Efavirenz

The standard recommended dose of Efavirenz for adults infected with HIV-1 is 600 mg taken orally once daily. This dose is almost always used in conjunction with other antiretroviral medications, such as tenofovir and emtricitabine or lamivudine. To minimize central nervous system side effects, it is strongly recommended that the dose be taken at bedtime. Taking the medication before sleep allows the peak plasma concentrations—which are associated with dizziness and confusion—to occur while the patient is asleep.

Pediatric dosing is based strictly on the child's weight. The following is a general guideline for Efavirenz capsules in children at least 3 months old:

• 3.5 kg to < 5 kg: 100 mg once daily.
• 5 kg to < 7.5 kg: 150 mg once daily.
• 7.5 kg to < 10 kg: 200 mg once daily.
• 10 kg to < 15 kg: 200 mg once daily.
• 15 kg to < 20 kg: 250 mg once daily.
• 20 kg to < 25 kg: 300 mg once daily.
• 25 kg to < 32.5 kg: 350 mg once daily.
• 32.5 kg to < 40 kg: 400 mg once daily.
• 40 kg or greater: 600 mg once daily.

For children who cannot swallow capsules, the capsules may be opened and the contents added to a small amount of food (like applesauce or yogurt), but this must be done carefully to ensure the full dose is consumed.

Renal Impairment

The pharmacokinetics of Efavirenz have not been extensively studied in patients with renal (kidney) failure. However, since less than 1% of Efavirenz is excreted unchanged in the urine, renal impairment is not expected to significantly impact the drug's clearance. No dosage adjustment is typically required for patients with kidney disease.

Hepatic Impairment

Because Efavirenz is extensively metabolized by the liver, patients with hepatic (liver) impairment must be monitored closely.

• Mild Impairment (Child-Pugh Class A): Use with caution; no specific dose adjustment is provided, but monitoring for side effects is essential.
• Moderate to Severe Impairment (Child-Pugh Class B or C): Efavirenz is generally not recommended, as the risk of toxicity is significantly increased.

Elderly Patients

Clinical studies did not include enough subjects over 65 to determine if they respond differently. However, because elderly patients are more likely to have decreased hepatic or cardiac function, healthcare providers usually start at the lower end of the dosing range and monitor closely.

• Empty Stomach: Efavirenz MUST be taken on an empty stomach. Taking it with food, especially high-fat food, increases the amount of drug in your blood to dangerous levels, which can worsen side effects.
• Bedtime Dosing: As mentioned, taking the dose at bedtime is a key strategy to improve tolerance of the drug's CNS effects.
• Consistency: Take the medication at the same time every night to maintain steady levels in your bloodstream.
• Do Not Crush: Tablets should be swallowed whole. If using capsules for a child, follow the specific 'sprinkle' instructions provided by your pharmacist.

If you miss a dose of Efavirenz, take it as soon as you remember. However, if it is almost time for your next scheduled dose, skip the missed dose and continue with your regular schedule. Do not take two doses at once to make up for a missed one. Consistency is vital in HIV treatment to prevent the virus from developing resistance to the medication.

Signs of Efavirenz overdose may include increased nervous system symptoms (dizziness, confusion, vivid dreams) and involuntary muscle contractions. If an overdose is suspected, contact a poison control center or seek emergency medical attention immediately. Treatment is supportive, focusing on maintaining vital signs and monitoring the patient's neurological status. Activated charcoal may be used to help remove unabsorbed drug from the gastrointestinal tract.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop taking the medication without medical guidance, as this can lead to treatment failure.

Efavirenz is well-known for causing central nervous system (CNS) side effects, which affect approximately 50% of patients starting the medication. These symptoms usually appear within the first 1-2 days of therapy and typically resolve or significantly diminish after 2 to 4 weeks of continued use.

