emtricitabine/tenofovir DF /efavirenz

Action and Spectrum

Actions and Spectrum: 

emtricitabine/tenofovir DF /efavirenz is a combination medication for treating HIV-1 infection. Each component of this drug has its unique action and spectrum of activity. emtricitabine and tenofovir belong to a class of antiviral drugs known as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), while efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI). 

emtricitabine and tenofovir work synergistically to inhibit the reverse transcriptase enzyme, which is crucial for the replication of the HIV. emtricitabine is incorporated into the viral DNA chain, preventing its elongation, while tenofovir inhibits the reverse transcriptase enzyme. Together, these drugs help interrupt the virus’s replication process, reducing the viral load and slowing disease progression. emtricitabine and tenofovir are active against both HIV-1 and HIV-2 strains. 

On the other hand, efavirenz acts by binding directly to the reverse transcriptase enzyme and inhibiting its activity. This prevents the conversion of viral RNA into DNA, thus preventing the virus from integrating into the host’s genetic material. efavirenz has a broader spectrum of activity and is effective against HIV-1 and some HIV-2 strains. It is known to be highly potent and can rapidly reduce viral load, leading to improved immune function and a decrease in the risk of opportunistic infections. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Hypercholesterolemia (22%) 

1-10% 

Increased ALT (2%) 

Dizziness (8%) 

Sinusitis (8%) 

Increased creatinine (9%) 

Nausea (9%) 

Rash (7%) 

Neutropenia (3%) 

Fatigue (9%) 

Increased alkaline phosphatase (1%) 

Depression (9%) 

Increased triglycerides (4%) 

Somnolence (4%) 

Increased serum amylase (8%) 

Insomnia (5%) 

Nasopharyngitis (5%) 

Vomiting (2%) 

Hematuria (3%) 

Abnormal dreams (4%) 

Upper respiratory infection (8%) 

Hyperglycemia (2%) 

<1% 

Gycosuria 

Black Box Warning

Black Box Warning: 

• Lactic Acidosis and Severe Hepatomegaly with Steatosis: emtricitabine/tenofovir DF /efavirenz, like another nucleoside/nucleotide analogs, can cause lactic acidosis and severe hepatomegaly with steatosis (enlarged liver with fat accumulation). These conditions can be life-threatening and have been reported, particularly in women, obesity, and individuals with prolonged use of nucleoside/nucleotide analogs. 
• Hepatic Toxicity: emtricitabine/tenofovir DF /efavirenz has been associated with hepatic toxicity, including hepatic decompensation, liver failure, and death. Patients with underlying liver disease or co-infection with hepatitis B or C may have an increased risk of developing liver-related complications. Close monitoring of liver function is essential during treatment. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

• Hypersensitivity: The medication is contraindicated in individuals with known hypersensitivity or allergy to any components, including emtricitabine, tenofovir, or efavirenz. Severe allergic reactions may occur in these cases and require immediate medical attention. 
• Concurrent Use of Certain Medications: emtricitabine/tenofovir DF /efavirenz may interact with other medications, such as certain anticonvulsants (carbamazepine, phenobarbital, phenytoin), St. John’s wort, rifampin, and some other antiretroviral drugs. These interactions can affect the medication’s effectiveness and safety; therefore, their use should be avoided or carefully managed. 
• Hepatic Impairment: The combination drug should be used cautiously in individuals with pre-existing liver disease or impaired liver function. It is contraindicated in individuals with moderate to severe hepatic impairment because of its risk of worsening liver function. 
• Pregnancy and Breastfeeding: emtricitabine/tenofovir DF /efavirenz should not be initiated during pregnancy or in individuals planning to become pregnant due to potential risks to the fetus. It is also not recommended during breastfeeding, as the components of the medication can be excreted in breast milk and might harm the nursing infant. 
• Pediatric Use: Safety and efficacy of emtricitabine/tenofovir DF /efavirenz have not been established in children below the age of 12 years or weighing less than 40 kg. Therefore, its use in this population is not recommended. 

Caution 

• Central Nervous System (CNS) Effects: efavirenz, one of the components of the medication, may cause central nervous system side effects, including dizziness, impaired concentration, abnormal dreams, and insomnia.  
• Psychiatric Symptoms: efavirenz has been associated with psychiatric symptoms, such as severe depression, suicidal ideation, psychosis, and aggressive behavior. Patients should be monitored for any mood or behavior changes and promptly report any symptoms to their healthcare provider. 
• Renal Impairment: emtricitabine and tenofovir are eliminated primarily by the kidneys. Individuals with impaired renal function should be monitored while taking emtricitabine/tenofovir DF /efavirenz, as adjustments in dosing may be necessary to prevent accumulation of the medications and potential renal toxicity. 
• Bone Effects: tenofovir, one of the components of the medication, may cause decreased bone mineral density, which can lead to an enhanced risk of fractures. This concerns patients with a history of bone disease or those at risk for osteoporosis. Regular monitoring of bone density and appropriate supplementation or treatment may be necessary. 
• Hepatitis B Coinfection: emtricitabine and tenofovir have activity against the hepatitis B virus (HBV). However, abrupt discontinuation of emtricitabine/tenofovir DF/efavirenz in patients coinfected with HIV and HBV can lead to severe acute exacerbations of hepatitis B. Therefore, close monitoring of liver function and consultation with a specialist is recommended when discontinuing the medication. 
• Immune Reconstitution Syndrome: In some HIV-infected patients with severe immune deficiency, the initiation of antiretroviral therapy, including emtricitabine/tenofovir DF /efavirenz, may trigger an inflammatory response known as immune reconstitution syndrome. This may manifest as the appearance or worsening of opportunistic infections or inflammatory conditions. Close monitoring and appropriate management of these conditions are necessary. 

Pregnancy / Lactation

Pregnancy consideration:  

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned 

Lactation:   

Excreted into human milk: Yes. 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    
• Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

emtricitabine/tenofovir DF /efavirenz is a combination antiretroviral medication used to treat HIV-1 infection. emtricitabine and tenofovir, both nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), inhibit the reverse transcriptase enzyme, thereby impeding the replication of HIV.

emtricitabine is incorporated into the viral DNA chain, preventing elongation, while tenofovir inhibits the reverse transcriptase enzyme. efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI), binds to and inhibits the reverse transcriptase enzyme directly, preventing the conversion of viral RNA into DNA. This combination drug acts synergistically to disrupt the viral replication process, reduce viral load, improve immune function, and manage HIV-1 infection. 

Pharmacodynamics: 

Mechanism of action: The combination medication emtricitabine/tenofovir DF /efavirenz exerts its antiviral effects against HIV-1: 

emtricitabine (Nucleoside Reverse Transcriptase Inhibitor – NRTI): 

• emtricitabine is a synthetic nucleoside analog incorporated into the viral DNA chain during reverse transcription. 
• Once incorporated, emtricitabine competitively inhibits the activity of reverse transcriptase, the viral enzyme responsible for converting viral RNA into DNA. 
• By interfering with viral DNA elongation, emtricitabine prevents the synthesis of the viral DNA strand, hindering viral replication and reducing the production of new viral particles. 

tenofovir (Nucleotide Reverse Transcriptase Inhibitor – NRTI): 

• tenofovir disoproxil fumarate (DF) is a prodrug of tenofovir. 
• After oral administration, tenofovir is converted to its active form, tenofovir diphosphate, within cells. 
• tenofovir diphosphate acts as a nucleotide analog and competes with natural nucleotides for incorporation into the viral DNA chain during reverse transcription. 
• By serving as a chain terminator, tenofovir prevents the elongation of the viral DNA strand and inhibits the reverse transcriptase enzyme, impeding viral replication. 

efavirenz (Non-Nucleoside Reverse Transcriptase Inhibitor – NNRTI): 

• efavirenz binds non-competitively to the reverse transcriptase enzyme at a hydrophobic pocket, distinct from the active site. 
• This binding induces conformational changes in the enzyme, impairing its activity and inhibiting the conversion of viral RNA into DNA. 
• efavirenz exhibits potent antiviral activity against HIV-1 and helps to suppress viral replication. 

