects. BMD declines of 7% or greater at the femoral neck were experienced by 1% of FTC+TAF with EVG+COBI subjects.
- In the pooled analysis of two 48-week trials of antiretroviral treatment-naive HIV-1 infected adult subjects, bone mineral density (BMD) from baseline to Week 48 was assessed by dual-energy X-ray absorptiometry (DXA). Mean BMD decreased from baseline to Week 48 by 1.30% with FTC+TAF with EVG+COBI at the lumbar spine and -0.66% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 10% of FTC+TAF with EVG+COBI subjects. BMD declines of 7% or greater at the femoral neck were experienced by 7% of FTC+TAF with EVG+COBI subjects. The long-term clinical significance of these BMD changes is not known. Fractures (excluding fingers and toes) were reported in 7 (0.8%) subjects in the FTC+TAF with EVG+COBI group.
- In 799 virologically-suppressed TDF-treated adult subjects that switched to FTC+TAF with EVG+COBI, at Week 48 mean BMD increased (1.86% lumbar spine, 1.95% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 1% of FTC+TAF with EVG+COBI subjects. BMD declines of 7% or greater at the femoral neck were experienced by 1% of FTC+TAF with EVG+COBI subjects.
- Adverse Reactions in Clinical Trials in Pediatric Subjects with HIV-1 Infection
In an open-label 48-week trial of 36 antiretroviral treatment-naive HIV-1 infected pediatric subjects 12 to less than 18 years old (weighing at least 32 kg) treated with 25 mg per day of RPV and other antiretrovirals, the most common adverse reactions were headache (19%), depression (19%), somnolence (14%), nausea (11%), dizziness (8%), abdominal pain (8%), vomiting (6%) and rash (6%).
In a 24-week, open-label trial of 23 antiretroviral treatment-naive HIV-1 infected pediatric subjects aged 12 to less than 18 years old (weighing at least 35 kg) who received FTC+TAF with EVG+COBI, the safety of this combination was similar to that of adults. Among these pediatric subjects, mean BMD increased from baseline to Week 24, +1.7% at the lumbar spine and +0.8% for the total body less head. Mean changes from baseline BMD Z-scores were -0.10 for lumbar spine and -0.11 for total body less head at Week 24. Two subjects had significant (greater than 4%) lumbar spine BMD loss at Week 24.
- In an open-label 48-week trial of 36 antiretroviral treatment-naive HIV-1 infected pediatric subjects 12 to less than 18 years old (weighing at least 32 kg) treated with 25 mg per day of RPV and other antiretrovirals, the most common adverse reactions were headache (19%), depression (19%), somnolence (14%), nausea (11%), dizziness (8%), abdominal pain (8%), vomiting (6%) and rash (6%).
- In a 24-week, open-label trial of 23 antiretroviral treatment-naive HIV-1 infected pediatric subjects aged 12 to less than 18 years old (weighing at least 35 kg) who received FTC+TAF with EVG+COBI, the safety of this combination was similar to that of adults. Among these pediatric subjects, mean BMD increased from baseline to Week 24, +1.7% at the lumbar spine and +0.8% for the total body less head. Mean changes from baseline BMD Z-scores were -0.10 for lumbar spine and -0.11 for total body less head at Week 24. Two subjects had significant (greater than 4%) lumbar spine BMD loss at Week 24.

## Postmarketing Experience
The following adverse reactions have been identified during postmarketing experience in patients receiving RPV-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.
- Metabolism and nutrition disorders
Weight increased
- Weight increased
- Skin and Subcutaneous Tissue disorders
Severe skin and hypersensitivity reactions including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
- Severe skin and hypersensitivity reactions including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
- Renal and Urinary Disorders
Nephrotic syndrome
- Nephrotic syndrome

