Efavirenz (Sustiva) - Class, Dose, Side effects, MOA, Contraindications

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

Risk Factor C (Monitor therapy)

Alcohol (Ethyl) Efavirenz may enhance the adverse/toxic effect of Alcohol (Ethyl). Efavirenz may decrease the serum concentration of Alcohol (Ethyl).
Alizapride May enhance the CNS depressant effect of CNS Depressants.
Artemether Efavirenz may decrease the serum concentration of Artemether. Concentrations of dihydroartemisinin (active metabolite of artemether) may also be decreased by efavirenz
AtorvaSTATin Efavirenz may decrease the serum concentration of AtorvaSTATin.
Bosentan May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Brexanolone CNS Depressants may enhance the CNS depressant effect of Brexanolone.
Brimonidine (Topical) May enhance the CNS depressant effect of CNS Depressants.
Bromopride May enhance the CNS depressant effect of CNS Depressants.
Buprenorphine Efavirenz may decrease serum concentrations of the active metabolite(s) of Buprenorphine. Efavirenz may decrease the serum concentration of Buprenorphine.
BuPROPion Efavirenz may decrease the serum concentration of BuPROPion. Management: Monitor for decreased response to bupropion in patients treated with efavirenz. Increased bupropion doses may be required. Avoid the use of naltrexone/bupropion for weight management in patients receiving efavirenz.
Calcium Channel Blockers Efavirenz may decrease the serum concentration of Calcium Channel Blockers.
Cannabidiol May enhance the CNS depressant effect of CNS Depressants.
Cannabis May enhance the CNS depressant effect of CNS Depressants.
Chlorphenesin Carbamate May enhance the adverse/toxic effect of CNS Depressants.
CloZAPine CYP3A4 Inducers (Moderate) may decrease the serum concentration of CloZAPine.
CNS Depressants May enhance the adverse/toxic effect of other CNS Depressants.
CYP2B6 Substrates (High risk with Inducers) CYP2B6 Inducers (Moderate) may decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers).
CYP3A4 Inducers (Moderate) May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
CYP3A4 Substrates (High risk with Inducers) CYP3A4 Inducers (Moderate) may decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Deferasirox May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
DilTIAZem Efavirenz may decrease the serum concentration of DilTIAZem.
Dimethindene (Topical) May enhance the CNS depressant effect of CNS Depressants.
Doxylamine May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended.
Dronabinol May enhance the CNS depressant effect of CNS Depressants.
Esketamine May enhance the CNS depressant effect of CNS Depressants.
Estriol (Systemic) CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Systemic).
Estriol (Topical) CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Topical).
Ginkgo Biloba May decrease the serum concentration of Efavirenz.
Haloperidol QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTcprolonging effect of Haloperidol.
HydrOXYzine May enhance the CNS depressant effect of CNS Depressants.
Ibrutinib CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ibrutinib.
Ifosfamide CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Ifosfamide.
Ivosidenib May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Kava Kava May enhance the adverse/toxic effect of CNS Depressants.
Lofexidine May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Lovastatin Efavirenz may decrease the serum concentration of Lovastatin.
Macimorelin Efavirenz may diminish the diagnostic effect of Macimorelin.
Magnesium Sulfate May enhance the CNS depressant effect of CNS Depressants.
MetyroSINE CNS Depressants may enhance the sedative effect of MetyroSINE.
MiFEPRIStone May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors).
Minocycline May enhance the CNS depressant effect of CNS Depressants.
Mirodenafil CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mirodenafil.
Mirtazapine CNS Depressants may enhance the CNS depressant effect of Mirtazapine.
Nabilone May enhance the CNS depressant effect of CNS Depressants.
Naldemedine CYP3A4 Inducers (Moderate) may decrease the serum concentration of Naldemedine.
Nilotinib May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers).
NiMODipine CYP3A4 Inducers (Moderate) may decrease the serum concentration of NiMODipine.
Orlistat May decrease the serum concentration of Antiretroviral Agents.
Piribedil CNS Depressants may enhance the CNS depressant effect of Piribedil.
Pramipexole CNS Depressants may enhance the sedative effect of Pramipexole.
Pravastatin Efavirenz may decrease the serum concentration of Pravastatin.
Proguanil Efavirenz may decrease serum concentrations of the active metabolite(s) of Proguanil. Efavirenz may decrease the serum concentration of Proguanil. Efavirenz may increase the serum concentration of Proguanil.
QT-prolonging Agents (Highest Risk) QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
RifAMPin May decrease the serum concentration of Efavirenz.
Ritonavir Efavirenz may enhance the adverse/toxic effect of Ritonavir. Efavirenz may increase the serum concentration of Ritonavir. Ritonavir may increase the serum concentration of Efavirenz.
Rolapitant CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rolapitant.
ROPINIRole CNS Depressants may enhance the sedative effect of ROPINIRole.
Rotigotine CNS Depressants may enhance the sedative effect of Rotigotine.
Rufinamide May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced.
Sarilumab May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Selective Serotonin Reuptake Inhibitors CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced.
Sertraline Efavirenz may decrease the serum concentration of Sertraline.
Siltuximab May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Simvastatin Efavirenz may decrease the serum concentration of Simvastatin.
Tetrahydrocannabinol May enhance the CNS depressant effect of CNS Depressants.
Tetrahydrocannabinol and Cannabidiol May enhance the CNS depressant effect of CNS Depressants.
Thiotepa May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors).
Tocilizumab May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Trimeprazine May enhance the CNS depressant effect of CNS Depressants.
Vitamin K Antagonists (eg, warfarin) Efavirenz may decrease the serum concentration of Vitamin K Antagonists. Efavirenz may increase the serum concentration of Vitamin K Antagonists.

