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Efavirenz

Class: Nonnucleoside Reverse Transcriptase Inhibitors
VA Class: AM800
Chemical Name: (±) - 6 - Chloro - 4 - (cyclopropylethynyl) - 1,4 - dihydro - 4 - (trifluoromethyl) - 2H - 3,1 - benzoxazin - 2 - one
Molecular Formula: C14H9ClF3NO2
CAS Number: 154635-17-3
Brands: Atripla, Sustiva

Introduction

Antiretroviral; nonnucleoside reverse transcriptase inhibitor (NNRTI).1 2 3 12 14

Uses for Efavirenz

Treatment of HIV Infection

Treatment of HIV-1 infection in conjunction with other antiretrovirals.1

The preferred NNRTI when NNRTI-based regimens are used for initial treatment, except during first trimester of pregnancy or in women of childbearing age who may become pregnant.200 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Slideshow: Flashback: FDA Drug Approvals 2013

Efavirenz/emtricitabine/tenofovir (Atripla) used alone or in conjunction with other antiretrovirals.232 Used to decrease pill burden and improve compliance.232

Postexposure Prophylaxis of HIV

Postexposure prophylaxis of HIV infection in health-care workers and others exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with risk for transmission of the virus.199 Used in conjunction with other antiretrovirals.199

Postexposure prophylaxis of HIV infection following nonoccupational exposure to blood, genital secretions, or other potentially infectious body fluids of a person known to be infected with HIV when such exposure represents a substantial risk for HIV transmission.198 Used in conjunction with other antiretrovirals.198

Efavirenz Dosage and Administration

Administration

Oral Administration

Administer efavirenz (Sustiva) or efavirenz/emtricitabine/tenofovir (Atripla) orally once daily on an empty stomach, preferably at bedtime.1 232

Administration at bedtime may make adverse CNS effects (dizziness, insomnia, impaired concentration, somnolence, abnormal dreams) more tolerable.1

Dosage

Antiretroviral agents contained in Atripla also are available in other single-entity or fixed-combination preparations; care should be taken to ensure that therapy is not duplicated when Atripla is used in conjunction with other antiretroviral agents.232 When selecting concomitant therapy, consider cautions and interactions for each drug in the fixed combination.232

Pediatric Patients

Treatment of HIV Infection
Oral
Efavirenz Dosage in Children ≥3 Years of Age1

Weight in kg

Efavirenz Dosage

10 to <15

200 mg once daily

15 to <20

250 mg once daily

20 to <25

300 mg once daily

25 to <32.5

350 mg once daily

32.5 to <40

400 mg once daily

≥40

600 mg once daily

Adults

Treatment of HIV Infection
Oral

600 mg once daily.1

Efavirenz/emtricitabine/tenofovir (Atripla): 1 tablet (efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg) once daily.232

Postexposure Prophylaxis of HIV
Occupational Exposure
Oral

600 mg once daily.199

Initiate postexposure prophylaxis as soon as possible following exposure (within hours rather than days) and continue for 4 weeks, if tolerated.199

Nonoccupational Exposure
Oral

600 mg once daily.198

Initiate postexposure prophylaxis as soon as possible following exposure (preferably ≤72 hours after exposure) and continue for 28 days.198

Special Populations

Hepatic Impairment

Treatment of HIV Infection

Efavirenz: Dosage adjustments not needed in patients with mild hepatic impairment;1 do not use in those with moderate or severe hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Efavirenz/emtricitabine/tenofovir (Atripla): Dosage adjustment not needed in adults with mild hepatic impairment; however, caution advised.232 Do not use in those with moderate or severe hepatic impairment.232

Renal Impairment

Treatment of HIV Infection

Efavirenz: Dosage adjustments not necessary.200

Efavirenz/emtricitabine/tenofovir (Atripla): Dosage adjustment not needed in adults with Clcr ≥50 mL/minute;232 do not use in those with Clcr <50 mL/minute.232

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 232

Cautions for Efavirenz

Contraindications

  • History of clinically important hypersensitivity reaction (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic skin eruption) to efavirenz or any ingredient in the formulation.1 232

  • Concomitant use of efavirenz with drugs for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., bepridil, cisapride, ergot alkaloids, midazolam, pimozide, triazolam).1 (See Specific Drugs under Interactions.)

  • Concomitant use with drugs that may result in decreased plasma concentrations of efavirenz, possible loss of virologic response, and development of resistance (e.g., St. John's wort [Hypericum perforatum]).1 (See Specific Drugs under Interactions.)

  • When used in fixed combination with other antiretrovirals (e.g., emtricitabine, tenofovir), consider contraindications associated with each drug.232

Warnings/Precautions

Interactions

Serious and/or life-threatening drug interactions, clinically important drug interactions, or loss of virologic effect can occur with some drugs.1 (See Specific Drugs under Interactions.)

