Emtricitabine, Rilpivirine, and Tenofovir Alafenamide

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Odefsey: Emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir alafenamide 25 mg

Pharmacology

Mechanism of Action

Non-nucleoside, nucleoside, and nucleotide reverse transcriptase inhibitor combination; rilpivirine binds to reverse transcriptase and does not require intracellular phosphorylation for antiviral activity; emtricitabine is a cytosine analogue while tenofovir alafenamide fumarate (TAF) is an analog of adenosine 5'-monophosphate. Each drug interferes with HIV viral RNA dependent DNA polymerase activities resulting in inhibition of viral replication.

Use: Labeled Indications

HIV-1 infection: Treatment of HIV-1 infection (as a complete regimen) in patients ≥12 years of age as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA ≤100,000 copies/mL; or to replace a stable antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) for ≥6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components.

Limitations of use: More rilpivirine-treated patients with no history of antiretroviral treatment with HIV-1 RNA >100,000 copies/mL at therapy initiation experienced virologic failure (HIV-1 RNA ≥50 copies/mL) compared to rilpivirine-treated patients with HIV-1 RNA ≤100,000 copies/mL.

Contraindications

Concurrent use of carbamazepine, systemic dexamethasone (>1 dose), oxcarbazepine, phenobarbital, phenytoin, proton pump inhibitors (PPIs) (eg, dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole), rifampin, rifapentine, and/or St John's wort.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to emtricitabine, rilpivirine, tenofovir alafenamide, or any component of the formulation.

Dosage and Administration

Dosing: Adult

HIV-1 infection: Oral: One tablet once daily.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Prior to initiation, patients should be tested for hepatitis B infection, and baseline estimated creatinine clearance, urine glucose, and urine protein should be assessed in all patients.

HIV-1 infection, treatment:

Ages <12 years or weight <35 kg: Not recommended; product is a fixed-dose combination

Children ≥12 years and Adolescents weighing ≥35 kg: Oral: One tablet once daily

Administration

Oral: Administer with a meal.

Dietary Considerations

Take with a meal.

Storage

Store below 30°C (86°F). Dispense in original container.

Drug Interactions

Acyclovir-Valacyclovir: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Acyclovir-Valacyclovir. Monitor therapy

Adefovir: May diminish the therapeutic effect of Tenofovir Products. Adefovir may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Adefovir. Avoid combination

Aminoglycosides: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Aminoglycosides. Monitor therapy

Antacids: May decrease the serum concentration of Rilpivirine. Management: Administer antacids at least 2 hours before or 4 hours after rilpivirine. Administer antacids at least 6 hours before or 4 hours after the rilpivirine/dolutegravir combination product. Consider therapy modification

Antihepaciviral Combination Products: May increase the serum concentration of Rilpivirine. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Cabozantinib: MRP2 Inhibitors may increase the serum concentration of Cabozantinib. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

CarBAMazepine: May decrease the serum concentration of Rilpivirine. Avoid combination

Cidofovir: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Cidofovir. Monitor therapy

Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Avoid combination

Cobicistat: May enhance the adverse/toxic effect of Tenofovir Products. More specifically, cobicistat may impair proper tenofovir monitoring and dosing. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Rilpivirine. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Darunavir: May increase the serum concentration of Rilpivirine. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

DexAMETHasone (Systemic): May decrease the serum concentration of Rilpivirine. Avoid combination

Diclofenac (Systemic): May enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to this combination whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose. Consider therapy modification

Didanosine: Rilpivirine may decrease the absorption of Didanosine. More specifically, simultaneous coadministration of these drugs creates a conflict between recommendations to administer with (rilpivirine) and without (didanosine) food. Didanosine may decrease the absorption of Rilpivirine. More specifically, simultaneous coadministration of these drugs creates a conflict between recommendations to administer with (rilpivirine) and without (didanosine) food. Management: Administer didanosine on an empty stomach at least 2 hours before or 4 hours after rilpivirine, due to the requirement that rilpivirine be administered with food. Consider therapy modification