Risk Factor D (Consider therapy modification)

Atazanavir Efavirenz may decrease the serum concentration of Atazanavir. Management: When used with efavirenz, the adult atazanavir dose should be 400 mg daily, boosted with ritonavir 100 mg daily or cobicistat 150 mg daily, for treatment-naive patients only; treatment-experienced patients should not use atazanavir with efavirenz.
Atovaquone Efavirenz may decrease the serum concentration of Atovaquone. Management: Consider alternatives to the use of atovaquone with efavirenz when possible. If this combination must be used, monitor for evidence of reduced atovaquone clinical effectiveness.
Blonanserin CNS Depressants may enhance the CNS depressant effect of Blonanserin.
Brigatinib CYP3A4 Inducers (Moderate) may decrease the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inducers when possible. If combined, increase the daily dose of brigatinib in 30 mg increments after 7 days of treatment with the current brigatinib dose, up to maximum of twice the dose.
Canagliflozin Efavirenz may decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 300 mg/day in patients with estimated GFR >60 mL/min/1.73 m2 who tolerate canagliflozin 100 mg/day and require greater glycemic control. Consider alternatives in patients with estimated GFR 45-60 mL/min/1.73 m2.
Caspofungin Inducers of Drug Clearance may decrease the serum concentration of Caspofungin. Management: Consider using an increased caspofungin dose of 70 mg daily in adults (or 70 mg/m , up to a maximum of 70 mg, daily in pediatric patients) when coadministered with known inducers of drug clearance.
Chlormethiazole May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used.
Clarithromycin Efavirenz may enhance the QTc-prolonging effect of Clarithromycin. Efavirenz may decrease the serum concentration of Clarithromycin. Additionally, efavirenz may increase the active metabolite of clarithromycin Management: Consider using an alternative antibiotic in patients taking efavirenz. If concomitant therapy cannot be avoided, monitor for decreased therapeutic effect of clarithromycin and for QT interval prolongation.
CycloSPORINE (Systemic) Efavirenz may decrease the serum concentration of CycloSPORINE (Systemic). Management: Increase monitoring of cyclosporine concentrations when starting, stopping, or adjusting doses of concurrent efavirenz, particularly within the first 2 weeks. Cyclosporine dose adjustment may be required.
CYP3A4 Inducers (Strong) May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling.
Dabrafenib May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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).
Daclatasvir CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer.
Darunavir May increase the serum concentration of Efavirenz. Efavirenz may decrease the serum concentration of Darunavir. Management: Monitor for decreased concentrations and effects of darunavir and/or increased concentrations and effects of efavirenz when darunavir/ritonavir is combined with efavirenz. The use of darunavir/cobicistat in combination with efavirenz is not recommended.
Dolutegravir Efavirenz may decrease the serum concentration of Dolutegravir. Management: Increase dolutegravir dose to 50 mg twice daily in adults or children. Consider alternatives to efavirenz for INSTI experienced patients with clinically suspected INSTI resistance or certain INSTI associated resistance substitutions.
Droperidol May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Enzalutamide May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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.
Erdafitinib CYP3A4 Inducers (Moderate) may decrease the serum concentration of Erdafitinib. Management: Dose modifications of erdafitinib may be required. See full monograph for details.
Etonogestrel Efavirenz may diminish the therapeutic effect of Etonogestrel. Management: Use a reliable barrier contraceptive if efavirenz is used in combination with etonogestrel. Continue using barrier contraception for 12 weeks after discontinuation of efavirenz.
Everolimus Efavirenz may decrease the serum concentration of Everolimus. Management: Closely monitor everolimus serum concentrations when starting, stopping, or changing doses of efavirenz, particularly during the first 2 weeks after any change. Dose adjustment of everolimus may be required.
Flunitrazepam CNS Depressants may enhance the CNS depressant effect of Flunitrazepam.
Fosamprenavir Efavirenz may decrease serum concentrations of the active metabolite(s) of Fosamprenavir. Management: For once-daily fosamprenavir/ritonavir with efavirenz, an increased ritonavir dose to 300 mg/day is recommended in adult patients. No ritonavir dose adjustment is required if using twice-daily fosamprenavir/ritonavir.
Fosphenytoin Efavirenz may increase the serum concentration of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Efavirenz.
GuanFACINE CYP3A4 Inducers (Moderate) may decrease the serum concentration of GuanFACINE. Management: Increase the guanfacine dose by up to double when initiating guanfacine in a patient taking a moderate CYP3A4 inducer. Increase guanfacine dose gradually over 1 to 2 weeks if initiating a moderate CYP3A4 inducer in a patient already taking guanfacine.
