Efavirenz

Class: HIV 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

Warning(s)

  • Fixed Combinations
  • If using efavirenz/emtricitabine/tenofovir DF (Atripla), consider that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported in patients receiving HIV nucleoside reverse transcriptase inhibitors (NRTIs) in conjunction with other antiretrovirals.232

  • If using efavirenz/emtricitabine/tenofovir DF (Atripla), consider that severe, acute exacerbations of HBV have been reported following discontinuance of emtricitabine or tenofovir DF in HIV-infected patients coinfected with HBV.232 The fixed combination is not labeled by FDA for treatment of chronic HBV infection; safety and efficacy not established in HIV-infected patients coinfected with HBV.232 Monitor hepatic function closely with both clinical and laboratory follow-up for at least several months after the fixed combination is discontinued in coinfected patients.232 If appropriate, initiation of HBV treatment may be warranted.232

Introduction

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

Uses for Efavirenz

Treatment of HIV Infection

Treatment of HIV-1 infection in adults, adolescents, and pediatric patients ≥3 months of age weighing ≥3.5 kg;1 2 10 11 12 200 201 usually used in conjunction with 2 NRTIs.1

For initial treatment in antiretroviral-naive adults and adolescents, experts state that efavirenz in conjunction with tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine) is a recommended NNRTI-based regimen that can be used regardless of baseline viral load or CD4+ T-cell count.200 Efavirenz in conjunction with abacavir and lamivudine (or emtricitabine) is another recommended NNRTI-based regimen for initial treatment in adults and adolescents, but use only in those with baseline plasma HIV RNA levels <100,000 copies/mL who are human leukocyte antigen (HLA)-B*5701 negative.200

Slideshow: Flashback: FDA Drug Approvals 2013

For initial treatment in antiretroviral-naive pediatric patients, experts state that efavirenz and 2 NRTIs is a preferred regimen for initial treatment in children ≥3 years of age,201 but is not recommended for initial treatment in those 3 months to <3 years of age.201

Usually avoid efavirenz in pregnant women (especially during first trimester) and in women of childbearing age who may become pregnant.1 200 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Efavirenz/emtricitabine/tenofovir DF fixed combination (Atripla) can be used in adults, adolescents, and children ≥12 years of age weighing ≥40 kg to decrease pill burden and improve adherence;232 used alone as a complete treatment regimen or used in conjunction with other antiretrovirals.232

Postexposure Prophylaxis following Occupational Exposure to HIV

Postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel and others exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.199

USPHS recommends 3-drug regimen of raltegravir in conjunction with emtricitabine and tenofovir DF as the preferred regimen for PEP following occupational exposures to HIV.199 Efavirenz and 2 NRTIs can be considered an alternative regimen, but use for PEP only with expert consultation.199 Preferred dual NRTI option for PEP regimens is emtricitabine and tenofovir DF (may be given as emtricitabine/tenofovir DF; Truvada); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be given as lamivudine/zidovudine; Combivir), or zidovudine and emtricitabine.199

Management of occupational exposures to HIV is complex and evolving; consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) whenever possible.199 Do not delay initiation of PEP while waiting for expert consultation.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP) in individuals exposed 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 DF (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.1 232

Efavirenz (Sustiva): Use in conjunction with other antiretrovirals.1

Efavirenz/emtricitabine/tenofovir DF (Atripla): Use alone as a complete treatment regimen or use in conjunction with other antiretrovirals.232 Because antiretrovirals in the fixed combination also are available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated if used in conjunction with other antiretrovirals.232 (See Use of Fixed Combinations under Cautions.)

Do not use single-entity efavirenz (Sustiva) and efavirenz/emtricitabine/tenofovir DF (Atripla) concomitantly, unless needed for adjustment of efavirenz dosage (e.g., when fixed combination used concomitantly with rifampin).1 232

Capsules (Sustiva)

Swallow capsules whole on an empty stomach.1

For adults and pediatric patients ≥3 months of age not able to swallow capsules or tablets, administer capsule contents by mixing with small amount (1–2 teaspoonfuls) of soft food (capsule sprinkle method).1 Consider mixing with infant formula only if infant cannot consume solid foods.1 Administer efavirenz mixture within 30 minutes after preparation; do not consume any additional food or infant formula for 2 hours after the mixture.1