Efavirenz: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Efavirenz. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Efavirenz. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ergonovine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Ergonovine. Specifically, this would be most likely with delavrdine, while other Non-Nucleoside Reverse Transcriptase Inhibitors may be more likely to decrease the concentration of Ergonovine. Avoid combination

Etravirine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Etravirine. This has been observed with the NNRTIs efavirenz and nevirapine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Etravirine. This has been observed with delavirdine. Avoid combination

Fosphenytoin: May decrease the serum concentration of Rilpivirine. Avoid combination

Ganciclovir-Valganciclovir: Tenofovir Products may increase the serum concentration of Ganciclovir-Valganciclovir. Ganciclovir-Valganciclovir may increase the serum concentration of Tenofovir Products. Monitor therapy

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

Histamine H2 Receptor Antagonists: May decrease the serum concentration of Rilpivirine. Management: Administer histamine H2 receptor antagonists at least 12 hours before or 4 hours after rilpivirine. Consider therapy modification

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Rilpivirine. Rilpivirine may decrease the serum concentration of Ketoconazole (Systemic). Monitor therapy

LamiVUDine: May enhance the adverse/toxic effect of Emtricitabine. Avoid combination

Levomethadone: Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Levomethadone. Management: Levomethadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Monitor therapy

Lopinavir: May increase the serum concentration of Rilpivirine. Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Macrolide Antibiotics: May increase the serum concentration of Rilpivirine. Management: Consider the use of azithromycin or another non-macrolide alternative when appropriate to avoid this potential interaction. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. Consider therapy modification

Methadone: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the metabolism of Methadone. Management: Methadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents: May enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to these combinations whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose. Consider therapy modification

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

OXcarbazepine: May decrease the serum concentration of Rilpivirine. Avoid combination

OXcarbazepine: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

PHENobarbital: May decrease the serum concentration of Rilpivirine. Avoid combination

PHENobarbital: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Phenytoin: May decrease the serum concentration of Rilpivirine. Avoid combination

Primidone: May decrease the serum concentration of Rilpivirine. Avoid combination

Primidone: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Proton Pump Inhibitors: May decrease the serum concentration of Rilpivirine. Avoid combination

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Reverse Transcriptase Inhibitors (Non-Nucleoside): May increase the serum concentration of Rilpivirine. This mechanism applies to coadministration of delavirdine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Rilpivirine. This mechanism applies to coadministration of efavirenz, etravirine, and nevirapine. Avoid combination

Rifabutin: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

RifAMPin: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Rifapentine: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Saquinavir: May enhance the arrhythmogenic effect of Rilpivirine. Saquinavir may increase the serum concentration of Rilpivirine. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Sofosbuvir: May increase the serum concentration of Tenofovir Alafenamide. Monitor therapy

St John's Wort: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Tipranavir: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Adverse Reactions

Also see individual agents.

1% to 10%:

Central nervous system: Headache (2%), sleep disorder (2%), abnormal dreams (1%)

Gastrointestinal: Diarrhea (1%), nausea (1%), flatulence (≤1%)

Neuromuscular & skeletal: Decreased bone mineral density (1% to 2%)

Frequency not defined: Endocrine: Decreased HDL cholesterol, decreased LDL cholesterol, decreased serum cholesterol, decreased serum triglycerides, increased HDL cholesterol, increased LDL cholesterol, increased serum cholesterol, increased serum triglycerides

Warnings/Precautions

Concerns related to adverse effects:

• Depressive disorders: Rilpivirine may cause depression, depressed mood, dysphoria, major depression, mood changes, negative thoughts, suicide attempts, or suicidal ideation. Promptly evaluate patients with severe depressive symptoms and reevaluate risk versus benefit of continued combination therapy.
• Hepatotoxicity: Hepatotoxicity has been reported with rilpivirine-containing regimens. Patients with hepatitis B or C or increased baseline liver function tests may be at greater risk, although some cases have occurred in patients with no preexisting disease or hepatic disease risk factors. Evaluate liver function tests in patients with increased baseline liver function tests or with hepatitis B or C prior to treatment initiation and periodically during therapy; also consider evaluation of patients with no preexisting hepatic disease or hepatic disease risk factors.
• Hypersensitivity: Hypersensitivity and severe skin reactions have been reported, including severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis or eosinophilia, or drug reaction with eosinophilia and systemic symptoms (DRESS), with regimens containing rilpivirine. Some skin reactions were accompanied by constitutional symptoms (eg, fever); other skin reactions were associated with organ dysfunction (eg, hepatic serum biochemistry elevations). In clinical trials, treatment-related rashes ≥ grade 2 were reported in 1% of patients. Most rashes were grade 1 or 2 and occurred within the first 4 to 6 weeks of therapy. Monitor laboratory parameters and clinical status; discontinue if any severe hypersensitivity or skin rash develops.
• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves disease, polymyositis, Guillain-Barré syndrome, autoimmune hepatitis) later in therapy; further evaluation and treatment may be required.
• Lactic acidosis/hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, sometimes fatal, have been reported with the use of nucleoside analogs, alone or in combination with other antiretrovirals. Suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (marked transaminase elevation may/may not accompany hepatomegaly and steatosis).
• QT prolongation: In healthy subjects, supratherapeutic dosages of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram; consider alternative therapy in patients at high risk for torsades de pointes or when coadministered with medications with known risk for torsades de pointes.
• Renal toxicity: Cases of acute renal failure and/or Fanconi syndrome have been reported with use of tenofovir prodrugs; patients with preexisting renal impairment and those taking nephrotoxic agents (including nonsteroidal anti-inflammatory drugs) are at increased risk. Assess serum creatinine, estimated CrCl, serum phosphorus (chronic kidney disease patients), urine protein, and urine glucose prior to initiation of therapy and during therapy. Discontinue therapy in patients that develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Disease-related concerns:

• Chronic hepatitis B: [US Boxed Warning]: Safety and efficacy during coinfection of HIV-1 and hepatitis B virus (HBV) have not been established; acute, severe exacerbations of HBV have been reported following discontinuation of antiretroviral therapy. Not indicated for treatment of chronic hepatitis B. Closely monitor hepatic function with clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue emtricitabine/rilpivirine/tenofovir alafenamide therapy. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced hepatic disease or cirrhosis (post-treatment exacerbation of hepatitis may lead to hepatic decompensation or liver failure). All patients with HIV should be tested for HBV prior to initiation of treatment.
• Renal impairment: Use is not recommended in patients with CrCl <30 mL/minute (unless receiving hemodialysis).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

CD4 count, HIV RNA plasma levels; serum creatinine, estimated creatinine clearance, serum phosphorus (chronic kidney disease patients), urine glucose, urine protein (prior to initiation and as clinically indicated during therapy); hepatic function tests, bone density (patients with a history of bone fracture or have risk factors for bone loss); fever, skin reactions, and/or hypersensitivity reactions; HBV testing (prior to or when initiating therapy). Patients with HIV and HBV coinfection should be monitored for several months following therapy discontinuation.

Pregnancy

Pregnancy Considerations

The Health and Human Services (HHS) perinatal HIV guidelines note data are insufficient to recommend this fixed-dose combination for initiation in pregnant females living with HIV who are antiretroviral naive, who have had antiretroviral therapy (ART) in the past but are restarting, who require a new ART regimen (due to poor tolerance or poor virologic response of current regimen), and who are not yet pregnant but are trying to conceive. Females who become pregnant while taking this combination may continue if viral suppression is effective and the regimen is well tolerated; however, more frequent monitoring is recommended. Alternately, consider changing tenofovir alafenamide to tenofovir disoproxil fumarate (HHS [perinatal] 2019).

Refer to individual monographs for additional information.

Patient Education

What is this drug used for?

• It is used to treat HIV infection.

Frequently reported side effects of this drug

• Headache
• Fatigue
• Nausea
• Vomiting
• Dizziness
• Abdominal pain
• Trouble sleeping

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Lactic acidosis like fast breathing, fast heartbeat, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps.
• Depression like thoughts of suicide, anxiety, emotional instability, or confusion.
• Abnormal heartbeat
• Infection
• Sores in mouth, throat, nose, or eyes
• Eye irritation
• Eye redness
• Trouble swallowing
• Severe skin problems like red, blistered, or swollen skin; peeling skin; itchy or painful skin.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.