Psychiatric Symptoms

Serious adverse psychiatric symptoms (severe depression, suicidal ideation, nonfatal suicide attempts, aggressive behavior, paranoid reactions) reported rarely in clinical studies.1 Factors associated with increased occurrence of psychiatric symptoms include history of injection drug use, history of psychiatric disorders, and treatment with antipsychotic drugs at study entry.1

If serious psychiatric adverse events occur, evaluate to determine if symptoms are related to efavirenz; if so, determine whether risks of continued efavirenz outweigh benefits.1

Nervous System Effects

Dizziness or insomnia reported frequently; abnormal dreams, hallucinations, or impaired concentration also reported.1 These adverse effects generally begin during first 1–2 days of therapy, improve with continued therapy, and usually resolve after first 2–4 weeks.1

Seizures reported rarely.1 Generally have occurred in patients with a history of seizures; caution advised in these patients.1 Patients receiving anticonvulsant therapy may require periodic monitoring.1 (See Specific Drugs under Interactions.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm if administered during first trimester of pregnancy.1 232 Teratogenicity demonstrated in animals.1 Birth defects (including neural tube defects) reported in humans, usually with first-trimester exposure.1

Advise women of childbearing potential about the teratogenic potential of efavirenz;1 232 perform test to rule out pregnancy before initiating efavirenz.1 232

Avoid pregnancy during and for 12 weeks after efavirenz therapy.1 232 Women of childbearing potential should use a reliable method of barrier contraception in addition to or instead of a hormonal contraceptive (oral or other hormonal contraceptive).1 200 202 232 (See Specific Drugs under Interactions.)

Dermatologic Reactions

Rash (maculopapular skin eruptions) reported frequently; rash associated with blistering, moist desquamation, or ulceration, erythema multiforme, and Stevens-Johnson Syndrome also reported.1 2 Median time to onset 11 days; median duration 16 days.1

Discontinue efavirenz in patients with life-threatening cutaneous reactions (e.g., Stevens-Johnson syndrome) and consider alternative therapy.1 Discontinue efavirenz in patients with serious rash (e.g., rash associated with blistering, desquamation, mucosal involvement, or fever).1 Mild to moderate rash generally resolves within 1 month with continued efavirenz.1 May be reinitiated after temporary interruption for rash.1 Antihistamines and/or corticosteroids may improve tolerability and hasten resolution of rash.1

Hepatotoxicity

Substantial increases in serum AST or ALT concentrations (>5 times ULN) reported in clinical studies in HIV-infected patients coinfected with HBV and/or HCV.1

Hepatic failure and hepatitis reported, some with a fulminant course requiring transplantation or resulting in death.1 Hepatic failure has occurred in some patients with no preexisting hepatic disease or other identifiable risk factors.1

Use with caution in patients with hepatic impairment.1 232 (See Hepatic Impairment under Cautions.)

Assess serum liver enzyme concentrations prior to and during efavirenz treatment in patients with underlying hepatic disease (including those with HBV and/or HCV infection), patients with markedly increased serum transaminase concentrations, and patients receiving other drugs associated with liver toxicity.1 232

Also consider monitoring serum liver enzymes in patients without preexisting hepatic dysfunction or other risk factors.1 232

In patients with serum hepatic enzyme concentrations >5 times ULN, consider whether benefits of continued efavirenz therapy outweigh risks of hepatotoxicity.1 232

Use of Fixed Combinations

Do not use multiple efavirenz-containing preparations concomitantly.1 232

When used in fixed combination with other antiretrovirals (e.g., emtricitabine, tenofovir), consider cautions, precautions, contraindications, and interactions associated with each drug.232 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug in the fixed combination.232

Lipid Effects

Increased serum concentrations of total cholesterol and triglycerides reported.1

Assess serum cholesterol and triglycerides prior to and periodically during therapy.1

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance.1

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jiroveci [formerly P. carinii]); this may necessitate further evaluation and treatment.1

Specific Populations

Pregnancy

Efavirenz: Category D.1 232

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202

Women of childbearing potential should use effective contraceptive measures during and for 12 weeks after efavirenz therapy.1 232 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Use in pregnant women (especially during first trimester) only if potential benefits justify potential risks to the fetus, such as in pregnant women without other therapeutic options.1 200 202 232

Experts state initiation of efavirenz should be avoided during first trimester of pregnancy, but can be considered after first trimester if it is the best choice for a specific woman after considering alternatives.202 If a pregnant woman already receiving an efavirenz-containing regimen presents for antenatal care during first trimester, these experts suggest the regimen can be continued if well tolerated and providing adequate virologic suppression.202 Risk of neural tube defects is limited to first 5–6 weeks of pregnancy and pregnancy rarely recognized until after 4–6 weeks; unnecessary changes in antiretroviral regimens during pregnancy may be associated with loss of virologic control and increased risk of perinatal HIV transmission.202

