Efavirenz (Sustiva) is an antiretroviral medicine that belongs to the class of drugs called Non-nucleoside reverse transcriptase inhibitors used to treat HIV-1 infections in combination with other antiretroviral medicines.

Efavirenz (Sustiva) Uses:

• HIV-1 infection:

  • Used in the treatment of HIV-1 infection in combination with other antiretroviral agents in adults and pediatric patients at least 3 months old and weighing at least 3.5 kg

Adult dose:

Efavirenz (Sustiva) Dose in the treatment of HIV-1 infection:

• Oral: 600 mg once in a day.

• Dosage adjustment for concomitant rifampin (only if the patient weighs ≥50 kg):

  • Increase efavirenz dose to 800 mg once in a day.

• Dosage adjustment for concomitant voriconazole:

  • Reduce efavirenz dose to 300 mg one time in a day and increase voriconazole to 400 mg every 12 hours.

Dose in children:

Efavirenz (Sustiva) Dose in the treatment of HIV-1 infection:

Use in combination with other antiretroviral agents; dosage adjustments for concomitant drug administration may be required; see below Dosage adjustment for concomitant drugs:

• Infants <3 months or <3 kg:

  • Not recommended for use

• Infants ≥3 months weighing ≥3 kg and Children <3 years: Oral:

  • AIDS info recommendation: Very limited data available:

Note:

• In general, current guidelines do not recommend efavirenz use in patients less than 3 years of age unless the use is unavoidable due to the clinical situation; CYP2B6 genotype testing should be performed prior to therapy initiation.
• The following doses are under investigation and have been suggested by the expert panel based on pharmacokinetic data.

• • • Extensive metabolizers (CYP2B6 516 G/G or G/T genotypes):

      • 3 kg to <5 kg:
        • 200 mg once in a day.
      • 5 kg to <7 kg:
        • 300 mg once in a day.
      • 7 kg to <14 kg:
        • 400 mg once in a day.
      • 14 kg to <17 kg:
        • 500 mg once in a day.
      • ≥17 kg:
        • 600 mg once in a day.

    • Slow metabolizer (CYP 2B6 516 T/T genotype):

      • 3 kg to <7 kg:
        • 50 mg once in a day.
      • 7 kg to <14 kg:
        • 100 mg once in a day.
      • ≥14 kg:
        • 150 mg once in a day.

  • Manufacturer's labeling:

Note:

• Although FDA approved in pediatric patients of 3 months or more than 3 months of age and weighing 3.5 kg or more than 3.5 kg, pharmacokinetic data suggest that the FDA approved dosing may result in subtherapeutic levels in extensive metabolizers and supratherapeutic in slow metabolizers and use should be avoided.
  • • • 5 kg to <5 kg:
        • 100 mg once in a day.
      • 5 kg to <7.5 kg:
        • 150 mg once in a day.
      • 5 kg to <15 kg:
        • 200 mg once in a day.
      • 15 kg to <20 kg:
        • 250 mg once in a day.

• Children ≥3 years and Adolescents:

  • Weight-directed dosing: Oral:

    • 10 kg to <15 kg:
      • 200 mg once in a day.
    • 15 kg to <20 kg:
      • 250 mg once in a day.
    • 20 kg to <25 kg:
      • 300 mg once in a day.
    • 25 kg to <32.5 kg:
      • 350 mg once in a day.
    • 5 kg to <40 kg:
      • 400 mg once in a day.
    • ≥40 kg:
      • 600 mg once in a day.

  • BSA-directed dosing:

    • Oral: 367 mg/m  per dose once in a day, maximum dose: 600 mg per dose; recommended by some experts due to concern of underdosing at the upper end of each weight range.

• Dosage adjustment for concomitant rifampin:

  • Pediatric patients weighing <50 kg:

    • The manufacturer’s labeling doesn't provide any dosage adjustments; however, efavirenz dosage increase may be considered.

  • Pediatric patients weighing ≥50 kg:

    • Oral: Increase efavirenz dose to 800 mg once in a day.

• Dosage adjustment for concomitant voriconazole:

  • Infants ≥3 months, Children, and Adolescents:
    • The manufacturer's labeling doesn't provide any dosage adjustments; however, efavirenz dose reduction and voriconazole dosage increase may be considered.