HYDROcodone CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.
Indinavir Efavirenz may decrease the serum concentration of Indinavir. Management: The appropriate dose adjustments for indinavir when used together with efavirenz are unknown. The use of higher unboosted indinavir doses is not likely an adequate approach. Use of a ritonavir-boosted indinavir regimen could be considered.
Lopinavir Efavirenz may decrease the serum concentration of Lopinavir. Management: Avoid once daily use of lopinavir/ritonavir with efavirenz. Avoid use of this combination in patients less than 6 months of age. See lopinavir/ritonavir prescribing information for specific recommended dose increases in particular patient populations.
Lorlatinib CYP3A4 Inducers (Moderate) may enhance the hepatotoxic effect of Lorlatinib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with moderate CYP3A4 inducers. If such a combination must be used, monitor AST, ALT, and bilirubin within 48 hours of starting the combination and at least three times within the first week of combined use.
Lorlatinib May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
Lurasidone CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lurasidone. Management: Monitor for decreased lurasidone effects if combined with moderate CYP3A4 inducers and consider increasing the lurasidone dose if coadministered with a moderate CYP3A4 inducer for 7 or more days.
Maraviroc Efavirenz may decrease the serum concentration of Maraviroc. Of note, this effect only applies in the absence of a strong CYP3A4 inhibitor Management: Increase maraviroc adult dose to 600 mg twice daily if used with efavirenz. This does not apply to patients also receiving strong CYP3A4 inhibitors. This combination is contraindicated in patients with CrCl less than 30 mL/min.
Methotrimeprazine CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established.
Mitotane May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane.
Norgestimate Efavirenz may decrease serum concentrations of the active metabolite(s) of Norgestimate. Management: Use a reliable barrier contraceptive if efavirenz is used in combination with norgestimate. Continue using barrier contraception for 12 weeks after discontinuation of efavirenz.
Opioid Agonists CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.
OxyCODONE CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.
Palbociclib CYP3A4 Inducers (Moderate) may decrease the serum concentration of Palbociclib. Management: The US label does not provide specific recommendations concerning use with moderate CYP3A4 inducers, but the Canadian label recommends avoiding use of moderate CYP3A4 inducers.
Perampanel May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination.
Perampanel CYP3A4 Inducers (Moderate) may decrease the serum concentration of Perampanel. Management: Increase the perampanel starting dose to 4 mg/day when perampanel is used concurrently with moderate and strong CYP3A4 inducers.
Phenytoin May decrease the serum concentration of Efavirenz. Efavirenz may increase the serum concentration of Phenytoin.
Pitolisant May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant.
Progestins (Contraceptive) Efavirenz may decrease the serum concentration of Progestins (Contraceptive). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction.
Rifabutin Efavirenz may decrease the serum concentration of Rifabutin. Rifabutin may decrease the serum concentration of Efavirenz. Management: If efavirenz is to be used with daily rifabutin, increase the planned rifabutin adult dose by 50%. If used with regimens where rifabutin is administered 2-3 times per week, consider doubling the rifabutin dose.
Saquinavir May enhance the adverse/toxic effect of Efavirenz. Efavirenz may decrease the serum concentration of Saquinavir. Management: When used together with efavirenz, saquinavir should not be used as the sole protease inhibitor. Appropriate doses of the combination of efavirenz with saquinavir/ritonavir have not been established.
Sirolimus Efavirenz may decrease the serum concentration of Sirolimus. Management: Closely monitor sirolimus serum concentrations when starting, stopping, or changing doses of efavirenz, particularly during the first 2 weeks after any change. Dose adjustment of sirolimus may be required.
Sodium Oxybate May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated.
Suvorexant CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended.
Tacrolimus (Systemic) Efavirenz may decrease the serum concentration of Tacrolimus (Systemic). Management: Closely monitor tacrolimus serum concentrations when starting, stopping, or changing doses of efavirenz, particularly during the first 2 weeks after any change. Dose adjustment of tacrolimus may be required.
Tapentadol May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.
Voriconazole Efavirenz may decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Efavirenz. Management: Use of standard doses of these drugs is contraindicated. The voriconazole oral maintenance dose should be increased to 400 mg every 12 hours, and the efavirenz dose should be reduced to 300 mg/day.
Zolpidem CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol.

Risk Factor X (Avoid combination)

Abemaciclib CYP3A4 Inducers (Moderate) may decrease the serum concentration of Abemaciclib.
Amodiaquine Efavirenz may enhance the hepatotoxic effect of Amodiaquine. Efavirenz may increase the serum concentration of Amodiaquine.
Antihepaciviral Combination Products CYP3A4 Inducers (Moderate) may decrease the serum concentration of Antihepaciviral Combination Products.
Asunaprevir CYP3A4 Inducers (Moderate) may decrease the serum concentration of Asunaprevir.
Axitinib CYP3A4 Inducers (Moderate) may decrease the serum concentration of Axitinib.
Azelastine (Nasal) CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal).
Bedaquiline CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bedaquiline.
Bosutinib CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bosutinib.
Bromperidol May enhance the CNS depressant effect of CNS Depressants.
CarBAMazepine May decrease the serum concentration of Efavirenz. Efavirenz may decrease the serum concentration of CarBAMazepine.
Cobimetinib CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cobimetinib.
Dasabuvir CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dasabuvir.
Deflazacort CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Deflazacort.
Doravirine Efavirenz may decrease the serum concentration of Doravirine.
Elbasvir Efavirenz may decrease the serum concentration of Elbasvir.
Elvitegravir Efavirenz may decrease the serum concentration of Elvitegravir.
Encorafenib CYP3A4 Inducers (Moderate) may decrease the serum concentration of Encorafenib.
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.
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.
Flibanserin CYP3A4 Inducers (Moderate) may decrease the serum concentration of Flibanserin.
Glecaprevir and Pibrentasvir Efavirenz may decrease the serum concentration of Glecaprevir and Pibrentasvir.
Grazoprevir CYP3A4 Inducers (Moderate) may decrease the serum concentration of Grazoprevir.
Itraconazole Efavirenz may decrease the serum concentration of Itraconazole.
Ketoconazole (Systemic) Efavirenz may decrease the serum concentration of Ketoconazole (Systemic).
Neratinib CYP3A4 Inducers (Moderate) may decrease the serum concentration of Neratinib.
Nevirapine Efavirenz may enhance the adverse/toxic effect of Nevirapine. Nevirapine may enhance the adverse/toxic effect of Efavirenz. Nevirapine may decrease the serum concentration of Efavirenz.
Nisoldipine CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nisoldipine.
Olaparib CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olaparib.
Orphenadrine CNS Depressants may enhance the CNS depressant effect of Orphenadrine.
Oxomemazine May enhance the CNS depressant effect of CNS Depressants.
Paraldehyde CNS Depressants may enhance the CNS depressant effect of Paraldehyde.
Posaconazole Efavirenz may decrease the serum concentration of Posaconazole.
Ranolazine CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ranolazine.
Reverse Transcriptase Inhibitors (Non-Nucleoside) May increase the serum concentration of Efavirenz. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Efavirenz.
Rilpivirine 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.
Simeprevir CYP3A4 Inducers (Moderate) may decrease the serum concentration of Simeprevir.
Sonidegib CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sonidegib.
St John's Wort May decrease the serum concentration of Efavirenz.
Thalidomide CNS Depressants may enhance the CNS depressant effect of Thalidomide.
Ulipristal Efavirenz may decrease the serum concentration of Ulipristal.
Velpatasvir CYP2B6 Inducers (Moderate) may decrease the serum concentration of Velpatasvir.
Velpatasvir CYP3A4 Inducers (Moderate) may decrease the serum concentration of Velpatasvir.
Venetoclax CYP3A4 Inducers (Moderate) may decrease the serum concentration of Venetoclax.

 

  •  

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:

Efavirenz Tablets 200 mg in Pakistan

Efavir A. J. Mirza Pharma (Pvt) Ltd

 

Efavirenz Tablets 600 mg in Pakistan

Efavir A. J. Mirza Pharma (Pvt) Ltd
Zirenz Mass Pharma (Private) Limited