If used during first trimester or if pregnancy occurs, apprise patient of potential harm to the fetus.1 232

Lactation

Efavirenz distributed into human milk.202

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202 232

Pediatric Use

Safety and efficacy of efavirenz not evaluated in neonates and children <3 years of age or who weigh <13 kg;1 not recommended in this age group.201

Safety and efficacy of efavirenz in fixed combination with emtricitabine and tenofovir not established in pediatric patients <18 years of age.232

Adverse effects reported with efavirenz in children 3–16 years of age are similar to those reported in adults with the exception of rash.1 Rash reported more frequently in children than adults and the incidence of moderate to severe rash has been greater in children than adults.1

Not recommended in sexually active adolescent females of childbearing potential who desire to become pregnant or when reliable contraception cannot be ensured.201 (See Pregnancy under Cautions.)

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1 232

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 232

Hepatic Impairment

Use efavirenz with caution in mild hepatic impairment;1 232 do not use in moderate or severe hepatic impairment.1 232

Monitor hepatic enzyme concentrations in patients with known or suspected HBV or HCV infection, patients with substantially increased transaminase concentrations, and in patients receiving other drugs associated with hepatotoxicity.1 (See Hepatotoxicity under Cautions.)

Renal Impairment

Pharmacokinetics of efavirenz not specifically studied; clinically important decreases in clearance not anticipated.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Rash, dizziness, nausea, headache, fatigue, insomnia, vomiting.1

Interactions for Efavirenz

Metabolized by CYP3A and CYP2B6.1

Inhibits CYP2C9, CYP2C19, and CYP3A4, and to a lesser extent, CYP2D6 and CYP1A2.1 Does not inhibit CYP2E1.1

Induces CYP3A.1

The following drug interactions are based on studies using efavirenz.1 Drug interaction studies have not been performed using fixed combination containing efavirenz, emtricitabine, and tenofovir.232 When used in fixed combination with other antiretrovirals (e.g., emtricitabine, tenofovir), consider interactions associated with each drug in the fixed combination.232

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A, CYP29C, or CYP2C19 with possible alteration in metabolism of efavirenz and/or other drug.1 May also affect plasma concentrations of drugs metabolized by CYP2B6.1

Specific Drugs

Drug

Interaction

Comments

Abacavir

In vitro evidence of additive antiretroviral effects1

Alcohol

Potential for additive CNS effects1

Antacids (aluminum hydroxide, magnesium hydroxide, simethicone)

Pharmacokinetic interaction unlikely1

Dosage adjustment not needed1

Anticoagulants, oral

Warfarin concentrations likely to be affected1

Use with caution; closely monitor INR1 200

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Carbamazepine: Decreased concentrations and AUCs of efavirenz and carbamazepine1 200

Phenobarbital, phenytoin: Possible decreased concentrations of phenobarbital and phenytoin and/or efavirenz1 200

Use with caution; monitor anticonvulsant concentrations;1 200 data insufficient to make dosage recommendations for concomitant carbamazepine;1 consider alternative anticonvulsant200

Antifungals, azoles (fluconazole, itraconazole, ketoconazole, voriconazole)

Fluconazole: No clinically important pharmacokinetic interactions1 200

Itraconazole: Decreased concentrations of itraconazole; no change in efavirenz concentrations1

Ketoconazole: Possible decreased concentrations of the antifungal1

Posaconazole: Decreased posaconazole concentrations and AUC;1 200 does not affect efavirenz concentrations200

Voriconazole: Decreased voriconazole concentrations; increased efavirenz concentrations1 200

Fluconazole: Dosage adjustment not needed1

Itraconazole: Dosage recommendation for concomitant use not available;1 consider alternative antifungal;1 some experts state avoid concomitant use;200 if used concomitantly, closely monitor itraconazole concentrations and adjust antifungal dosage accordingly200

Posaconazole: Avoid concomitant use unless potential benefits outweigh risks;1 200 if used concomitantly, monitor posaconazole concentrations and adjust antifungal dosage accordingly200

Voriconazole: Concomitant use of usual dosages of voriconazole and efavirenz contraindicated;1 200 if used with voriconazole, increase voriconazole maintenance dosage to 400 mg every 12 hours and decrease efavirenz dosage to 300 mg (use capsules; do not divide tablet) once daily1 200

Antihistamines

Decreased cetirizine concentrations; no change in efavirenz concentrations1

When used with cetirizine, dosage adjustment not needed1

Antimycobacterials (rifabutin, rifampin, rifapentine)

Rifabutin: Decreased rifabutin concentrations; no change in efavirenz AUC1 54 200

Rifampin: Decreased efavirenz concentrations and AUC1 200

Rifabutin: Efavirenz dosage adjustment not needed; increase rifabutin dosage to 450–600 mg once daily or 600 mg 3 times weekly provided regimen does not include an HIV protease inhibitor1 200