Mixing capsule contents into food: Add 1–2 teaspoonfuls of age-appropriate soft food (e.g., applesauce, grape jelly, yogurt) to a small container.1 Hold appropriate number of capsules (see Table 1) horizontally over the small container, twist open, and empty onto the food.1 Gently mix with a spoon; feed entire mixture to patient.1 Then, add additional 2 teaspoonfuls of soft food to the small container, stir to disperse remaining efavirenz residue, and feed to patient.1

Mixing capsule contents into infant formula: Add 10 mL (2 teaspoonfuls) of reconstituted room temperature infant formula to a 30-mL medicine cup.1 Hold appropriate number of capsules (see Table 1) horizontally over the medicine cup, twist open, and empty onto the formula.1 Gently mix with small spoon.1 Draw up infant formula mixture into 10-mL oral dosing syringe; administer into infant's right or left inner cheek.1 Then, add additional 2 teaspoonfuls of infant formula to the medicine cup, stir to disperse remaining efavirenz residue, draw up into oral dosing syringe, and administer to infant.1

Tablets (Sustiva, Atripla)

Swallow tablets whole on an empty stomach; do not break or crush.1

Dosage

Pediatric Patients

Treatment of HIV Infection
Oral

Efavirenz (Sustiva): Dosage in children ≥3 months of age weighing 3.5 to <40 kg is based on weight.1 (See Table 1.) Adolescents and children weighing ≥40 kg may receive usual adult dosage.1

Table 1. Efavirenz (Sustiva) Dosage in Children ≥3 Months of Age Weighing ≥3.5 kg1

Weight in kg

Efavirenz Dosage

Number of Capsules or Tablets

3.5 to <5

100 mg once daily

Two 50-mg capsules

5 to <7.5

150 mg once daily

Three 50-mg capsules

7.5 to <15

200 mg once daily

One 200-mg capsule

15 to <20

250 mg once daily

One 200-mg and one 50-mg capsule

20 to <25

300 mg once daily

One 200-mg and two 50-mg capsules

25 to <32.5

350 mg once daily

One 200-mg and three 50-mg capsules

32.5 to <40

400 mg once daily

Two 200-mg capsules

≥40

600 mg once daily

One 600-mg tablet or three 200-mg capsules

Efavirenz/emtricitabine/tenofovir DF (Atripla) in children ≥12 years of age weighing ≥40 kg: 1 tablet (600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir DF) once daily.232

Adults

Treatment of HIV Infection
Oral

Efavirenz (Sustiva): 600 mg once daily.1

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

Treatment of HIV Infection in Patients Weighing ≥50 kg Receiving Rifampin
Oral

Efavirenz (Sustiva): 800 mg once daily.1 (See Specific Drugs and Laboratory Tests under Interactions.)

Efavirenz/emtricitabine/tenofovir DF (Atripla): 1 tablet (efavirenz 600 mg, emtricitabine 200 mg, and tenofovir DF 300 mg) once daily and 200 mg of single-entity efavirenz (Sustiva) once daily to provide total efavirenz dosage of 800 mg daily.232

Postexposure Prophylaxis of HIV following Occupational Exposure
Oral

Efavirenz (Sustiva): 600 mg once daily.199 Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).199

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.199

Postexposure Prophylaxis of HIV following Nonoccupational Exposure
Oral

Efavirenz (Sustiva): 600 mg once daily.198 Use in conjunction with other antiretrovirals.198

Initiate nPEP as soon as possible following nonoccupational exposure to HIV (preferably ≤72 hours after exposure); continue for 28 days.198

Special Populations

Hepatic Impairment

Treatment of HIV Infection

Efavirenz (Sustiva): 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 DF (Atripla): Use usual dosage in patients 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 (Sustiva): Dosage adjustments not needed.200

Efavirenz/emtricitabine/tenofovir DF (Atripla): Use usual dosage in patients 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

  • Efavirenz and efavirenz/emtricitabine/tenofovir DF: 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

  • Efavirenz/emtricitabine/tenofovir DF: Consider contraindications associated with each drug in the fixed combination.232

Warnings/Precautions

Interactions

Efavirenz plasma concentrations may be altered if CYP3A substrates, inhibitors, or inducers used concomitantly.1 In addition, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A or 2B6.1 (See Interactions.)