# Drug Interactions
- Potential for Other Drugs to Affect One or More Components of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate
Drugs that Induce or Inhibit CYP3A Enzymes
RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV. 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. Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV and possible adverse events.
Drugs that Induce or Inhibit P-glycoprotein
TAF, a component of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate, is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp activity (e.g., cyclosporine) may lead to changes in TAF absorption (see TABLE 1). 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate and development of resistance. Coadministration of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate with other drugs that inhibit P-gp may result in increased absorption and plasma concentrations of TAF and possible adverse events.
Drugs that Increase Gastric pH
Coadministration of RPV with drugs that increase gastric pH (e.g., famotidine) may decrease plasma concentrations of RPV and lead to loss of virologic response and possible resistance to RPV or to the class of NNRTIs (see TABLE 1).
- Drugs that Induce or Inhibit CYP3A Enzymes
RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV. 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. Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV and possible adverse events.
- RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV. 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. Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV and possible adverse events.
- Drugs that Induce or Inhibit P-glycoprotein
TAF, a component of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate, is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp activity (e.g., cyclosporine) may lead to changes in TAF absorption (see TABLE 1). 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate and development of resistance. Coadministration of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate with other drugs that inhibit P-gp may result in increased absorption and plasma concentrations of TAF and possible adverse events.
- TAF, a component of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate, is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp activity (e.g., cyclosporine) may lead to changes in TAF absorption (see TABLE 1). 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate and development of resistance. Coadministration of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate with other drugs that inhibit P-gp may result in increased absorption and plasma concentrations of TAF and possible adverse events.
- Drugs that Increase Gastric pH
Coadministration of RPV with drugs that increase gastric pH (e.g., famotidine) may decrease plasma concentrations of RPV and lead to loss of virologic response and possible resistance to RPV or to the class of NNRTIs (see TABLE 1).
- Coadministration of RPV with drugs that increase gastric pH (e.g., famotidine) may decrease plasma concentrations of RPV and lead to loss of virologic response and possible resistance to RPV or to the class of NNRTIs (see TABLE 1).
- 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 subjects, higher than recommended doses of RPV, 75 mg once daily and 300 mg once daily (3 times and 12 times recommended daily dose in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate) prolonged the QTc interval. Consider alternative medications to emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate in patients taking a drug with a known risk of Torsade de Pointes.
- 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 subjects, higher than recommended doses of RPV, 75 mg once daily and 300 mg once daily (3 times and 12 times recommended daily dose in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate) prolonged the QTc interval. Consider alternative medications to emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate in patients taking a drug with a known risk of Torsade de Pointes.
- Drugs that affect Renal Function
Because FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate 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.
- Because FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate 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.
- Established and Other Potentially Significant Drug Interactions
Table 1 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate, the components of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate (FTC, RPV and TAF) as individual agents, or are predicted drug interactions that may occur with emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.This image is provided by the National Library of Medicine.
- Table 1 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate, the components of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate (FTC, RPV and TAF) as individual agents, or are predicted drug interactions that may occur with emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.This image is provided by the National Library of Medicine.
- Drugs Without Clinically Significant Interactions with emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate
Based on drug interaction studies conducted with the fixed dose combination or components of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate, no clinically significant drug interactions have been either observed or expected when emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is combined with the following drugs: acetaminophen, atorvastatin, buprenorphine, chlorzoxazone, digoxin, ethinyl estradiol, ledipasvir, lorazepam, metformin, midazolam, naloxone, norbuprenorphine, norethindrone, norgestimate/ethinyl estradiol, sildenafil, simeprevir and sofosbuvir.
- Based on drug interaction studies conducted with the fixed dose combination or components of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate, no clinically significant drug interactions have been either observed or expected when emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is combined with the following drugs: acetaminophen, atorvastatin, buprenorphine, chlorzoxazone, digoxin, ethinyl estradiol, ledipasvir, lorazepam, metformin, midazolam, naloxone, norbuprenorphine, norethindrone, norgestimate/ethinyl estradiol, sildenafil, simeprevir and sofosbuvir.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate during pregnancy to inform a drug-associated risk of birth defects and miscarriage. Tenofovir alafenamide (TAF) and rilpivirine (RPV) use in women during pregnancy have not been evaluated; however, emtricitabine (FTC) use during pregnancy has been evaluated in a limited number of women reported to the Antiretroviral Pregnancy Registry. Available data from the APR show no difference in the risk of overall major birth defects for FTC (2.4%) compared with the background rate for major birth defects of 2.7% in a US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 1520%. In animal studies, no adverse developmental effects were observed when the components of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate were administered separately during the period of organogenesis at exposures up to 60 and 108 times (mice and rabbits, respectively; FTC), 15 and 70 times (rats and rabbits, respectively; RPV) and equal to and 53 times (rats and rabbits, respectively; TAF) the exposure at the recommended daily dose of these components in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. Likewise, no adverse developmental effects were seen when FTC was administered to mice and RPV was administered to rats through lactation at exposures up to approximately 60 and 63 times, respectively, the exposure at the recommended daily dose of these components in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. No adverse effects were observed in the offspring when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