Rifampin: Increase efavirenz dosage to 800 mg once daily in those weighing ≥50 kg;1 some experts recommend efavirenz 600 mg once daily for patients weighing <60 kg and efavirenz 800 mg once daily in those weighing >60 kg and state virologic response should be monitored and therapeutic drug monitoring considered200

Rifapentine: Concomitant use not recommended200

Antipsychotics (pimozide)

Pimozide: Potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)1

Pimozide: Concomitant use contraindicated1

Atazanavir

Atazanavir (without low-dose ritonavir): Substantially decreased atazanavir concentrations and AUC;1 203 no clinically important change in efavirenz concentrations200

Ritonavir-boosted atazanavir: Possible increased atazanavir concentrations and AUC depending on specific regimen1 203

No in vitro evidence of antagonistic antiretroviral effects203

Ritonavir-boosted atazanavir in treatment-naive adults: Use atazanavir 400 mg and ritonavir 100 mg once daily (with food) and efavirenz 600 mg once daily (without food, preferably at bedtime)1 200 203

Ritonavir-boosted atazanavir in antiretroviral-experienced adults: Concomitant use not recommended1 200 203

Atazanavir (without low-dose ritonavir): Do not use with efavirenz200 203

Atovaquone and proguanil

Decreased atovaquone and proguanil AUCs200

Consider alternative for malaria prophylaxis, if possible200

Benzodiazepines

Midazolam, triazolam: Pharmacokinetic interaction; potential for prolonged or increased sedation or respiratory depression1

Lorazepam: Increased lorazepam concentrations and AUC1

Alprazolam: Data not available200

Midazolam, triazolam: Concomitant use contraindicated;1 some experts state a single parenteral midazolam dose can be used with caution in a monitored situation for procedural sedation200

Lorazepam: Dosage adjustments not needed1

Alprazolam: Monitor for benzodiazepine effectiveness200

Boceprevir

Decreased boceprevir concentrations and AUC and possible loss of boceprevir therapeutic effects; slightly increased efavirenz concentrations and AUC185

Avoid concomitant use185 200

Buprenorphine

Decreased buprenorphine and norbuprenorphine AUCs200

Dosage adjustments not recommended, but monitor patients for withdrawal symptoms200

Bupropion

Decreased bupropion concentrations and AUC;1 200 increased concentrations of hydroxybupropion (an active metabolite)1

Titrate bupropion dosage based on clinical response;200 do not exceed recommended bupropion dosage1

Calcium-channel blocking agents

Diltiazem: Decreased diltiazem concentrations; slightly increased efavirenz concentrations1

Possible decreased concentrations of other calcium-channel blocking agents that are substrates of CYP 3A4 (e.g., felodipine, nicardipine, nifedipine, verapamil)1

Diltiazem: Titrate diltiazem dosage based on clinical response; efavirenz dosage adjustment not needed1

Verapamil: Titrate verapamil dosage based on clinical response; efavirenz dosage adjustment not needed1

Calcium-channel blocking agents that are substrates of CYP 3A4: Adjust dosage according to clinical response1

Cisapride

Pharmacokinetic interaction; potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)1

Concomitant use contraindicated1 200

Corticosteroids

Dexamethasone: Possible decreased efavirenz concentrations200

Dexamethasone: Monitor virologic response;200 consider alternative corticosteroids for long-term use200

Darunavir

Ritonavir-boosted darunavir: Increased efavirenz AUC; decreased darunavir AUC;200 204 clinical importance unknown200

No in vitro evidence of antagonistic antiretroviral effects204

Ritonavir-boosted darunavir: Manufacturer states dosage adjustments not necessary;204 some experts state usual dosages can be used with close monitoring and if drug concentration monitoring is considered200

Delavirdine

Concomitant use not recommended200

Didanosine

In vitro evidence of additive antiretroviral effects1

Emtricitabine

In vitro evidence of additive antiretroviral effects1

Enfuvirtide

In vitro evidence of additive to synergistic antiretroviral effects1 223

Ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine)

Possibility of pharmacokinetic interaction; potential for serious or life-threatening reactions (e.g., acute ergot toxicity)1

Concomitant use contraindicated1 200

If treatment of uterine atony and excessive postpartum bleeding is indicated in a woman receiving efavirenz, use methylergonovine maleate (Methergine) only if alternative treatments cannot be used and if potential benefits outweigh risks; use methylergonovine at lowest dosage and shortest duration possible202

Estrogens/Progestins

Oral hormonal contraceptive containing ethinyl estradiol and norgestimate: Substantially decreased concentrations and AUC of norelgestromin and levonorgestrel (metabolites of norgestimate); no effect on peak concentrations or AUC of ethinyl estradiol; no effect on efavirenz concentrations1 76 200 202