Psychiatric Symptoms

Serious adverse psychiatric symptoms (severe depression, suicidal ideation, nonfatal suicide attempts, aggressive behavior, paranoid reactions) reported rarely in efavirenz clinical studies.1 232 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.1 232

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.1 232

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,1 generally in those with a history of seizures.1 Use with caution in patients with history of seizures.1 Monitor anticonvulsant plasma concentrations if used in patients receiving anticonvulsants that are metabolized principally by the liver (e.g., phenytoin, phenobarbital).1 (See Specific Drugs and Laboratory Tests 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 (See Pregnancy under Cautions.)

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

Avoid pregnancy during therapy and for 12 weeks after discontinuance of efavirenz or fixed combination containing efavirenz.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 and Laboratory Tests under Interactions.)

Dermatologic and Sensitivity Reactions

Rash (maculopapular skin eruptions) reported frequently.1 2 Pruritus; rash associated with blistering, moist desquamation, or ulceration; allergic reaction; photoallergic dermatitis; erythema multiforme; and Stevens-Johnson syndrome also reported.1 2

Median time to rash onset 11 days in adults and 28 days in pediatric patients; median duration 16 days.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

Discontinue in patients with life-threatening cutaneous reactions (e.g., Stevens-Johnson syndrome) and consider alternative therapy.1 232

Discontinue in patients with serious rash (e.g., rash associated with blistering, desquamation, mucosal involvement, or fever).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

Efavirenz/emtricitabine/tenofovir DF: Consider cautions, precautions, contraindications, and interactions associated with each drug in the fixed combination.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.232

Do not use efavirenz/emtricitabine/tenofovir DF concomitantly with single-entity efavirenz, unless needed for adjustment of efavirenz dosage (e.g., when fixed combination used concomitantly with rifampin).1 232 (See Specific Drugs and Laboratory Tests under Interactions.)

Because the antiretrovirals contained in efavirenz/emtricitabine/tenofovir DF also are available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated if the fixed combination is used in conjunction with other antiretrovirals.232

Do not use efavirenz/emtricitabine/tenofovir DF concomitantly with any preparation containing emtricitabine or tenofovir DF.232 In addition, do not use concomitantly with any preparation containing lamivudine or with adefovir.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 Mechanism and long-term consequences of fat redistribution unknown; causal relationship not established.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 jirovecii [formerly P. carinii]); this may necessitate further evaluation and treatment.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) reported in the setting of immune reconstitution; time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1

Specific Populations

Pregnancy

Efavirenz (Sustiva): Category D.1

Efavirenz/emtricitabine/tenofovir DF (Atripla): Category D.232

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

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

Manufacturer states 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.1 232

Experts state efavirenz in conjunction with 2 NRTIs is the preferred NNRTI-based regimen for initial treatment in antiretroviral-naive pregnant women, especially when drug interactions with HIV protease inhibitor-based (PI-based) regimens are a concern.202 However, these experts state efavirenz should only be initiated after the first 8 weeks of pregnancy.202

Experts also state that antiretroviral regimens that do not include efavirenz should be strongly considered in women who are planning to become pregnant or are sexually active and not using effective contraception, provided such regimens are acceptable to the provider and not expected to compromise the health of the woman.202

If a pregnant woman already receiving an efavirenz-containing regimen presents for antenatal care during first trimester, some experts suggest the regimen can be continued if well tolerated and providing adequate virologic suppression.202 This strategy recognizes that risk of neural tube defects is limited to first 5–6 weeks of pregnancy and pregnancy rarely recognized until after 4–6 weeks and that unnecessary changes in antiretroviral regimens during pregnancy may be associated with loss of virologic control and increased risk of perinatal HIV transmission.202

If efavirenz or a fixed combination containing efavirenz is 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

Efavirenz (Sustiva): Safety and efficacy not evaluated in neonates and infants <3 months of age or who weigh <3.5 kg;1 not recommended in these pediatric patients.1 201 Some experts state efavirenz not recommended for initial treatment in antiretroviral-naive pediatric patients 3 months to <3 years of age.201

Efavirenz/emtricitabine/tenofovir DF (Atripla): Safety and efficacy not established in pediatric patients <12 years of age or weighing <40 kg.232

Adverse effects reported with efavirenz in pediatric patients 3 months to 21 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

Efavirenz (Sustiva): Use with caution in mild hepatic impairment;1 do not use in moderate or severe hepatic impairment.1

Efavirenz/emtricitabine/tenofovir DF (Atripla): Use with caution in mild hepatic impairment;232 do not use in moderate or severe hepatic impairment.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