- There are insufficient human data on the use of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate during pregnancy to inform a drug-associated risk of birth defects and miscarriage. Tenofovir alafenamide (TAF) and rilpivirine (RPV) use in women during pregnancy have not been evaluated; however, emtricitabine (FTC) use during pregnancy has been evaluated in a limited number of women reported to the Antiretroviral Pregnancy Registry. Available data from the APR show no difference in the risk of overall major birth defects for FTC (2.4%) compared with the background rate for major birth defects of 2.7% in a US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 1520%. In animal studies, no adverse developmental effects were observed when the components of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate were administered separately during the period of organogenesis at exposures up to 60 and 108 times (mice and rabbits, respectively; FTC), 15 and 70 times (rats and rabbits, respectively; RPV) and equal to and 53 times (rats and rabbits, respectively; TAF) the exposure at the recommended daily dose of these components in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. Likewise, no adverse developmental effects were seen when FTC was administered to mice and RPV was administered to rats through lactation at exposures up to approximately 60 and 63 times, respectively, the exposure at the recommended daily dose of these components in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. No adverse effects were observed in the offspring when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
- Data
Human data
Emtricitabine: Based on prospective reports to the APR through July 2015 of 2933 exposures to FTC-containing regimens during pregnancy (including 1984 exposed in the first trimester and 949 exposed in the second/third trimester), there was no difference between FTC and overall birth defects compared with the background birth defects rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.4% (95% CI: 1.7% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.1% (95% CI: 1.3% to 3.2%) with the second/third trimester exposure to FTC-containing regimens.
Animal data
Emtricitabine: FTC was administered orally to pregnant mice (250, 500, or 1000 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 108 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study with FTC, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended daily dose.
Rilpivirine: RPV was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) 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 RPV 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 RPV, 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.
Tenofovir Alafenamide: TAF was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures similar to (rats) and approximately 53 (rabbits) times higher than the exposure in humans at the recommended daily dose of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 59 (rats) and 93 (rabbits) times higher than human tenofovir exposures at the recommended daily doses. Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to tenofovir disoproxil fumarate (TDF, another prodrug for tenofovir) administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation, no adverse effects were observed in the offspring on gestation day 7  at tenofovir exposures of approximately 14  times higher than the exposures in humans at the recommended daily dose of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
- Human data
Emtricitabine: Based on prospective reports to the APR through July 2015 of 2933 exposures to FTC-containing regimens during pregnancy (including 1984 exposed in the first trimester and 949 exposed in the second/third trimester), there was no difference between FTC and overall birth defects compared with the background birth defects rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.4% (95% CI: 1.7% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.1% (95% CI: 1.3% to 3.2%) with the second/third trimester exposure to FTC-containing regimens.
- Emtricitabine: Based on prospective reports to the APR through July 2015 of 2933 exposures to FTC-containing regimens during pregnancy (including 1984 exposed in the first trimester and 949 exposed in the second/third trimester), there was no difference between FTC and overall birth defects compared with the background birth defects rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.4% (95% CI: 1.7% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.1% (95% CI: 1.3% to 3.2%) with the second/third trimester exposure to FTC-containing regimens.
- Animal data
Emtricitabine: FTC was administered orally to pregnant mice (250, 500, or 1000 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 108 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study with FTC, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended daily dose.
Rilpivirine: RPV was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) 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 RPV 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 RPV, 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.
Tenofovir Alafenamide: TAF was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures similar to (rats) and approximately 53 (rabbits) times higher than the exposure in humans at the recommended daily dose of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 59 (rats) and 93 (rabbits) times higher than human tenofovir exposures at the recommended daily doses. Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to tenofovir disoproxil fumarate (TDF, another prodrug for tenofovir) administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation, no adverse effects were observed in the offspring on gestation day 7  at tenofovir exposures of approximately 14  times higher than the exposures in humans at the recommended daily dose of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
- Emtricitabine: FTC was administered orally to pregnant mice (250, 500, or 1000 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 108 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study with FTC, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended daily dose.
- Rilpivirine: RPV was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) 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 RPV 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 RPV, 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.
- Tenofovir Alafenamide: TAF was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures similar to (rats) and approximately 53 (rabbits) times higher than the exposure in humans at the recommended daily dose of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 59 (rats) and 93 (rabbits) times higher than human tenofovir exposures at the recommended daily doses. Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to tenofovir disoproxil fumarate (TDF, another prodrug for tenofovir) administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation, no adverse effects were observed in the offspring on gestation day 7  at tenofovir exposures of approximately 14  times higher than the exposures in humans at the recommended daily dose of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate during labor and delivery.