• Dizziness and Lightheadedness: Patients often describe a 'spinning' sensation or feeling unsteady on their feet.
• Vivid or Abnormal Dreams: Many patients report extremely realistic, sometimes intense or strange dreams.
• Insomnia: Difficulty falling or staying asleep is common, especially if the drug is not taken at bedtime.
• Impaired Concentration: A feeling of 'brain fog' or difficulty focusing on complex tasks.
• Somnolence (Drowsiness): Excessive sleepiness during daylight hours.
• Rash: A mild-to-moderate skin rash (maculopapular) occurs in about 26% of adults. It usually appears within the first two weeks and often resolves without stopping the drug.

• Nausea and Vomiting: General gastrointestinal upset, which may be mitigated by bedtime dosing.
• Fatigue: A persistent sense of tiredness or lack of energy.
• Headache: Mild to moderate tension-style headaches.
• Hypertriglyceridemia: An increase in the levels of triglycerides (fats) in the blood.
• Increased Liver Enzymes: Elevated ALT and AST levels, indicating stress on the liver.

• Gynecomastia: Enlargement of breast tissue in males.
• Photosensitivity: Increased sensitivity of the skin to sunlight, leading to easier sunburn.
• Tinnitus: Ringing in the ears.
• Pancreatitis: Inflammation of the pancreas, which causes severe abdominal pain.

> Warning: Stop taking Efavirenz and call your doctor immediately if you experience any of these symptoms. These may indicate life-threatening reactions.

• Severe Psychiatric Symptoms: This includes severe depression, suicidal ideation (thoughts of self-harm), or actual suicide attempts. Patients with a history of psychiatric disorders are at higher risk.
• Psychosis and Catatonia: Some patients may experience hallucinations, delusions, or a state of unresponsiveness (catatonia).
• Hepatotoxicity (Liver Failure): Symptoms include yellowing of the skin or eyes (jaundice), dark urine, pale stools, and pain in the upper right side of the stomach.
• Severe Rash (Stevens-Johnson Syndrome): If a rash is accompanied by blistering, fever, mouth sores, or peeling skin, it is a medical emergency.
• Convulsions (Seizures): Efavirenz may lower the seizure threshold, especially in those with a history of epilepsy.
• QT Prolongation: A heart rhythm disorder that can cause fainting or sudden cardiac arrest.

• Lipodystrophy: Long-term use of ART, including Efavirenz, has been associated with changes in body fat distribution. This may include loss of fat from the legs, arms, and face (lipoatrophy) and increased fat in the abdomen, upper back ('buffalo hump'), and breasts.
• Bone Loss: Some studies suggest a decrease in bone mineral density over years of use, increasing the risk of osteopenia or osteoporosis.
• Chronic Cholesterol Elevation: Persistent increases in total cholesterol and LDL ('bad' cholesterol) may require the addition of lipid-lowering medications.

While Efavirenz does not carry a traditional 'Black Box Warning' in the same format as some other drugs (like NRTIs and lactic acidosis), it carries strong boxed warnings in its prescribing information regarding:

1. 1Psychiatric Symptoms: Serious psychiatric adverse experiences, including suicide, delusions, and psychosis-like behavior.
2. 2Nervous System Symptoms: High frequency of dizziness, insomnia, and impaired concentration.
3. 3Embryo-Fetal Toxicity: Potential risk to the fetus if used during the first trimester of pregnancy.

Report any unusual symptoms to your healthcare provider immediately. Do not wait for your next scheduled appointment if you feel your mental health is declining.

Efavirenz is a potent medication that requires strict adherence and careful monitoring. It is essential that patients do not share this medication with others and that they inform all healthcare providers (including dentists and specialists) that they are taking an NNRTI. Because Efavirenz remains in the body for a long time, its effects and potential for drug interactions can persist for weeks after the last dose is taken.

No FDA black box warnings for Efavirenz are currently mandated in the standard 'black box' format, but the 'Warnings and Precautions' section of the FDA label is exceptionally robust regarding psychiatric and hepatic risks. (Note: Older formulations or combination products like Atripla may have boxed warnings related to other components like Tenofovir and Hepatitis B exacerbation).

