emtricitabine/tenofovir DF/efavirenz (Rx)

>10%

Hypercholesterolemia (22%)

1-10%

Depression (9%)

Dizziness (8%)

Fatigue (9%)

Insomnia (5%)

Somnolence (4%)

Abnormal dreams (4%)

Rash (7%)

Increased triglycerides (4%)

Hyperglycemia (2%)

Nausea (9%)

Vomiting (2%)

Incrased serum amylase (8%)

Neutropenia (3%)

Increased ALT (2%)

Increased alkaline phosphatase (1%)

Increased creatinine (9%)

Hematuria (3%)

Sinusitis (8%)

Upper respiratory infection (8%)

Nasopharyngitis (5%)

<1%

Gycosuria

Postmarketing Reports

QTc prolongation

Fat redistribution

Psychiatric disorders, including aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia

Contraindications

Hypersensitivity

Concurrent administration with voriconazole or elbasvir/grazoprevir

Cautions

QTc prolongation reported with use of efavirenz; consider alternatives when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes

(All NRTIs): Suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in absence of marked transaminase elevations)

Do not coadminister with drugs containing emtricitabine, tenofovir, lamivudine, or efavirenz

Rash may occur; therapy can be reinitiated in patients interrupting therapy because of rash; treatment should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever; appropriate antihistamines and/or corticosteroids may improve tolerability and hasten resolution of rash; for patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome), alternative therapy should be considered; discontinue therapy if severe rash develops

Increased risk of renal impairment; estimate CrCl in all patients before initiating and avoid concurrent or recent use of nephrotoxic drugs; renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), reported with use of TDF, a component of the combination drug; prior to initiation and during use of combination drug, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients; in patients with chronic kidney disease, also assess serum phosphorus; therapy is not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min); persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in patients at risk of renal dysfunction; discontinue therapy in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome

Use caution in history of hepatitis B or C

Patients receiving the combination drug should be alerted to potential for additive central nervous system effects when drug is used concomitantly with alcohol or psychoactive drugs; patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery

May cause redistribution of fat (cushingoid appearance)

Immune resonstitution syndrome may occur

Use caution in patients with a history of seizures

Redistribution/accumulation of body fat observed in patients receiving antiretroviral therapy

Caution in patients with predisposition to pshychological reactions; there have been occasional postmarketing reports of death by suicide, delusions, psychosis-like behavior, and catatonia, although causal relationship to use of efavirenz cannot be determined; serious psychiatric adverse experiences reported in patients treated with EFV, a component of the combination drug; patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess possibility that symptoms may be related to use of EFV, and if so, to determine whether risks of continued therapy outweigh benefits

Efavirenz may cause fetal harm when administered during the first trimester of pregnancy; advise adults and adolescents of childbearing potential who are receiving therapy to avoid pregnancy while receiving drug and for 12 weeks after discontinuation

In clinical trials in HIV-1 infected adults, TDF (a component of ATRIPLA) associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators; serum parathyroid hormone levels and 1,25 Vitamin D levels also reported higher in subjects receiving TDF

Hepatic impairment

• Not recommended with moderate-to-severe hepatic impairment because there are insufficient data
• Patients with mild hepatic impairment may be treated with Atripla at the approved dose
• Efavirenz extensively metabolized by CYP450; limited clinical experience in patients with hepatic impairment
• Monitoring of liver enzymes before and during treatment is recommended for all patients; consider discontinuing treatment in patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range; discontinue treatment if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation; also monitor liver enzymes in patients treated with other medications associated with liver toxicity

Bone effects of tenofovir

• Bone mineral density may decrease
• Osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported

See also individual drugs

• Emtricitabine
• Tenofovir
• Efavirenz

Pregnancy

Healthcare providers are encouraged to register patients at the pregnancy exposure registry that monitors pregnancy outcomes in adults and adolescents exposed to the drug during pregnancy by calling the Antiretroviral Pregnancy Registry (APR) at (800) 258-4263

There are retrospective case reports of neural tube defects in infants whose mothers were exposed to EFV-containing regimens in the first trimester of pregnancy; prospective pregnancy data from the APR are not sufficient to adequately assess this risk; although a causal relationship has not been established between exposure to EFV in the first trimester and neural tube defects, similar malformations have been observed in studies conducted in monkeys at doses similar to the human dose; in addition, fetal and embryonic toxicities occurred in rats at a dose 10 times less than the human exposure at the recommended clinical human dose (RHD) of EFV; because of potential risk of neural tube defects, EFV is not recommended for use in first trimester of pregnancy; avoid pregnancy while receiving therapy and for 12 weeks after discontinuation; advise pregnant patients of potential risk to a fetus; available data from APR show no increase in overall risk of major birth defects for EFV, FTC, or TDF compared with background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP); the rate of miscarriage is not reported in the APR; the estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15- 20%; the background risk of major birth defects and miscarriage for indicated population is unknown; the APR uses MACDP as the U.S. reference population for birth defects in general population; the MACDP evaluates mothers and infants from a limited geographic area and does not include outcomes for births that occurred at < 20 weeks’ gestation; in animal reproduction studies, no adverse developmental effects were observed when FTC and TDF were administered separately at doses/exposures ≥60 (FTC), ≥14 (TDF) and 2.7 (tenofovir) times those at the RHD of the drug

Perform pregnancy testing in adults and adolescents of childbearing potential before initiation of therapy because of potential risk of neural tube defect

Advise adults and adolescents of childbearing potential to use effective contraception during treatment and for 12 weeks after discontinuing therapy due to long half-life of EFV, a component of the drug; hormonal methods that contain progesterone may have decreased effectiveness; always use barrier contraception in combination with other methods of contraception

Lactation

The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1; based on limited published data; EFV, FTC, and tenofovir have been shown to be present in human breast milk; it is not known if components of the combination drug affect milk production or have effects on breastfed child; because of potential for HIV transmission (in HIV-negative infants); developing viral resistance (in HIV-positive infants); and adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving the combination drug

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Emtricitabine: Nucleoside Reverse Transcriptase Inhibitor (NRTI); following phosphorylation, interferes with HIV viral DNA polymerase and inhibits viral replication; cytosine analogue

Tenofovir: Nucleoside Reverse Transcriptase Inhibitor (NRTI); following hydrolysis and phosphorylation, inhibits HIV-1 reverse transcriptase by competing with AMP as substrate

Efavirenz: Non-nucleoside reverse transcriptase inhibitor (NNRTI); binds to reverse transcriptase and blocks DNA polymerase activity; does not require phosphorylation for activity

Oral Administration

Take only with water on empty stomach, preferably at bedtime

Administering at bedtime may increase tolerability to nervous system symptoms