Etonogestrel subcutaneous implant: Not studied, but decreased etonogestrel concentrations likely;1 202 subcutaneous implant contraceptive failure reported in women receiving efavirenz1 202

Oral levonorgestrel emergency contraceptive: Decreased efficacy likely77 200 202

Hormonal contraceptives (oral or other hormonal contraceptives): Use a barrier contraceptive as an alternative to or in addition to hormonal contraceptive in women of childbearing potential during and for 12 weeks after efavirenz therapy is discontinued1 200 202

Etravirine

Decreased etravirine concentrations and loss of therapeutic effect200 214

Concomitant use not recommended200 214

Fosamprenavir

Substantially decreased concentrations of amprenavir (active metabolite of fosamprenavir) if used with fosamprenavir (without low-dose ritonavir);1 205 additional pharmacokinetic interactions if used with ritonavir-boosted fosamprenavir205

In vitro evidence of synergistic antiretroviral effects205

Fosamprenavir (without low-dose ritonavir): Appropriate dosages with respect to safety and efficacy not established1 205

Ritonavir-boosted fosamprenavir: Use usual efavirenz dosage with fosamprenavir 1.4 g once daily and ritonavir 300 mg once daily or, alternatively, with fosamprenavir 700 mg twice daily and ritonavir 100 mg twice daily200

Histamine H2-receptor antagonists (famotidine)

Pharmacokinetic interaction unlikely with famotidine1

When used with famotidine, dosage adjustment not needed1

HMG-CoA reductase inhibitors (statins)

Atorvastatin, pravastatin, and simvastatin: Decreased concentrations of the antilipemic agent;1 200 no clinically important effect on efavirenz concentrations1

Rosuvastatin: Data not available200

Atorvastatin: Titrate atorvastatin dosage based on lipid response; do not exceed maximum recommended dosage200

Lovastatin: Avoid lovastatin if efavirenz regimen includes a ritonavir-boosted PI200

Pravastatin: Titrate pravastatin dosage based on lipid response; do not exceed the maximum recommended dosage200

Rosuvastatin: Titrate rosuvastatin dosage based on lipid response; do not exceed maximum recommended dosage200

Simvastatin: Titrate simvastatin dosage based on lipid response; do not exceed maximum recommended dosage;200 avoid simvastatin if efavirenz regimen includes a ritonavir-boosted PI200

Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)

Cyclosporine, sirolimus, tacrolimus: Possible decreased concentrations of the immunosuppressive agents; no effect on efavirenz concentrations1

Cyclosporine, sirolimus, tacrolimus: Dosage of immunosuppressive agent may need to be adjusted;1 whenever efavirenz is initiated or discontinued, monitor immunosuppressive agent concentrations for at least 2 weeks until stable1

Indinavir

Decreased indinavir AUC; no clinically important effect on efavirenz concentrations or AUC1

In vitro evidence of additive antiretroviral effects1

Optimum dosage for concomitant use not established; increasing indinavir dosage to 1 g every 8 hours does not compensate for increased indinavir metabolism due to efavirenz1

Lamivudine

No effect on lamivudine peak concentrations or AUC1

In vitro evidence of additive antiretroviral effects1

Dosage adjustments not needed1

Lopinavir/ritonavir

Decreased lopinavir concentrations and AUC1 207

In vitro evidence of additive antiretroviral effects1

Once-daily lopinavir/ritonavir regimen not recommended with efavirenz1 207

If used with efavirenz in adults, recommended dosage of lopinavir/ritonavir tablets is lopinavir 500 mg/ritonavir 125 mg twice daily;207 alternatively, recommended dosage of lopinavir/ritonavir oral solution is lopinavir 533 mg/ritonavir 133 mg (6.5 mL) twice daily207

Macrolides (azithromycin, clarithromycin, erythromycin)

Clarithromycin: Decreased clarithromycin concentrations and increased 14-hydroxyclarithromycin concentrations;1 rash reported with concomitant administration1

Azithromycin: Pharmacokinetic interaction unlikely1

Erythromycin: Not studied1

Clarithromycin: Monitor for efficacy of the macrolide or use an alternative anti-infective1 200

Azithromycin: Dosage adjustment not needed1

Maraviroc

Decreased maraviroc concentrations and AUC1 200 224

No in vitro evidence of antagonistic antiretroviral effects224

Recommended maraviroc dosage is 600 mg twice daily when used with efavirenz, provided regimen does not include a potent CYP3A inhibitor200 224

Methadone

Decreased methadone concentrations and AUC;1 opiate withdrawal manifestations required 22% increase in methadone dosage1

Inform patients of potential interaction; closely monitor for signs of opiate withdrawal; increased methadone maintenance dosage may be necessary1 200

Nelfinavir

Increased nelfinavir concentrations and AUC; decreased efavirenz concentrations and AUC1 208