Pharmacokinetics: 

Absorption 

emtricitabine is rapidly and well absorbed from the gastrointestinal tract following oral administration. 

tenofovir disoproxil fumarate (DF), the prodrug form of tenofovir, is rapidly absorbed from the gastrointestinal tract and undergoes conversion to tenofovir in the body. 

efavirenz is well absorbed from the gastrointestinal tract, with high oral bioavailability. 

Distribution 

emtricitabine has good distribution throughout the body, including penetration into cerebrospinal fluid, breast milk, and genital tract secretions. 

tenofovir has a relatively large volume of distribution and is distributed to various tissues, including the kidneys, liver, and lymphoid tissues. 

efavirenz is extensively distributed throughout the body, crossing the blood-brain barrier and penetrating cerebrospinal fluid. 

Metabolism 

emtricitabine is primarily metabolized by the liver via oxidation of the methyl group, forming the inactive metabolite 3′-sulfoxide emtricitabine. 

tenofovir undergoes minimal metabolism in the body. 

efavirenz is extensively metabolized in the liver via cytochrome P450 enzymes, primarily CYP2B6, forming several metabolites, including the active 8-hydroxyefavirenz. 

Elimination and Excretion 

Most emtricitabine and its metabolites are excreted renally through glomerular filtration and active tubular secretion. 

The primary route of excretion for tenofovir is renal, with about 70-80% of the administered dose excreted unchanged in the urine. 

efavirenz and its metabolites are primarily eliminated through hepatic metabolism, with only a tiny amount excreted unchanged in urine and feces. 

Adminstartion

Administration: 

Oral administration 

emtricitabine/tenofovir DF/efavirenz is typically available as a fixed-dose combination tablet. A healthcare professional should determine the dosage and administration of this medication, and it is crucial to follow their instructions and the prescribing information.  

• Dosage: Taking it on an empty stomach helps to minimize potential CNS side effects associated with efavirenz. 
• Swallowing: The tablet should be swallowed whole with water and not be chewed, crushed, or divided. 
• Food and Antacids: It is generally recommended to take emtricitabine/tenofovir DF /efavirenz on an empty stomach, as taking it with food, especially high-fat meals, may increase the absorption of efavirenz, leading to an increased risk of side effects. Additionally, antacids containing aluminum or magnesium should be avoided or taken at least 2 hours before or after taking emtricitabine/tenofovir DF/efavirenz, as they can reduce the absorption of tenofovir. 
• Adherence: It is crucial to consistently take emtricitabine/tenofovir DF /efavirenz as prescribed. Missing doses or not taking the medication regularly can reduce its effectiveness in controlling HIV infection and may increase the risk of developing drug resistance. 
• Renal Impairment: In patients with renal impairment, dosage adjustments may be necessary. Healthcare professionals will evaluate the patient’s renal function and adjust the dosing to ensure safe and effective medication use. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: emtricitabine/tenofovir DF /efavirenz  

Pronounced: [ ef-AV-ir-enz, em-trye-SYE-ta-been, and-ten-OF-oh-vir ] 

Why do we use emtricitabine/tenofovir DF /efavirenz? 

emtricitabine/tenofovir DF /efavirenz is a combination medication primarily used to treat HIV-1 infection in adults and adolescents. It is an antiretroviral therapy (ART) that helps to suppress the replication of HIV, reduce viral load, and improve immune function.  

• HIV-1 Treatment-Naive Patients: emtricitabine/tenofovir DF /efavirenz is commonly prescribed as a first-line therapy for treatment-naive individuals with HIV-1 infection. It is often recommended as part of a combination ART regimen to initiate early and effective treatment, reduce viral replication, and prevent disease progression. 
• HIV-1 Treatment-Experienced Patients: The combination medication may also be used in treatment-experienced patients who have previously received other antiretroviral therapies. It can be considered a switch or substitution therapy in individuals who require a change in their treatment regimen due to factors such as virologic failure, drug resistance, or intolerability to previous medications. 
• Pre-Exposure Prophylaxis (PrEP): emtricitabine/tenofovir DF /efavirenz is also approved for use as pre-exposure prophylaxis to decrease the risk of sexually acquired HIV-1 infection in individuals who are at high risk of contracting the virus. It is an option for individuals who engage in sexual activity with HIV-positive partners or have other risk factors for HIV transmission.