### Nursing Mothers
- Risk Summary
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, to avoid risking postnatal transmission of HIV.
FTC has been shown to be present in human breast milk; it is unknown if RPV and TAF are present in human breast milk. RPV is present in rat milk and tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF. It is unknown if TAF is present in animal milk.
It is not known if emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate affects milk production or has effects on the breastfed infant. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
- The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, to avoid risking postnatal transmission of HIV.
- FTC has been shown to be present in human breast milk; it is unknown if RPV and TAF are present in human breast milk. RPV is present in rat milk and tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF. It is unknown if TAF is present in animal milk.
- It is not known if emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate affects milk production or has effects on the breastfed infant. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
- Data
Human data
Emtricitabine: Samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is present in human milk. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown.
Animal data
Rilpivirine: In animals, no studies have been conducted to assess the excretion of rilpivirine directly; however RPV was measured in rat pups which were exposed through the milk of treated dams (dosed up to 400 mg/kg/day).
Tenofovir Alafenamide: Studies in rats and monkeys have demonstrated that tenofovir is secreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11. Tenofovir was excreted into the milk of lactating monkeys, following a single subcutaneous (30 mg/kg) dose of tenofovir, at concentrations up to approximately 4% of plasma concentration resulting in exposure (AUC) of approximately 20% of plasma exposure.
- Human data
Emtricitabine: Samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is present in human milk. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown.
- Emtricitabine: Samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is present in human milk. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown.
- Animal data
Rilpivirine: In animals, no studies have been conducted to assess the excretion of rilpivirine directly; however RPV was measured in rat pups which were exposed through the milk of treated dams (dosed up to 400 mg/kg/day).
Tenofovir Alafenamide: Studies in rats and monkeys have demonstrated that tenofovir is secreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11. Tenofovir was excreted into the milk of lactating monkeys, following a single subcutaneous (30 mg/kg) dose of tenofovir, at concentrations up to approximately 4% of plasma concentration resulting in exposure (AUC) of approximately 20% of plasma exposure.
- Rilpivirine: In animals, no studies have been conducted to assess the excretion of rilpivirine directly; however RPV was measured in rat pups which were exposed through the milk of treated dams (dosed up to 400 mg/kg/day).
- Tenofovir Alafenamide: Studies in rats and monkeys have demonstrated that tenofovir is secreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11. Tenofovir was excreted into the milk of lactating monkeys, following a single subcutaneous (30 mg/kg) dose of tenofovir, at concentrations up to approximately 4% of plasma concentration resulting in exposure (AUC) of approximately 20% of plasma exposure.

