Efavirenz + Emtricitabine + Tenofovir disoproxil fumarate

Usage

• Medical Conditions: This fixed-dose combination medication is prescribed for the treatment of HIV-1 infection in adults and pediatric patients 12 years and older weighing at least 40 kg. It is used as a complete regimen or in combination with other antiretroviral agents. It is not a cure for HIV, but helps manage the infection and slows its progression. It is not indicated for the treatment of chronic hepatitis B virus (HBV) infection.
• Pharmacological Classification: Antiretroviral, specifically a combination of a non-nucleoside reverse transcriptase inhibitor (NNRTI - efavirenz) and two nucleoside reverse transcriptase inhibitors (NRTIs - emtricitabine and tenofovir disoproxil fumarate).
• Mechanism of Action: This combination targets different stages of the HIV-1 replication cycle. Efavirenz inhibits reverse transcriptase directly, while emtricitabine and tenofovir disoproxil fumarate (after conversion to tenofovir diphosphate) act as competitive substrates and chain terminators for HIV-1 reverse transcriptase. This combined action disrupts the conversion of viral RNA into DNA, suppressing viral replication.

Alternate Names

• Atripla (brand name)

How It Works

• Pharmacodynamics: Efavirenz, emtricitabine, and tenofovir work synergistically to inhibit HIV-1 replication by targeting reverse transcriptase, a key viral enzyme. This prevents the virus from integrating its genetic material into the host’s DNA.

• Pharmacokinetics:

  • Absorption: Administered orally, preferably on an empty stomach at bedtime to improve the tolerability of nervous system side effects. Food may increase efavirenz absorption.
  • Metabolism: Primarily hepatic metabolism for efavirenz (CYP3A4, CYP2B6) and renal excretion for emtricitabine and tenofovir.
  • Elimination: Efavirenz is primarily eliminated via hepatic metabolism, while emtricitabine and tenofovir are primarily excreted renally.

• Mode of Action: Efavirenz directly inhibits HIV-1 reverse transcriptase by binding non-competitively to a site near the active site. Emtricitabine and tenofovir (after being metabolized to tenofovir diphosphate) competitively inhibit HIV-1 reverse transcriptase, getting incorporated into the growing DNA chain and causing chain termination.

• Receptor Binding/Enzyme Inhibition: Non-competitive binding of efavirenz to reverse transcriptase; competitive inhibition of reverse transcriptase by intracellular tenofovir diphosphate and emtricitabine triphosphate.

• Elimination Pathways: Efavirenz is metabolized by CYP3A4 and CYP2B6 and excreted in feces and urine. Emtricitabine and tenofovir are primarily eliminated via renal excretion (glomerular filtration and active tubular secretion).

Dosage

Standard Dosage

Adults: One tablet (600 mg efavirenz/200 mg emtricitabine/300 mg tenofovir disoproxil fumarate) orally once daily on an empty stomach, preferably at bedtime.

Children: Not recommended for use in children weighing less than 40 kg. Dosage for children weighing at least 40kg is the same as the adult dose.

Special Cases:

• Elderly Patients: Use with caution. Close monitoring is required.
• Patients with Renal Impairment: Not recommended for moderate to severe renal impairment (creatinine clearance <50 mL/min). Dosage adjustments are necessary for mild renal impairment.
• Patients with Hepatic Dysfunction: Use with caution in mild hepatic impairment. Not recommended for moderate to severe hepatic impairment.
• Patients with Comorbid Conditions: Close monitoring for patients with diabetes, cardiovascular disease, mental health conditions, or bone disorders is recommended.

Clinical Use Cases

The use of Efavirenz + Emtricitabine + Tenofovir disoproxil fumarate is specific to HIV-1 treatment and not used in scenarios like intubation, surgical procedures, mechanical ventilation, ICU, or general emergency situations like status epilepticus or cardiac arrest.

Dosage Adjustments

Dose adjustments are needed for patients with renal impairment, hepatic impairment, and when co-administered with rifampin. For patients with renal impairment, consider using separate formulations of the individual components to allow for appropriate dose adjustment. With rifampin, an additional 200 mg/day of efavirenz is recommended for patients weighing 50 kg or more.

Side Effects

Common Side Effects

Dizziness, headache, difficulty sleeping, abnormal dreams, difficulty concentrating, drowsiness, nausea, vomiting, diarrhea, skin rash, tiredness.