• Psychiatric Risks: There is a well-documented risk of severe depression, suicide attempts, and aggressive behavior. Patients must be monitored for new or worsening psychiatric symptoms. If you have a history of mental health issues, discuss this thoroughly with your doctor.
• Hepatotoxicity: Liver failure has occurred in patients with no pre-existing liver disease. However, the risk is significantly higher in those with Hepatitis B or C co-infection. Liver function tests (LFTs) must be performed before starting and periodically during treatment.
• Nervous System Effects: Patients should be warned that the CNS effects (dizziness, confusion) are likely. These are most intense during the first few weeks.
• Rash: Most rashes are mild, but Efavirenz must be discontinued if a severe rash with systemic symptoms (fever, blistering) develops.
• QT Prolongation: Efavirenz can affect the electrical activity of the heart. Caution is advised in patients taking other medications that prolong the QT interval or those with underlying heart conditions.
• Lipid Elevations: Efavirenz can significantly increase cholesterol and triglyceride levels. Baseline lipid testing is required.

Regular laboratory monitoring is a cornerstone of Efavirenz therapy:

• Viral Load and CD4+ Count: To ensure the medication is effectively suppressing the virus.
• Liver Function Tests (ALT, AST, Bilirubin): Monitored at baseline and frequently during the first 6 months of therapy.
• Lipid Profile: Cholesterol and triglycerides should be checked before starting and periodically thereafter.
• Pregnancy Testing: For individuals of childbearing potential, a pregnancy test should be performed before initiation.

Because Efavirenz frequently causes dizziness, sleepiness, and impaired concentration, patients should not drive or operate heavy machinery until they are certain the medication does not affect their ability to perform these tasks safely. These effects are most common in the first few weeks of treatment.

Alcohol should be avoided or strictly limited while taking Efavirenz. Alcohol can worsen the central nervous system side effects (dizziness, confusion) and may increase the risk of liver toxicity. Combining alcohol with Efavirenz significantly increases the risk of impaired judgment and coordination.

Never stop taking Efavirenz without consulting your doctor. Sudden discontinuation can lead to 'viral rebound,' where the amount of HIV in the blood increases rapidly. Furthermore, because Efavirenz has a very long half-life, stopping it while continuing other HIV drugs with shorter half-lives can lead to the virus being exposed to Efavirenz alone, which rapidly leads to drug resistance.

> Important: Discuss all your medical conditions with your healthcare provider before starting Efavirenz, especially any history of liver disease, seizures, or mental health disorders.

Efavirenz is a potent inducer of the CYP3A4 enzyme, which means it speeds up the breakdown of many other drugs, making them less effective. Conversely, some drugs can dangerously increase Efavirenz levels. The following must NEVER be used with Efavirenz:

• Elbasvir/Grazoprevir: Efavirenz significantly reduces the levels of these Hepatitis C medications, leading to treatment failure.
• Midazolam and Triazolam: Efavirenz can alter the metabolism of these sedatives, potentially leading to prolonged sedation or respiratory depression.
• Ergot Derivatives (Ergotamine, Dihydroergotamine): Risk of ergot toxicity (vasospasm and ischemia of the extremities).
• Pimozide: Increased risk of serious heart rhythm problems (arrhythmias).
• St. John’s Wort: This herbal supplement drastically lowers Efavirenz levels in the blood, which can lead to HIV resistance and treatment failure.

• Statins (Simvastatin, Atorvastatin): Efavirenz may decrease the concentration of these cholesterol drugs. Your doctor may need to adjust the statin dose.
• Warfarin: Efavirenz can either increase or decrease the blood-thinning effects of warfarin. Frequent INR (clotting) monitoring is required.
• Anticonvulsants (Phenytoin, Carbamazepine): These drugs can lower Efavirenz levels, and Efavirenz can change the levels of the anticonvulsants. Blood level monitoring is essential.
• Clopidogrel: Efavirenz may reduce the conversion of clopidogrel to its active form, making it less effective at preventing blood clots.
• Voriconazole: Standard doses of voriconazole and Efavirenz cannot be used together; significant dose adjustments are required for both.