### Pediatric Use
The efficacy and safety of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate as a complete regimen for the treatment of HIV-1 infection was established in pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg. Use of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate 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 infection, and by the following pediatric studies:
- 48-week open-label trial of 36 antiretroviral treatment-naive HIV-1 infected pediatric subjects 12 to less than 18 years old weighing at least 32 kg treated with 25 mg per day of RPV and other antiretrovirals. The safety and efficacy of RPV and other antiretrovirals was similar to that of antiretroviral treatment-naive HIV-1 infected adults on this regimen.
- 24-week open-label trial of 23 antiretroviral treatment-naive HIV-1 infected pediatric subjects 12 to less than 18 years old (weighing at least 35 kg) treated with FTC+TAF with EVG+COBI. The safety and efficacy of FTC+TAF with EVG+COBI was similar to that of antiretroviral treatment-naive HIV-1 infected adults on this regimen.
Because it is a fixed-dose combination tablet, the dose of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate cannot be adjusted for patients of lower age and weight. The safety and efficacy of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate have not been established in pediatric patients less than 12 years of age or weighing less than 35 kg.

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

### Gender
There is no FDA guidance on the use of Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate with respect to specific racial populations.

### Renal Impairment
Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is not recommended in patients with severe renal impairment (estimated creatinine clearance below 30 mL per minute). No dosage adjustment of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is recommended in patients with estimated creatinine clearance greater than or equal to 30 mL per minute.

### Hepatic Impairment
No dosage adjustment of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate has not been studied in patients with severe hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate in patients who are immunocompromised.

# Administration and Monitoring

### Administration

### HIV-1
- Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is indicated as a complete regimen for the treatment of HIV-1 infection in patients 12 years of age and older as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies per mL; or to replace a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) for at least six months with no history of treatment failure and no known substitutions associated with resistance to the individual components of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
- Prior to initiation of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate, patients should be tested for hepatitis B virus infection. Estimated creatinine clearance, urine glucose, and urine protein should be assessed before initiating emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate therapy.
- Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is not recommended in patients with estimated creatinine clearance below 30 mL per minute

### Monitoring
- Estimated creatinine clearance, urine glucose, and urine protein should be monitored during therapy in all patients.
- In virologically-suppressed patients, additional monitoring of HIV-1 RNA and regimen tolerability is recommended after replacing therapy to assess for potential virologic failure or rebound.

# IV Compatibility
There is limited information regarding the compatibility of Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate and IV administrations.

# Overdosage
No data are available on overdose of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate in patients. If overdose occurs, monitor the patient for evidence of toxicity. Treatment of overdose with emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient.
- Emtricitabine (FTC): Limited clinical experience is available at doses higher than the recommended dosage of FTC in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. In one clinical pharmacology study, single doses of FTC 1200 mg (6 times the dose in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate) were administered to 11 subjects. No severe adverse reactions were reported. The effects of higher doses are not known. 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. Administration of activated charcoal may be used to aid in removal of unabsorbed active substance.
- Tenofovir Alafenamide (TAF): Limited clinical experience is available at doses higher than the recommended dosage of TAF in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. A single dose of 125 mg TAF (5 times the dose of TAF in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate) was administered to 48 healthy subjects; no serious adverse reactions were reported. The effects of higher doses are unknown. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.

# Pharmacology
There is limited information regarding the Drug Box of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.

## Mechanism of Action
Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate is a fixed dose combination of antiretroviral drugs emtricitabine, rilpivirine, and tenofovir alafenamide.
- Emtricitabine: FTC, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5-triphosphate is a weak inhibitor of mammalian DNA polymerases , , , and mitochondrial DNA polymerase .
- Rilpivirine: RPV is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 RT. RPV does not inhibit the human cellular DNA polymerases , , and mitochondrial DNA polymerase .
- Tenofovir Alafenamide: TAF is a phosphonoamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analog). Plasma exposure to TAF allows for permeation into cells and then TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain termination.
- Tenofovir has activity against human immunodeficiency virus (HIV-1). Cell culture studies have shown that both tenofovir and FTC can be fully phosphorylated when combined in cells. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase  and there is no evidence of toxicity to mitochondria cell culture.

## Structure
There is limited information regarding Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate Structure in the drug label.

## Pharmacodynamics
Cardiac Electrophysiology
- When higher than recommended RPV doses of 75 mg (3 times the recommended dosage in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate) once daily and 300 mg (12 times the recommended dosage in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate) once daily were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of RPV 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6 times and 6.7 times, respectively, higher than the mean Cmax observed with the recommended 25 mg once daily dose of RPV
- The effect of RPV at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo-, and active- (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction was 2 (5) milliseconds (i.e., below the threshold of clinical concern).
- In a thorough QT/QTc study in 48 healthy subjects, TAF at the recommended dose and at a dose approximately 5 times the recommended dose, did not affect the QT/QTc interval and did not prolong the PR interval.
- The effect of FTC on the QT interval is not known.