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

Efavirenz/emtricitabine/tenofovir DF (Atripla): Do not use in those with Clcr <50 mL/minute.232

Common Adverse Effects

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

Interactions for Efavirenz

Metabolized by CYP3A and CYP2B6.1

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

Induces CYP3A and CYP2B6.1

The following drug interactions are based on studies using efavirenz.1 Drug interaction studies not performed using efavirenz/emtricitabine/tenofovir DF.232 When fixed combinations are used, 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 CYP isoenzymes 3A, 2B6, 2C9, or 2C19 with possible alteration in metabolism of efavirenz and/or other drug.1

Specific Drugs and Laboratory Tests

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 adjustments 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

Carbamazepine: Data insufficient to make dosage recommendations for concomitant use with efavirenz;1 use with caution and monitor anticonvulsant concentrations;1 200 consider alternative anticonvulsant200

Phenobarbital, phenytoin: Use with caution and monitor anticonvulsant concentrations;1 200 consider alternative anticonvulsant200

Antifungals, azoles (fluconazole, itraconazole, ketoconazole, posaconazole, 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 adjustments not needed1

Itraconazole: Dosage recommendation for concomitant use not available;1 consider alternative antifungal;1 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: Increase voriconazole maintenance dosage to 400 mg every 12 hours and decrease efavirenz dosage to 300 mg once daily (use efavirenz capsules; do not divide tablet);1 200 do not use usual voriconazole dosage with usual efavirenz dosage1 200

Antihistamines

Decreased cetirizine concentrations; no change in efavirenz concentrations1

When used with cetirizine, dosage adjustments not needed1

Antimalarials

Fixed combination of artemether and lumefantrine (artemether/lumefantrine): Decreased concentrations and AUC of artemether and active metabolite of artemether; decreased lumefantrine AUC; may decrease antimalarial effect of artemether/lumefantrine, but clinical importance unknown1 200

Fixed combination of atovaquone and proguanil (atovaquone/proguanil): Decreased AUC of atovaquone and proguanil200

Artemether/lumefantrine: Use concomitantly with caution;1 monitor patient for antimalarial efficacy200

Atovaquone/proguanil: Consider alternative antimalarial, if possible200

Antimycobacterials (bedaquiline, rifabutin, rifampin, rifapentine)

Bedaquiline: Clinically important effect on bedaquiline AUC not expected200

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

Rifampin: Decreased efavirenz concentrations and AUC1 200

Bedaquiline: Dosage adjustments not necessary200

Rifabutin: Manufacturer of efavirenz states increase daily rifabutin dosage by 50% and consider doubling rifabutin dosage when given 2 or 3 times weekly; experts suggest increase rifabutin dosage to 450–600 mg once daily or 600 mg 3 times weekly, provided regimen does not include a PI1 200

Rifampin: Manufacturer states increase efavirenz dosage to 800 mg once daily in those weighing ≥50 kg;1 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 considered;200 if using efavirenz/emtricitabine/tenofovir DF, use 1 tablet of fixed combination (see Preparations) and 200 mg of single-entity efavirenz once daily to provide efavirenz dosage of 800 mg daily232

Rifapentine: Do not use concomitantly200

Antipsychotics (pimozide)

Pimozide: Do not use concomitantly200

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

Avanafil

Data not available200

Concomitant use not recommended200

Benzodiazepines

Midazolam, triazolam: Possible increased midazolam or triazolam concentrations200

Lorazepam: Increased lorazepam concentrations, but no effect on lorazepam AUC1 200

Alprazolam: Data not available200

Midazolam (oral), triazolam: Do not use concomitantly200

Midazolam (parenteral): Experts state a single parenteral midazolam dose can be used with caution in a monitored situation for procedural sedation200

Lorazepam: Dosage adjustments not needed1 200

Alprazolam: Monitor for benzodiazepine effectiveness200

Boceprevir

Decreased boceprevir concentrations and AUC and possible loss of boceprevir therapeutic effects; slightly increased efavirenz concentrations and AUC1 185

Avoid concomitant use1 185 200

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 adjustments not needed1

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

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

Cisapride

Do not use concomitantly200

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 experts state usual dosages can be used with close monitoring and if drug concentration monitoring is considered200

Delavirdine

Concomitant use not recommended1 200

Didanosine

In vitro evidence of additive antiretroviral effects1

Dolutegravir

Decreased dolutegravir concentrations and AUC;200 236 effect on efavirenz pharmacokinetics unlikely236