Rare but Serious Side Effects

Severe skin reactions (Stevens-Johnson syndrome), lactic acidosis, severe liver problems, worsening kidney problems, depression, suicidal thoughts, pancreatitis, bone problems, changes in body fat.

Long-Term Effects

Kidney disease, bone loss, changes in body fat.

Adverse Drug Reactions (ADR)

Hepatitis B exacerbation in co-infected individuals, immune reconstitution inflammatory syndrome (IRIS).

Contraindications

Hypersensitivity to any component of the medication, coadministration with drugs such as voriconazole, bepridil, midazolam, triazolam, cisapride, pimozide, ergot derivatives, or St. John’s wort, severe hepatic impairment.

Drug Interactions

Numerous drug interactions exist; consult a comprehensive drug interaction resource. Notable interactions include: rifampin, didanosine, other nephrotoxic agents, medications metabolized by CYP3A4 or CYP2B6, some anticonvulsants, some antidepressants, St. John’s wort.

Pregnancy and Breastfeeding

Use only if clearly needed and the benefit outweighs the potential fetal risk (especially in the first trimester). Efavirenz is associated with birth defects in animal studies. Effective contraception is necessary during treatment and for 12 weeks after discontinuation. Breastfeeding is not recommended due to potential HIV transmission and infant drug exposure.

Drug Profile Summary Mechanism of Action: Inhibits HIV-1 replication by targeting reverse transcriptase via different mechanisms.

Side Effects: Dizziness, headache, insomnia, nausea, rash, psychiatric symptoms, serious hepatic/renal/bone effects. Contraindications: Hypersensitivity, coadministration with several specific drugs, severe hepatic impairment. Drug Interactions: Numerous; consult a drug interaction resource. Pregnancy & Breastfeeding: Use with caution if benefits outweigh risks during pregnancy. Breastfeeding not recommended. Dosage: One tablet once daily on an empty stomach, preferably at bedtime. Dose adjustments required in specific circumstances. Monitoring Parameters: Renal function, hepatic function, HIV-1 viral load, CD4 cell count, mental health status, bone density.

Popular Combinations

Often used as a stand-alone regimen for HIV-1 treatment. If resistance or intolerance develops, alternative antiretroviral combinations are used.

Precautions

Pre-screening for renal/hepatic dysfunction, mental health issues, and HBV/HCV co-infection is crucial. Monitor for adverse effects throughout treatment. Counsel patients on safe sex practices and the importance of adherence.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Efavirenz + Emtricitabine + Tenofovir disoproxil fumarate?

A: One tablet once daily, preferably at bedtime and on an empty stomach, for adults and children 12 years and older weighing at least 40 kg.

Q2: What are the common side effects?

A: Dizziness, headache, difficulty sleeping, unusual dreams, nausea, vomiting, diarrhea, skin rash, and tiredness.

Q3: What are the most serious side effects?

A: Severe skin reactions (Stevens-Johnson syndrome), lactic acidosis, severe liver problems, worsening kidney problems, psychiatric effects (e.g., depression, suicidal ideation), pancreatitis, bone problems.

Q4: What are the contraindications for this medication?

A: Hypersensitivity, coadministration with specific medications (voriconazole, bepridil, midazolam, etc.), and severe hepatic impairment.

Q5: Can this drug be used during pregnancy?

A: Only if the benefits clearly outweigh the potential fetal risks. Efavirenz carries a risk of birth defects, and effective contraception must be used during and after treatment. Consult a specialist for individualized guidance.

Q6: Can this drug be used during breastfeeding?

A: Breastfeeding is not recommended due to the risk of transmitting HIV to the infant and potential drug exposure.

Q7: Are there any drug interactions I should be aware of?

A: Yes, numerous drug interactions exist. Always consult a comprehensive drug interaction resource. Inform your patients to disclose all medications, supplements, and herbal remedies they are taking.

Q8: What monitoring is required during treatment?

A: Regular monitoring of renal and hepatic function, HIV-1 viral load, CD4 cell count, mental health, and bone density is essential.

Q9: What should I do if a patient misses a dose?

A: If a dose is missed, instruct the patient to take it as soon as possible. However, if it is almost time for their next dose, they should skip the missed dose and return to their regular dosing schedule. They should not double the dose.

Q10: What patient education is important for this medication?

A: Counsel patients on the importance of medication adherence, potential side effects, drug interactions, safe sex practices to prevent HIV transmission, and the need for regular monitoring.