In vitro evidence of additive to synergistic antiretroviral effects1 208

Dosage adjustments not needed1 200

Nevirapine

Decreased efavirenz concentrations and AUC;200 215 no change in nevirapine concentrations200

Increased incidence of adverse effects;215 no improvement in efficacy215

Concomitant use not recommended200 215

Psychotherapeutic agents

Potential for additive CNS effects1

Raltegravir

Decreased raltegravir concentrations and AUC;200 225 clinical importance unknown225

In vitro evidence of additive to synergistic antiretroviral effects225

Some experts state dosage adjustments not necessary200

Rilpivirine

Decreased rilpivirine concentrations;226 no change in efavirenz concentrations226

Concomitant use not recommended200 226

Ritonavir

Increased ritonavir AUC and increased efavirenz AUC1 40 200

Higher incidence of dizziness, nausea, paresthesia, and elevated hepatic enzyme values with regimens that include both drugs1 201

In vitro evidence of additive antiretroviral effects1

Monitor hepatic enzymes;1 201 use usual dosages200

St. John’s wort (Hypericum perforatum)

Decreased efavirenz concentrations; possible loss of virologic response and increased risk of efavirenz resistance1 63 64

Concomitant use contraindicated1 200

Saquinavir

Decreased saquinavir concentrations and AUC;1 210 decreased efavirenz concentrations and AUC1 210

In vitro evidence of additive antiretroviral effects1

Saquinavir: Do not use as sole PI in regimens that include efavirenz;1 appropriate dosages with respect to safety and efficacy not established210

Ritonavir-boosted saquinavir: Some experts recommend saquinavir 1 g twice daily and ritonavir 100 mg twice daily with usual efavirenz dosage200

Selective serotonin-reuptake inhibitors (SSRIs)

Paroxetine: No pharmacokinetic interaction1

Sertraline: Decreased sertraline concentrations and AUC1

Paroxetine: Dosage adjustments not needed1

Sertraline: Adjust sertraline dosage based on clinical response1

Stavudine

In vitro evidence of additive antiretroviral effects1

Telaprevir

Decreased telaprevir concentrations and AUC; no clinically important effect on efavirenz concentrations and AUC184 200

Some experts recommend increasing telaprevir dosage to 1125 mg every 7–9 hours in patients receiving efavirenz and 2 NRTIs200

Tenofovir

No effect on concentrations or AUCs of either drug1 221

In vitro evidence of additive to synergistic antiretroviral effects1 221

Dosage adjustments not needed1

Tipranavir

Ritonavir-boosted tipranavir: Decreased tipranavir concentrations and no change in efavirenz concentrations using tipranavir 500 mg twice daily and ritonavir 100 mg twice daily with efavirenz 600 mg once daily200 211

In vitro evidence of additive antiretroviral effects211

Some experts state dosage adjustment not necessary200

Valproic acid

No evidence of pharmacokinetic interaction75

Zidovudine

No effect on zidovudine peak concentrations or AUC1

In vitro evidence of additive antiretroviral effects1

Dosage adjustments not necessary1

Efavirenz Pharmacokinetics

Absorption

Bioavailability

Peak plasma efavirenz concentrations attained within 3–5 hours.1

Fixed-combination tablet containing efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg (Atripla) is bioequivalent to a 600-mg efavirenz tablet, a 200-mg emtricitabine capsule, and a 300-mg tenofovir disoproxil fumarate tablet taken simultaneously.232

Food

Administration with food increases efavirenz bioavailability.1

Compared with administration in the fasting state, AUC increased 22 or 17% when a single 600-mg efavirenz dose as capsules was administered with a high-fat, high-calorie meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat normal calorie meal (440 kcal, 2 g fat, 4% calories from fat), respectively.1

Compared with administration in the fasting state, AUC increased 28% when a single 600-mg efavirenz dose as tablets was administered with a high-fat, high-calorie meal (1000 kcal, 500–600 kcal from fat).1

Distribution

Extent

Not fully characterized.1

Low efavirenz concentrations distributed into CSF.1

Animal studies indicate efavirenz crosses placenta in rats, rabbits, and primates.202 Distributed into human milk.202

Plasma Protein Binding

99.5–99.75%.1

Elimination

Metabolism

Metabolized by CYP3A and CYP2B6; undergoes subsequent glucuronidation.1

Elimination Route

16–61% excreted in feces (principally as unchanged drug) and 14–34% eliminated in urine as unchanged drug (<1%) or metabolites.1

Not removed by hemodialysis; probably not removed by peritoneal dialysis.1 67

Half-life

52–76 hours after a single dose and 50–55 hours after multiple doses.1

Special Populations

Hepatic impairment: Pharmacokinetics not affected by mild impairment (Child-Pugh class A);1 data insufficient to determine whether affected by moderate or severe impairment (Child-Pugh class B or C).1