## Pharmacokinetics
Absorption, Distribution, Metabolism, and Excretion
The pharmacokinetic properties of the components of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate are provided in Table 2. The multiple dose pharmacokinetic parameters of FTC, RPV and TAF and its metabolite tenofovir are provided in Table 3.
Specific populations
- Patients with renal impairment
Rilpivirine: Population pharmacokinetic analysis indicated that RPV exposure was similar in HIV-1 infected subjects with eGFR 60 to 89 mL per minute by Cockcroft-Gault method relative to HIV-1 infected subjects with normal renal function. There is limited or no information regarding the pharmacokinetics of RPV in patients with moderate or severe renal impairment or in patients with end-stage renal disease
Tenofovir Alafenamide: The pharmacokinetics of FTC+TAF with EVG+COBI in HIV-1 infected subjects with renal impairment (eGFR 30 to 69 mL per minute by Cockcroft-Gault method) were evaluated within a subset of virologically-suppressed subjects in an open-label trial (Table 4).
- Rilpivirine: Population pharmacokinetic analysis indicated that RPV exposure was similar in HIV-1 infected subjects with eGFR 60 to 89 mL per minute by Cockcroft-Gault method relative to HIV-1 infected subjects with normal renal function. There is limited or no information regarding the pharmacokinetics of RPV in patients with moderate or severe renal impairment or in patients with end-stage renal disease
- Tenofovir Alafenamide: The pharmacokinetics of FTC+TAF with EVG+COBI in HIV-1 infected subjects with renal impairment (eGFR 30 to 69 mL per minute by Cockcroft-Gault method) were evaluated within a subset of virologically-suppressed subjects in an open-label trial (Table 4).
- Patients with hepatic impairment
Emtricitabine: The pharmacokinetics of FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of hepatic impairment should be limited.
Rilpivirine: In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple-dose exposure of RPV was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment
Tenofovir Alafenamide: Clinically relevant changes in tenofovir pharmacokinetics in subjects with hepatic impairment were not observed in subjects with mild to moderate (Child-Pugh Class A and B) hepatic impairment
- Emtricitabine: The pharmacokinetics of FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of hepatic impairment should be limited.
- Rilpivirine: In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple-dose exposure of RPV was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment
- Tenofovir Alafenamide: Clinically relevant changes in tenofovir pharmacokinetics in subjects with hepatic impairment were not observed in subjects with mild to moderate (Child-Pugh Class A and B) hepatic impairment
Hepatitis B and/or Hepatitis C Virus Coinfection
- The pharmacokinetics of FTC and TAF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus. Population pharmacokinetic analysis indicated that hepatitis B and/or C virus coinfection had no clinically relevant effect on the exposure of RPV.
Pediatric Patients
- Exposures of TAF in 24 pediatric subjects with HIV-1 infection aged 12 to less than 18 years who received FTC+TAF with EVG+COBI were decreased (23% for TAF AUC) compared to exposures achieved in treatment-naive adults following administration of FTC+TAF with EVG+COBI. These exposure differences are not thought to be clinically significant based on exposure-response relationships. FTC exposures were similar in adolescents compared to treatment-naive adults. The PK of RPV in antiretroviral HIV-1-infected pediatric subjects 12 to less than 18 years of age who received RPV 25 mg once daily were comparable to those in HIV-1 infected adults. As in adults, there was no impact of body weight on RPV PK in pediatric subjects.
Geriatric patients
- The pharmacokinetics of FTC and TAF have not been fully evaluated in the elderly (65 years of age and older). Population pharmacokinetics analysis of HIV-infected subjects in Phase 2 and Phase 3 trials of FTC+TAF with EVG+COBI showed that age did not have a clinically relevant effect on exposures of TAF up to 75 years of age.
- The pharmacokinetics of RPV have not been fully evaluated in the elderly (65 years of age and older)
Race
Based on population pharmacokinetic analyses, no dosage adjustment is recommended based on race.
Gender
Based on population pharmacokinetic analyses, no dosage adjustment is recommended based on gender.
Drug Interaction Studies
- Rilpivirine: RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV. RPV at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.
- TAF is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A1. TAF is a weak inhibitor of CYP3A in vitro. TAF is not an inhibitor or inducer of CYP3A in vivo.
- The drug interaction studies described in Tables 58 were conducted with emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate (FTC/RPV/TAF) or the components of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate (FTC, RPV, or TAF) administered individually.
- The effects of coadministered drugs on the exposures of RPV and TAF are shown in Tables 5 and 6, respectively. The effects of RPV and TAF on the exposure of coadministered drugs are shown in Tables 7 and 8, respectively.

## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
Emtricitabine: In long-term carcinogenicity studies of FTC, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (23 times the human systemic exposure at the recommended dose of 200 mg per day in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate) or in rats at doses up to 600 mg per kg per day (28 times the human systemic exposure at the recommended dose in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate).
FTC was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.
FTC did not affect fertility in male rats at approximately 140 times or in male and female mice at approximately 60 times higher exposures (AUC) than in humans given the recommended 200 mg daily dose in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended 200 mg daily dose in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
Rilpivirine: RPV was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 20, 60, and 160 mg per kg per day were administered to mice and doses of 40, 200, 500, and 1500 mg per kg per day were administered to rats. In rats, there were no drug-related neoplasms. In mice, RPV was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent-specific. At the lowest tested doses in the carcinogenicity studies, the systemic exposures (based on AUC) to RPV were 21 times (mice) and 3 times (rats) relative to those observed in humans at the recommended dose (25 mg once daily) in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
RPV has tested negative in the absence and presence of a metabolic activation system, in the in vitro Ames reverse mutation assay and in vitro clastogenicity mouse lymphoma assay. RPV did not induce chromosomal damage in the in vivo micronucleus test in mice.
In a study conducted in rats, there were no effects on mating or fertility with RPV up to 400 mg per kg per day, a dose of RPV that showed maternal toxicity. This dose is associated with an exposure that is approximately 40 times higher than the exposure in humans at the recommended dose of 25 mg once daily in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
Tenofovir Alafenamide: Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF administration, carcinogenicity studies were conducted only with TDF. Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the recommended dose of TDF (300 mg) for HIV-1 infection. The tenofovir exposure in these studies was approximately 167 times (mice) and 55 times (rat) those observed in humans after administration of the daily recommended dose of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. At the high dose in female mice, liver adenomas were increased at tenofovir exposures approximately 10 times (300 mg TDF) and 167 times (emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate) the exposure observed in humans. In rats, the study was negative for carcinogenic findings.
TAF was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.
There were no effects on fertility, mating performance or early embryonic development when TAF was administered to male rats at a dose equivalent to 62 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 14 days prior to mating through Day 7 of gestation.
- Emtricitabine: In long-term carcinogenicity studies of FTC, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (23 times the human systemic exposure at the recommended dose of 200 mg per day in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate) or in rats at doses up to 600 mg per kg per day (28 times the human systemic exposure at the recommended dose in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate).
- FTC was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.
- FTC did not affect fertility in male rats at approximately 140 times or in male and female mice at approximately 60 times higher exposures (AUC) than in humans given the recommended 200 mg daily dose in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended 200 mg daily dose in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
- Rilpivirine: RPV was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 20, 60, and 160 mg per kg per day were administered to mice and doses of 40, 200, 500, and 1500 mg per kg per day were administered to rats. In rats, there were no drug-related neoplasms. In mice, RPV was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent-specific. At the lowest tested doses in the carcinogenicity studies, the systemic exposures (based on AUC) to RPV were 21 times (mice) and 3 times (rats) relative to those observed in humans at the recommended dose (25 mg once daily) in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
- RPV has tested negative in the absence and presence of a metabolic activation system, in the in vitro Ames reverse mutation assay and in vitro clastogenicity mouse lymphoma assay. RPV did not induce chromosomal damage in the in vivo micronucleus test in mice.
- In a study conducted in rats, there were no effects on mating or fertility with RPV up to 400 mg per kg per day, a dose of RPV that showed maternal toxicity. This dose is associated with an exposure that is approximately 40 times higher than the exposure in humans at the recommended dose of 25 mg once daily in emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
- Tenofovir Alafenamide: Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF administration, carcinogenicity studies were conducted only with TDF. Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the recommended dose of TDF (300 mg) for HIV-1 infection. The tenofovir exposure in these studies was approximately 167 times (mice) and 55 times (rat) those observed in humans after administration of the daily recommended dose of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. At the high dose in female mice, liver adenomas were increased at tenofovir exposures approximately 10 times (300 mg TDF) and 167 times (emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate) the exposure observed in humans. In rats, the study was negative for carcinogenic findings.
- TAF was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.
- There were no effects on fertility, mating performance or early embryonic development when TAF was administered to male rats at a dose equivalent to 62 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 14 days prior to mating through Day 7 of gestation.
- 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
- 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.