• Oral Contraceptives: Efavirenz may decrease the effectiveness of hormonal birth control (the pill, patch, or ring). A reliable barrier method (like condoms) should always be used to prevent pregnancy and reduce HIV transmission risk.
• Antifungals (Itraconazole, Ketoconazole): Levels of these drugs may be reduced by Efavirenz.
• Antibiotics (Clarithromycin): Efavirenz decreases clarithromycin levels; an alternative like azithromycin may be preferred.

• High-Fat Meals: As previously noted, high-fat meals increase the absorption of Efavirenz by nearly 30%. This is not a beneficial increase; it leads to a spike in plasma levels that significantly increases the risk of toxicity and CNS side effects. Always take Efavirenz on an empty stomach.
• Grapefruit Juice: While Efavirenz is primarily a CYP2B6 substrate, grapefruit juice (a CYP3A4 inhibitor) could theoretically increase levels, though the clinical impact is less significant than with other HIV drugs.

• Ginkgo Biloba: May potentially interfere with the metabolism of Efavirenz.
• Kava Kava and Valerian Root: These herbs have sedative properties and may worsen the dizziness and somnolence caused by Efavirenz.

• Cannabinoid Screen: Efavirenz can cause a false-positive result for marijuana (cannabinoids) on some rapid urine drug screening tests. If this occurs, a more specific confirmatory test (such as Gas Chromatography-Mass Spectrometry) should be performed to verify the result.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking. Keep a current list and present it at every medical appointment.

There are specific clinical scenarios where Efavirenz must never be used due to the risk of life-threatening complications:

1. 1Hypersensitivity: Patients with a known, clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or erythema multiforme) to Efavirenz or any of its excipients must not take the medication.
2. 2Co-administration with Specific Drugs: As detailed in the interactions section, Efavirenz is contraindicated with drugs that depend heavily on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious/life-threatening events (e.g., Pimozide, Midazolam).
3. 3Severe Hepatic Impairment: Patients with Child-Pugh Class C liver disease should not use Efavirenz, as the liver cannot process the drug, leading to dangerous accumulation.

These conditions require a careful risk-benefit analysis by a specialist:

• Moderate Hepatic Impairment (Child-Pugh B): Generally avoided unless no other options exist.
• History of Severe Psychiatric Disorders: While not an absolute contraindication, a history of psychosis or suicidal behavior requires extreme caution and frequent psychiatric monitoring.
• Pre-existing Cardiac Arrhythmias: Specifically those with a history of QT prolongation or those taking other QT-prolonging drugs.
• History of Seizures: Efavirenz may increase the frequency of seizures in predisposed individuals.

There is no significant evidence of cross-sensitivity between Efavirenz and other classes of HIV medications (like Protease Inhibitors or Integrase Inhibitors). However, there may be a limited risk of cross-reactivity with other NNRTIs (like Nevirapine) regarding skin rashes. If a patient has had a life-threatening rash from another NNRTI, Efavirenz should be used with extreme caution or avoided.

> Important: Your healthcare provider will evaluate your complete medical history, including mental health and liver function, before prescribing Efavirenz.

Efavirenz is classified as a drug that may cause fetal harm when administered during the first trimester. Historically, it was categorized as FDA Pregnancy Category D.

• Teratogenicity: Data from animal studies and some human reports suggested a risk of neural tube defects (like spina bifida). However, more recent and extensive data from the Antiretroviral Pregnancy Registry have shown that the risk of birth defects with Efavirenz is similar to that of other antiretroviral drugs.
• Current Guidelines: Most international guidelines (WHO and DHHS) now state that Efavirenz can be used in pregnancy, including the first trimester, if the benefits outweigh the risks. However, women of childbearing potential should be counseled on the potential risks and the importance of effective contraception.

