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Emtricitabine, Rilpivirine, and Tenofovir Alafenamide

Pronunciation

(em trye SYE ta been, ril pi VIR een, & ten OF oh vir al a FEN a mide)

Index Terms

  • Emtricitab/Rilpiviri/Tenof Ala
  • Rilpivirine, Emtricitabine, and Tenofovir Alafenamide
  • Tenofovir Alafenamide, Emtricitabine, and Rilpivirine
  • Tenofovir Alafenamide, Rilpivirine, and Emtricitabine

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

Brand Names: U.S.

  • Odefsey

Pharmacologic Category

  • Antiretroviral, Reverse Transcriptase Inhibitor, Non-nucleoside (Anti-HIV)
  • Antiretroviral, Reverse Transcriptase Inhibitor, Nucleoside (Anti-HIV)
  • Antiretroviral, Reverse Transcriptase Inhibitor, Nucleotide (Anti-HIV)

Pharmacology

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 and older 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 at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components.

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.

Dosing: Adult

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

HIV-1 infection: Children and Adolescents ≥12 years and ≥35 kg: Oral: Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: Use is not recommended.

Dosing: Hepatic Impairment

Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustments necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Administration

Oral: Administer with a meal.

Dietary Considerations

Take with a meal. Consider calcium and vitamin D supplementation.

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. Consider therapy modification

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

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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. 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

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. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. 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. 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. 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. 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

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

H2-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

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

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

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

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: Roxithromycin. 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. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

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

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

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

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. 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. Monitor therapy

Adverse Reactions

See individual agents.

ALERT: U.S. Boxed Warning

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 in combination with other antiretrovirals.

HIV-1 and hepatitis B coinfection:

Emtricitabine/rilpivirine/tenofovir alafenamide is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and safety and efficacy have not been established in patients coinfected with human immunodeficiency virus-1 (HIV-1) and HBV. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate, and may occur with discontinuation of emtricitabine/rilpivirine/tenofovir alafenamide.

Hepatic function should be monitored closely with both 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. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Warnings/Precautions

Concerns related to adverse effects:

• Decreased bone mineral density: In clinical trials, tenofovir has been associated with decreases in bone mineral density in HIV-1 infected adults and increases in bone metabolism markers. Consider monitoring of bone density in adult and pediatric patients with a history of pathologic fractures or with other risk factors for bone loss or osteoporosis. Calcium and vitamin D supplementation may be beneficial for all patients. Long-term significance of these changes are unknown. If abnormalities are suspected, expert assessment is recommended.

• Depressive disorders: May cause depression, depressed mood, dysphoria, major depression, mood changes, negative thoughts, suicide attempts, or suicidal ideation; if symptoms are noted, patients should be advised to seek professional intervention immediately; reevaluate risk versus benefit of continued combination therapy.

• Fat redistribution: May cause redistribution/accumulation of fat (eg, buffalo hump, peripheral wasting facial wasting, breast enlargement, cushingoid appearance).

• 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 hypersensitivity or skin rash develop.

• 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) later in therapy; further evaluation and treatment may be required.

• Lactic acidosis/hepatomegaly: [US Boxed Warning]: Lactic acidosis and severe hepatomegaly with steatosis have been reported with nucleoside analogues (eg, tenofovir), including fatal cases; use with caution in patients with risk factors for liver disease (risk may be increased with female gender, obesity or prolonged nucleoside exposure) and suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (transaminase elevation may/may not accompany hepatomegaly and steatosis). Some cases of hepatotoxicity have occurred in patients with no hepatic disease prior to treatment.

• Osteomalacia and renal dysfunction: In patients taking tenofovir disoproxil fumarate, cases of osteomalacia associated with proximal renal tubulopathy with bone pain or extremity pain (which may contribute to fractures) have been reported; hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy have also occurred in patients at risk for renal dysfunction who present with persistent or worsening bone or muscle symptoms. The risk of osteomalacia in patients taking tenofovir alafenamide is not known. In patients at risk for renal dysfunction, persistent or worsening bone or muscle symptoms should be evaluated for renal dysfunction, hypophosphatemia and osteomalacia.

• 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 NSAIDs) are at increased risk. Assess estimated creatinine clearance, urine protein, and urine glucose prior to initiation of therapy and during therapy. Monitor serum phosphorus in patients with chronic kidney disease (increased risk of developing Fanconi syndrome). 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 and 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. All patients with HIV should be tested for HBV prior to initiation of treatment. Monitor hepatic function closely for several months following discontinuation in patients coinfected with HIV-1 and HBV. If appropriate, initiation of HBV therapy may be needed.

• Renal impairment: Use is not recommended in patients with CrCl <30 mL/minute.

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, urine glucose, urine protein (prior to initiation and as clinically indicated during therapy); serum phosphorus (in patients with chronic kidney disease); 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; testing for HBV is recommended prior to the initiation of antiretroviral therapy. If used as therapy replacement in virologically suppressed patients meeting criteria, additional HIV-1 RNA and regimen tolerability monitoring is recommended to assess potential virologic failure or rebound. Patients with HIV and HBV coinfection should be monitored for several months following therapy discontinuation.

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination; refer to individual monographs.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, fatigue, nausea, vomiting, abdominal pain, insomnia, or dizziness. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice); signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain); signs of lactic acidosis (fast breathing, tachycardia, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps); signs of depression (suicidal ideation, anxiety, emotional instability, or confusion); bone pain; change in body fat; signs of infection; sores in mouth, throat, nose, or eyes; eye irritation; eye redness; difficulty swallowing; or signs of severe skin problems (red, blistered, or swollen skin; peeling skin; itchy or painful skin) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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