No in vitro evidence of antagonistic antiretroviral effects236

HIV integrase strand transferase inhibitor-naive (INSTI-naive) patients: Use dolutegravir 50 mg twice daily200 236

INSTI-experienced patients with documented or suspected INSTI resistance: Consider alternative to efavirenz that is not a metabolic inducer whenever possible200 236

Elvitegravir and cobicistat

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir DF (EVG/COBI/TDF/FTC): Possible altered concentrations of elvitegravir, cobicistat, and/or efavirenz200

EVG/COBI/TDF/FTC: Do not use concomitantly200

Emtricitabine

In vitro evidence of additive antiretroviral effects1

Enfuvirtide

In vitro evidence of additive to synergistic antiretroviral effects1 223

Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)

Possible decreased ergot alkaloid concentrations; possible inadequate treatment effect202

Do not use concomitantly200

If methylergonovine used to treat postpartum hemorrhage in a woman receiving efavirenz, additional uterotonic agents may be needed202

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 recommended1 200 214

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 adjustments 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

Pitavastatin: Decreased AUC and increased concentrations of pitavastatin200

Rosuvastatin: Data not available200

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

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

Pitavastatin: Dosage adjustments not necessary200

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 efavirenz used with lopinavir 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 adjustments 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

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 recommended1 200 215

Psychotherapeutic agents

Potential for additive CNS effects1

Raltegravir

Decreased raltegravir concentrations and AUC;1 200 225 clinical importance unknown1 225

In vitro evidence of additive to synergistic antiretroviral effects225

Experts state dosage adjustments not necessary200

Rilpivirine

Decreased rilpivirine concentrations;226 no change in efavirenz concentrations226

Concomitant use not recommended1 200 226

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 resistance63 64

Do not use concomitantly1 200

Saquinavir

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

In vitro evidence of additive antiretroviral effects1

Saquinavir: Appropriate dosages with respect to safety and efficacy not established1 210

Ritonavir-boosted saquinavir: 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

Simeprevir

Substantially decreased simeprevir concentrations and AUC;187 200 may result in loss of simeprevir therapeutic effect187

No clinically important effect on efavirenz pharmacokinetics187 200

Concomitant use not recommended187 200

Sofosbuvir

No clinically important pharmacokinetic interactions188

Dosage adjustments not needed for either drug188

Stavudine

In vitro evidence of additive antiretroviral effects1

Telaprevir

Decreased telaprevir and efavirenz concentrations and AUC1 184 200

Experts recommend increasing telaprevir dosage to 1125 mg every 8 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

Tests for cannabinoids

False-positive urine cannabinoid test when screening test used;1 efavirenz does not bind cannabinoid receptors1

Confirm positive cannabinoid screening test with a more specific test1

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

Experts state dosage adjustments 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 DF 300 mg (efavirenz/emtricitabine/tenofovir DF; Atripla) is bioequivalent to a 600-mg efavirenz tablet, 200-mg emtricitabine capsule, and 300-mg tenofovir DF tablet taken simultaneously in fasting state.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

In healthy adults, 600-mg efavirenz dose administered by opening 200-mg capsules and mixing contents of 3 capsules with 2 teaspoonfuls of soft food (e.g., applesauce, grape jelly, yogurt) or infant formula resulted in efavirenz AUC that met bioequivalency criteria compared with intact capsules administered in fasting state.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 (Sustiva): 25°C (may be exposed to 15–30°C).1

Tablets

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

Efavirenz/emtricitabine/tenofovir DF (Atripla): 25°C (may be exposed to 15–30°C).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 DF (Atripla) can be used alone as a complete treatment regimen or can be used in conjunction with other antiretrovirals.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.1 200

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

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

  • In patients not able to swallow capsules or tablets, importance of patient or caregiver reading and carefully following instructions for mixing and administering capsule contents in small amount of soft food or infant formula.1

  • If a dose is missed, patient should take the missed dose as soon as it is remembered, unless it is almost time for next dose.1 If a dose is missed, do not take a double dose to make up for missed dose.1

  • 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 10/2014. 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 October 22, 2014. 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.

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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 2013 Oct.

236. ViiV Healthcare. TIVICAY (dolutegravir) tablets prescribing information. Research Triangle Park, NC; 2014 May.

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