In the United States and other regions where clean water and infant formula are available, the CDC and FDA recommend that HIV-infected mothers do not breastfeed their infants. This is to avoid the risk of postnatal transmission of HIV to the baby. Additionally, Efavirenz is known to pass into human breast milk, and the effects on a nursing infant are not fully understood.

Efavirenz is approved for use in children at least 3 months of age and weighing at least 3.5 kg.

• Dosing Challenges: Pediatric dosing must be adjusted frequently as the child grows and gains weight.
• CNS Effects: Children may experience similar CNS side effects as adults, but they may manifest as irritability or behavioral changes. Parents should monitor their child’s school performance and mood closely.
• Rash: Rash is more common in children than in adults and should be reported to a pediatrician immediately.

Clinical experience in patients aged 65 and older is limited.

• Pharmacokinetics: Older adults may have reduced hepatic and renal function, which can affect drug metabolism.
• Polypharmacy: Elderly patients are often on multiple medications for other conditions (hypertension, heart disease), increasing the risk of significant drug-drug interactions.
• Cognitive Impact: The CNS effects of Efavirenz (confusion, dizziness) may be more pronounced in older adults and could be mistaken for age-related cognitive decline.

As less than 1% of the drug is excreted by the kidneys, no dose adjustment is required for patients with renal insufficiency. However, patients on dialysis should still be monitored for overall tolerance of the ART regimen.

• Mild (Child-Pugh A): No dose adjustment, but monitor for CNS toxicity.
• Moderate to Severe (Child-Pugh B or C): Not recommended. If used in moderate cases, extreme caution and frequent LFT monitoring are mandatory.

> Important: Special populations require individualized medical assessment and frequent follow-up to ensure safety and efficacy.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Its activity is mediated by non-competitive inhibition of the HIV-1 reverse transcriptase (RT) enzyme. It does not inhibit HIV-2 RT or human cellular DNA polymerases alpha, beta, gamma, or delta. The drug binds to a hydrophobic pocket in the p66 subunit of the HIV-1 RT heterodimer. This binding site is distinct from the substrate binding site used by NRTIs. By binding here, Efavirenz acts as a 'molecular wedge' that interferes with the flexibility of the enzyme, preventing it from catalyzing the conversion of viral RNA into DNA. This prevents the formation of the provirus and the subsequent infection of the host cell.

• Antiviral Activity: In cell culture, Efavirenz demonstrates potent activity against most laboratory and clinical isolates of HIV-1.
• Resistance: Resistance to Efavirenz can develop rapidly if it is used as monotherapy or if doses are missed. The most common resistance mutation is the K103N mutation in the RT enzyme, which significantly reduces the drug's binding affinity. This mutation also confers cross-resistance to other first-generation NNRTIs like Nevirapine.
• Relationship to Side Effects: There is a clear relationship between higher plasma concentrations and the frequency of CNS side effects. This is why empty-stomach dosing is critical.

| Parameter | Value |

|---|---|

| Bioavailability | Increased by 28% with high-fat meal |

| Protein Binding | 99.5% to 99.75% (Albumin) |

| Half-life | 40 to 55 hours (after multiple doses) |

| Tmax | 3 to 5 hours |

| Metabolism | Hepatic (CYP2B6, CYP3A4) |

| Excretion | Fecal (16-61%), Renal (14-34% as metabolites) |

• Molecular Formula: C14H9ClF3NO2
• Molecular Weight: 315.67 g/mol
• Solubility: Practically insoluble in water (<10 micrograms/mL).
• Structure: Efavirenz is chemically described as (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. It is a white to slightly pink crystalline powder.

Efavirenz is a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI). Related medications in this class include Nevirapine (Viramune), Delavirdine (Rescriptor), Etravirine (Intelence), Rilpivirine (Edurant), and Doravirine (Pifeltro). Efavirenz is considered a 'first-generation' NNRTI.