# Clinical Studies
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 and to replace a stable antiretroviral regimen in those who are virologically-suppressed was established in trials of:
- RPV+FTC/TDF in HIV-1 infected adults as initial therapy in those with no antiretroviral treatment history (n=550) and to replace a first or second stable antiretroviral regimen containing a protease inhibitor and ritonavir in those who were virologically-suppressed with no history of virologic failure or for at least 6 months with no known resistance substitutions (n=317). The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) in these two populations was 77% at Week 96 and 89% at Week 48, respectively. Among treatment-naive subjects, the virologic response rate at 96 weeks was 83% in subjects with baseline HIV-1 RNA less than or equal to 100,000 copies per mL and 71% in subjects with baseline HIV-1 RNA greater than 100,000 copies per mL. Further, the virologic response rate at 96 weeks among subjects 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 HIV-1 infected adults as initial therapy in those with no antiretroviral treatment history (n=866) and to replace a stable antiretroviral regimen in those who were virologically-suppressed for at least 6 months with no known resistance substitutions (n=799). At Week 48, 92% and 96% of patients in the two populations, respectively, had HIV-1 RNA less than 50 copies per mL.
The efficacy of RPV, FTC, and TAF in the treatment of HIV-1 infection in pediatric patients aged 12 to less than 18 years old and greater than 3235 kg as initial therapy in those with no antiretroviral treatment history and to replace a stable antiretroviral regimen in those who are virologically-suppressed was established in trials of antiretroviral treatment-naive HIV-1 infected pediatric subjects 12 to less than 18 years old with:
- RPV in combination with other antiretroviral agents in 36 treatment-naive HIV-1 infected adolescents weighing at least 32 kg. The majority of subjects (24/36) received RPV in combination with FTC and TDF. Of these 24 subjects, 20 had a baseline HIV-1 RNA less than or equal to 100,000 copies per mL. The virologic response rate in these 20 subjects (i.e., HIV-1 RNA less than 50 copies per mL) was 80% (16/20) at 48 weeks.
- FTC+TAF with EVG+COBI in 23 adolescents weighing at least 35 kg. The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 91% at 24 weeks.
In the clinical trial of 248 HIV-1 infected adult patients with 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-naive (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-RNA levels less than 50 copies per mL at Week 24.

# How Supplied
- Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate tablets are gray, capsule-shaped, and film coated with "GSI" debossed on one side and "255" on the other side. Each bottle contains 30 tablets (NDC 61958-2101-1), a silica gel desiccant, and a polyester coil, and is closed with a child-resistant closure.

## Storage
Store below 30 C (86 F).
- Keep container tightly closed.
- Dispense only in original container.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Post-treatment Acute Exacerbation of Hepatitis B in Patients with HBV Coinfection
Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing FTC and/or TDF, and may likewise occur with discontinuation of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. Advise the patient to not discontinue emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate without first informing their healthcare provider.
- Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing FTC and/or TDF, and may likewise occur with discontinuation of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. Advise the patient to not discontinue emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate 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.
- 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 emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate 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.
- Drug Interactions
Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate 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.
- Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- New Onset or Worsening Renal Impairment
Advise patients to avoid taking emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate with concurrent or recent use of nephrotoxic agents. Renal impairment, including cases of acute renal failure, has been reported in association with the use of tenofovir prodrugs.
- Advise patients to avoid taking emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate with concurrent or recent use of nephrotoxic agents. Renal impairment, including cases of acute renal failure, has been reported in association with the use of tenofovir prodrugs.
- Lactic Acidosis and Severe Hepatomegaly
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. Advise patients to stop taking emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. Advise patients to stop taking emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.
- Decrease in Bone Mineral Density
Advise patients that decreases in bone mineral density have been observed with the use of drugs similar to emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. Consider assessment of bone mineral density (BMD) in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.
- Advise patients that decreases in bone mineral density have been observed with the use of drugs similar to emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate. Consider assessment of bone mineral density (BMD) in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.
- Missed Dosage
Inform patients that it is important to take emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate on a regular dosing schedule with a meal and to avoid missing doses, as it can result in development of resistance.
- Inform patients that it is important to take emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate on a regular dosing schedule with a meal and to avoid missing doses, as it can result in development of resistance.
- Pregnancy Registry
Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
- Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate.
- Lactation
Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.
- Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.

# Precautions with Alcohol
Alcohol-Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
ODEFSEY

# Look-Alike Drug Names
There is limited information regarding Emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide fumarate Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price