Stability

Storage

Oral

Capsules

Efavirenz: 25°C (may be exposed to 15–30°C).1

Tablets

Single-entity efavirenz or fixed combination: 25°C (may be exposed to 15–30°C).1 232

Actions and Spectrum

  • Pharmacologically related to other NNRTIs (e.g., delavirdine, etravirine, nevirapine, rilpivirine); differs structurally from these drugs; also differs pharmacologically and structurally from other currently available antiretrovirals.1 2 3 6 12 14 52 53 212 215

  • Active against HIV-1; inactive against HIV-2.1 3

  • Inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.1 3

  • HIV-1 with reduced susceptibility to efavirenz have been selected in vitro and have emerged during therapy with the drug.1 3 9 14 18 18

  • Strains of HIV-1 resistant to efavirenz may be cross-resistant to some other NNRTIs (e.g., delavirdine, nevirapine).3 9 10 18 32 50 200 201 1 215

  • Cross-resistance between efavirenz and NRTIs unlikely since the drugs bind at difference sites on reverse transcriptase and have difference mechanisms of action.1 3 9 10 32 Cross-resistance between efavirenz and PIs unlikely since the drugs have different target enzymes and mechanisms of action.1 32

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 232 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1 232

  • Importance of using efavirenz in conjunction with other antiretrovirals—not for monotherapy.1 Efavirenz/emtricitabine/tenofovir (Atripla) can be used alone.232

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1 232

  • Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.200

  • Importance of reading patient information provided by the manufacturer.1 232

  • Importance of taking efavirenz on an empty stomach, preferably at bedtime.1 232

  • Advise patients that adverse CNS effects (e.g., dizziness, insomnia, impaired concentration, drowsiness, abnormal dreams) are common during first weeks of efavirenz therapy.1 232 Taking the drug at bedtime may improve tolerability.1 Additive effects may occur if used with alcohol or psychoactive drugs.1 232 If CNS effects occur, avoid potentially hazardous tasks such as driving or operating machinery.1 232

  • Advise patients that serious psychiatric symptoms (e.g., severe depression, suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like symptoms) have occurred.1 232 Importance of informing clinician of any history of mental illness or substance abuse.1 232 Importance of seeking immediate medical evaluation if severe psychiatric symptoms occur.1 232

  • Risk of rash.1 232 Since rash may be serious, importance of promptly contacting clinician if rash occurs.1 232

  • Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1 232

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, and any concomitant illnesses.1 232

  • Importance of women using a reliable barrier method of contraception instead of or in addition to a hormonal contraceptive (oral or other hormonal contraceptive) during and for 12 weeks after efavirenz therapy.1 232

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 232 Advise HIV-infected women not to breast-feed.1 232

  • Importance of advising patients of other important precautionary information.1 232 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Efavirenz

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

50 mg

Sustiva

Bristol-Myers Squibb

200 mg

Sustiva

Bristol-Myers Squibb

Tablets, film-coated

600 mg

Sustiva

Bristol-Myers Squibb

Efavirenz Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

600 mg with Emtricitabine 200 mg and Tenofovir Disoproxil Fumarate 300 mg

Atripla

Bristol-Myers Squibb and Gilead

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Atripla 600-200-300MG Tablets (BRISTOL-MYERS SQUIBB/GILEAD): 30/$1,878.96 or 90/$5,400.81

Sustiva 200MG Capsules (B-M SQUIBB U.S. (PRIMARY CARE)): 90/$633.96 or 270/$1,786.92

Sustiva 600MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$643.97 or 90/$1,817.95

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 1, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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5. Anon. Three new drugs for HIV infection. Med Lett. 1998; 40:114-6.

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23. Gallant JE, DeJesus E, Arribas JR et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006; 354:251-60. [PubMed 16421366]

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43. Yuen N (Agouron, La Jolla, CA): Personal communication; 1999 Mar 8.

45. Gallant J, Seekins D, Hicks C et al. A phase II, double-blind, placebo-control, dose-ranging study to assess the antiretroviral activity & safety of efavirenz (EFV, sustiva, DMP266) in combination with open-label zidovudine (ZDV) w/ lamivudine (3TC) at >48 weeks [DMP266-005]. Proceedings of 38th ICAAC San Diego, CA 1998. Abstracts-On-Disk. Abstract No. I-245.

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50. Miller V, de Bethune MP, Kober A et al. Patterns of resistance and cross-resistance to human immunodeficiency virus type 1 reverse transcriptase inhibitors in patients treated with the nonnucleoside reverse transcriptase inhibitor loviride. Antimicrob Agents Chemother. 1998; 42:3123-9. [IDIS 419417] [PubMed 9835502]

52. DuPont Pharmaceuticals, Wilmington, DE: Personal communication.

53. Reviewers’ comments (personal observations).

54. Benedek IH, Fiske WD, White SJ et al. Pharmacokinetic interaction between multiple doses of efavirenz and rifabutin in healthy volunteers. Presented at 36th annual meeting of Infectious Disease Society of America, Denver, CO: 1998 Nov 12-15. Abstract No. 461.