Efavirenz (Sustiva) Pregnancy Risk Category: D

• Efavirenz is able to transfer moderately through the human placenta.
• There have been reports of neural tube and other CNS defects. However, a meta-analysis showed that there is no greater risk after efavirenz in the first trimester than in the general population.
• Data from the Antiretroviral Pregnancy Registry show that there is no increased risk of birth defects in general if efavirenz is first administered to a pregnant woman.
• Although maternal antiretroviral treatment (ART) may increase preterm births, the information available is inconsistent due to variability in maternal factors (disease severity and gestational age at the initiation of therapy),
• Maternal ART is an important treatment option that has clear benefits. Avoid delay if you are concerned about adverse neonatal outcomes.
• Some studies have shown an increased risk of stillbirth and low birth weight in infants.
• All infants who have been exposed to antiretroviral medication should be followed up for a long time.
• Potential mitochondrial dysfunction should be considered for children who have significant organ abnormalities of unknown origin (especially the heart or CNS).
• Women on NNRTI therapy are at greater risk for hypersensitivity reactions, including rash and hepatic toxicities. It is not known if pregnancy increases the risk.
• The Health and Human Services (HHS) Perinatal HIV Guidelines consider efavirenz an alternative ART for HIV-infected pregnant females who are antiretroviral-naive, who have had ART therapy 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.
• The available studies have not shown that dose adjustments are necessary during pregnancy based on pharmacokinetic data.
• If efavirenz is well tolerated and effective in viral suppression, females who are pregnant may continue to take the drug.
• Females who have drug interactions or require convenience in once-daily dosing may be eligible.
• To keep HIV-positive pregnant women under the control and to reduce the chance of perinatal transmission, it is generally recommended that ART be performed.
• Monitoring during pregnancy is more common than monitoring in adults who are not pregnant.
• All HIV-positive women should continue ART after birth. ART can also be modified once the baby is born.
• The manufacturer suggests that women with reproductive potential undergo pregnancy testing before initiating efavirenz.
• You should use barrier contraception in conjunction with hormonal methods during therapy, and for 12 weeks after the discontinuation of efavirenz.
• Although not recommended by HHS, efavirenz can be used in the first trimester.
• If the efavirenz-containing regimen has to be stopped for more than 7 days because of toxic effects, consult current guidelines.
• The current HHS Perinatal HIV Guidelines are not intended to restrict the use of HIV in pregnant women.
• Health care providers are encouraged to enroll pregnant females exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-2584263 or http://www.APRegistry.com).

Efavirenz use during breastfeeding:

• Breast milk contains Efavirenz.
• The plasma concentrations of efavirenz in breastfeeding infants was reported to be 13% of the maternal plasma concentrations.
• A multiclass-resistant virus was also detected in breastfed infants, despite maternal therapy.
• Postnatal HIV transmission is not completely eliminated by infant or maternal antiretroviral treatment.
• In the US, where there is a safe and affordable formula and low infant mortality from diarrhea and respiratory infections, HIV-infected females should avoid breastfeeding to decrease the potential transmission of HIV.

Efavirenz (Sustiva) Dose in Kidney Disease:

The manufacturer's labeling doesn't provide any dosage adjustments (has not been studied); however, undergoes minimal renal excretion. 

Efavirenz (Sustiva) Dose in Liver disease:

• Mild impairment (Child-Pugh class A):

  • No dosage adjustment required; use with caution.

• Moderate-to-severe impairment (Child-Pugh class B or C):

  • Use is not recommended.

Side effects:

Unless otherwise noted, the frequency of adverse events is as reported for patients receiving combination antiretroviral therapy.

Common Side Effects of Efavirenz (Sustiva):

• Central Nervous System:

  • Dizziness
  • Headache
  • Depression
  • Insomnia
  • Anxiety
  • Pain

• Dermatologic:

  • Skin Rash

• Endocrine & Metabolic:

  • Increased HDL Cholesterol
  • Increased Serum Triglycerides
  • Increased Serum Cholesterol

• Gastrointestinal:

  • Nausea
  • Vomiting
  • Diarrhea

Less Common Side Effects Of Efavirenz (Sustiva):

• Central Nervous System:

  • Fatigue
  • Nervousness
  • Abnormal Dreams
  • Hallucination
  • Lack Of Concentration
  • Drowsiness

• Dermatologic:

  • Pruritus
  • Erythema Multiforme

• Endocrine & Metabolic:

  • Increased Amylase
  • Hyperglycemia
  • Increased Gamma-Glutamyl Transferase

• Gastrointestinal:

  • Dyspepsia
  • Abdominal Pain
  • Anorexia

• Hematologic & Oncologic:

  • Neutropenia

• Hepatic:

  • Increased Serum AST
  • Increased Serum ALT

Contraindications to Efavirenz (Sustiva):

Hypersensitivity (eg Stevens-Johnson syndrome, toxic erythema multiforme) to efavirenz and any component; concurrent administration of grazoprevir/elbasvir. Canadian labeling: Additional contraindications not in US labeling

Concurrent administration of cisapride (not accessible in Canada), ergot derivatives, (eg, ergonovine ergotamine dihydroergotamine), pimozide and midazolam.

Warnings and precautions

• CNS effects

  • CNS effects may occur (eg, disturbed dreams, sleeplessness, impaired concentration, hallucinations or dizziness), and symptoms typically resolve in 2 to 4 weeks. Dosing at night can improve tolerability. Avoid potentially dangerous tasks like driving or operating machinery.
  • Concomitant use of ethanol or other psychoactive drugs can increase the potential for CNS effects.

• Fat redistribution

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

• Hepatotoxicity:

  • You should examine the liver function of all patients. If serum transaminase levels persist more than 5x ULN, or if there are signs or symptoms that indicate hepatitis/hepatic decompensation, you may want to discontinue treatment.
  • Patients with no preexisting hepatic disease, or any other risk factors, have been diagnosed with hepatitis.