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59. Villani P, Regazzi MB, Castelli F et al. Pharmacokinetics of efavirenz (EFV) alone and in combination therapy with nelfinavir (NFV) in HIV-1 infected patients. Br J Clin Pharmacol. 1999; 48:712-5. [IDIS 438790] [PubMed 10594473]

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61. Centers for Disease Control and Prevention. Notice to readers: updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR Recomm Rep. 2000; 49:185-9.

62. Falloon J, Piscitelli S, Vogel S et al. Combination therapy with amprenavir, abacavir, and efavirenz in human immunodeficiency virus (HIV)-infected patients failing a protease-inhibitor regimen: pharmacokinetic drug interactions and antiviral activity. Clin Infect Dis. 2000; 30:313-8. [IDIS 444316] [PubMed 10671334]

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68. Podzamczer D, Consiglio E, Ferrer E et al. Efavirenz associated with corticosteroids in patients with previous severe hypersensitivity reaction due to nevirapine. AIDS. 2000; 14:331-2. [PubMed 10716515]

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75. DiCenzo R, Peterson D, Cruttenden K et al. Effects of valproic acid coadministration on plasma efavirenz and lopinavir concentrations in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2004; 48:4328-31. [IDIS 524915] [PubMed 15504860]

76. Sevinsky H, Eley T, Persson A et al. The effect of efavirenz on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy HIV-negative women. Antivir Ther. 2011; 16:149-56. [PubMed 21447863]

77. Carten ML, Kiser JJ, Kwara A et al. Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (Plan B), and Efavirenz. Infect Dis Obstet Gynecol. 2012; 2012:137192. [PubMed 22536010]

184. Vertex Pharmaceuticals Incorporated. Incivek (telaprevir) film-coated tablets prescribing information. Cambridge, MA; 2012 Jun.

185. Merck & Co. Victrelis (boceprevir) capsules prescribing information. Whitehouse Station, NJ; 2012 Apr.

198. Centers for Disease Control and Prevention. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: Recommendations from the U.S. Department of Health and Human Services. MMWR Recomm Rep. 2005; 54(No. RR-2):1-19.

199. Center for Disease Control and Prevention. Updated U.S. public health service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep. 2005; 54(No. RR-9):1-17.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (April 18, 2012). Updates may be available at HHS AIDS Information (AIDSinfo) website.

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (August 11, 2011). Updates may be available at HHS AIDS Information (AIDSinfo) website.

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (September 14, 2011). Updates may be available at HHS AIDS Information (AIDSinfo) website.

203. Bristol-Myers Squibb. Reyataz (atazanavir sulfate) capsules prescribing information. Princeton, NJ; 2012 Mar.

204. Janssen. Prezista (darunavir) oral suspension and tablets prescribing information. Titusville, NJ; 2012 Jun.

205. ViiV Healthcare. Lexiva (fosamprenavir calcium) tablets and oral suspension prescribing information. Research Triangle Park, NC; 2012 Feb.

207. Abbott Laboratories. Kaletra (lopinavir/ritonavir) tablets and oral solution prescribing information. North Chicago, IL; 2012 Feb.

208. ViiV Healthcare. Viracept (nelfinavir mesylate) tablets and oral powder prescribing information. Research Triangle Park, NC; 2012 Apr.

210. Genentech USA. Invirase (saquinavir mesylate) capsules and tablets prescribing information. South San Francisco, CA; 2012 Feb.

211. Boehringer Ingelheim. Aptivus (tipranavir) capsules and oral solution prescribing information. Ridgefield, CT; 2012 Apr.

212. ViiV Healthcare. Rescriptor (delavirdine mesylate) tablets prescribing information. Research Triangle Park, NC; 2010 Sep.

214. Janssen. Intelence (etravirine) tablets prescribing information. Raritan, NJ; 2012 Mar.

215. Boehringer Ingelheim. Viramune (nevirapine) tablets and oral suspension prescribing information. Ridgefield, CT; 2011 Nov.

221. Gilead Sciences. Viread (tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2012 Jan.

223. Genentech USA. Fuzeon (enfuvirtide) for injection prescribing information. South San Francisco, CA; 2011 Aug.

224. ViiV Healthcare. Selzentry (maraviroc) tablets prescribing information. Research Triangle Park, NC; 2011 Nov.

225. Merck Sharp & Dohme. Isentress (raltegravir) film-coated tablets and chewable tablets prescribing information. Whitehouse Station, NJ; 2012 Apr.

226. Tibotec Therapeutics. Edurant (rilpivirine) tablets prescribing information. Raritan, NJ; 2011 May.

232. Bristol-Myers Squibb and Gilead Sciences. Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA 2011 Sep.

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