• Hypercholesterolemia:

  • There have been reports of an increase in total cholesterol and triglycerides.
  • Screening should be performed prior to treatment and every so often throughout the course of treatment.

• Immune reconstitution syndrome:

  • There is a possibility that patients may develop an immune reconstitution syndrome. This can occur when there is an indolent or residual infection. Patients might also be activated by autoimmune disorders, such as polymyositis or Graves disease. Further evaluation and treatment may also be required.

• Psychiatric effects

  • Use of the drug has been linked to serious psychiatric side effect, including aggressive behavior and delusions, suicide attempts that fail or are fatal, severe depression, suicidal ideastion, paranoia and psychosis-like behaviors, as well as severe depression.
  • Patients with a history or drug abuse/mental illness (predisposition for psychological reactions) should be cautious.
  • If patients experience serious psychiatric symptoms, they should be directed to call their healthcare provider immediately.

• Rash:

  • It can cause mild-to moderate maculopapular skin rash. Most cases resolve in one month of continued therapy.
  • Children are more susceptible to the development of rash; prophylactic antihistamines/corticosteroids may be used.
  • If severe rash develops (desquamation, which can cause blistering, mucosal involvement or fever), discontinue use.
  • Patients with a history or severe cutaneous reaction (eg Stevens-Johnson syndrome) are not advised to use this product.

• Extension of QT

  • There have been reports of QT prolongation. Consider alternative therapy for patients at high risk or those who are taking medications that carry a known risk of torsades.

• Hepatic impairment

  • Not recommended for moderate-to-severe liver impairment (Child Puugh class B orC);
  • Patients with mild hepatic impairment (Child Puugh class A) should be used with caution. Monitoring is highly recommended.

• HIV-associated dementia

  • Patients with HIV-associated dementia should avoid efavirenz-based treatments. Neuropsychiatric side effects such as efavirenz can hinder evaluation of the effects antiretrovirals have on improving symptoms.

• Seizure disorder:

  • Patients with seizure disorders should be cautious.
  • Use has been linked to seizures

Efavirenz: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• cholesterol and triglycerides (prior to therapy and periodically during);
• Serum transaminases;
• signs and symptoms of infection;
• psychiatric effects

How to administer Efavirenz (Sustiva)?

Oral:

• Administer on an empty stomach.
• Dosing at bedtime is recommended to limit central nervous system effects.
• Tablets must not be broken.
• Capsule contents may be sprinkled onto a small amount of soft food (eg, yogurt applesauce, grape jelly) for patients who cannot swallow capsules.
• Place 1 to 2 teaspoonfuls of food in a small container.
• Hold the capsule horizontally over a container and carefully twist in opposite directions to open, sprinkling contents over food.
• If more than 1 capsule is needed for a dose, add contents of all capsules needed to 1 to 2 teaspoonfuls of food; do not add more food.
• Use a small spoon to gently resolve capsule contents with food and administer all of the mixtures to the patient.
• To ensure entire capsule contents are monitored, add another 2 teaspoonfuls of food to the container, mix to incorporate any drug residue, and administer.
• Administer within 30 minutes of mixing.
• The patient should not consume any additional food or administer additional formula for 2 hours after administration.

Mechanism of action of Efavirenz (Sustiva):

Effavirenz is a non-nucleoside reverse transcriptionase inhibitor and has activity against HIV-1 through binding to reverse transcriptase. It also blocks the RNA-dependent DNA polymerase activities, including HIV-1 replication. For antiviral activity, it does not require intracellular Phosphorylation. Absorption:

• High-fat or high-calorie meals can increase your risk

Distribution:

• Plasma concentrations of CSF are 0.69 percent (range: 0.26% - 1.2%); however, the CSF to plasma ratio is three times greater than that of plasma.

Protein binding:

• longer than 99 percent, primarily to albumin

Metabolism:

• Hepatic via CYP3A and 2B6 to inactive hydroxylated metabolites which then undergo glucuronidation; induces P450 enzymes and its own metabolism

Bioavailability:

• 42 percent

Half-life elimination:

• Single-dose: 52 to 76 hours;
• Multiple doses: 40 to 55 hours

Time to peak:

• 3 to 5 hours

Excretion:

• Feces (16 percent  to 61 percent primarily as unchanged drug);
• urine (~14 percent  to 34 percent  as metabolites;  less than 1 percent  unchanged drug)

International Brand Names of Efavirenz:

• Sustiva
• Auro-Efavirenz
• MYLAN-Efavirenz
• Efacure
• Efamat
• Efavir
• Efcur
• Estiva
• Estiva-600
• Filginase
• Stocrin
• Stovirenz
• TEVA-Efavirenz
• Adiva
• Antiretro
• Avifanz
• Aviranz
• Cloviralex
• Delfavir
• Sustiva
• Virorrever
• Virzen

Efavirenz Brand Names in Pakistan: