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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)

Emtricitabine

(Last updated:February 12, 2014; last reviewed:February 12, 2014)

Emtricitabine (FTC, Emtriva)
Emtricitabine (FTC, Emtriva)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Formulations
 Pediatric Oral Solution:
10 mg/mL
Capsules: 200 mg
Combination Tablets:
  • With tenofovir disoproxil fumarate (tenofovir): 200 mg emtricitabine plus 300 mg tenofovir (Truvada)
  • With tenofovir and efavirenz: 200 mg emtricitabine plus 300 mg tenofovir plus 600 mg efavirenz (Atripla) 
  • With tenofovir and rilpivirine: 200 mg emtricitabine plus 300 mg tenofovir plus 25 mg rilpivirine (Complera)
  • With emtricitabine and elvitegravir and cobicistat: 200 mg emtricitabine plus 150 mg elvitegravir plus 150 mg cobicistat plus 300 mg tenofovir (Stribild)
Dosing Recommendations
Neonate/Infant Dose (Aged 0 to <3 Months):
Oral Solution: 
  • 3 mg/kg once daily.
Pediatric Dose (Aged ≥3 Months to 17 Years)
Oral Solution:
  • 6 mg/kg (maximum dose 240 mg) once daily; higher maximum dose because the oral solution has 20% lower plasma exposure in pediatric pharmacokinetic analysis.
Capsules (for Children who Weigh >33 kg):
  • 200 mg once daily.
Adolescent (Aged ≥18 Years)/Adult Dose
Oral Solution: 
  • 240 mg (24 mL) once daily.
Capsules: 
  • 200 mg once daily.
Combination Tablets
Truvada
Adolescent (Aged ≥12 Years And ≥35 Kg and Adult Dose: 
  • 1 tablet once daily.
Atripla
Adolescent (Aged ≥12 Years And ≥40 Kg) and Adult Dose: 
  • 1 tablet once daily.
  • See efavirenz section for pregnancy warning.
Complera
Adult Dose (Aged ≥18 Years):
  • 1 tablet once daily in treatment-naive adults with baseline plasma RNA <100,000 copies/mL.
  • Administer with food.
Stribild
Adult Dose (Aged ≥18 Years):
  • 1 tablet once daily in treatment-naive adults.
  • Administer with food.
Selected Adverse Events
  • Minimal toxicity
  • Severe acute exacerbation of hepatitis can occur in hepatitis B virus (HBV)-coinfected patients who discontinue emtricitabine
  • Hyperpigmentation/skin discoloration on palms and/or soles
Special Instructions
  • Emtricitabine can be given without regard to food; however, administer Atripla on an empty stomach because it also contains efavirenz.
  • Emtricitabine oral solution can be kept at room temperature up to 77ºF (25ºC) if used within 3 months; refrigerate for longer-term storage.
  • Before using emtricitabine, screen patients for HBV. 
Metabolism
  • Limited metabolism: No cytochrome P (CYP) 450 interactions.
  • Renal excretion 86%: Competition with other compounds that undergo renal elimination.
  • Dosing of emtricitabine in patients with renal impairment: Decrease dosage in patients with impaired renal function. Consult manufacturer’s prescribing information.
  • Do not use Atripla (fixed-dose combination) in patients with creatinine clearance (CrCl) <50 mL/min or in patients requiring dialysis.
  • Do not use Truvada (fixed-dose combination) in patients with CrCl <30 mL/min or in patients requiring dialysis.
  • Use Complera with caution in patients with severe renal impairment or end-stage renal disease. Increase monitoring for adverse effects because rilpivirine concentrations may be increased in patients with severe renal impairment or end-stage renal disease.
  • If using Stribild, please see the elvitegravir section of the drug appendix for additional information.

Drug Interactions (See also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.)

  • Other nucleoside reverse transcriptase inhibitors (NRTIs): Do not use emtricitabine in combination with lamivudine because the agents share similar resistance profiles and lack additive benefit. Do not use separately with Combivir, Epzicom, or Trizivir because lamivudine is a component of these combinations. Do not use separately when prescribing Truvada, Atripla, Complera, or Stribild because emtricitabine is a component of these formulations. 
  • Renal elimination: Competition with other compounds that undergo renal elimination (possible competition for renal tubular secretion). Drugs that decrease renal function could decrease clearance.
  • Use with Stribild: If using Stribild, please see the elvitegravir section of the drug appendix for additional information.

Major Toxicities

  • More common: Headache, insomnia, diarrhea, nausea, rash, and hyperpigmentation/skin discoloration (possibly more common in children).
  • Less common (more severe): Neutropenia. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Exacerbations of hepatitis have occurred in HIV/hepatitis B virus-coinfected patients who changed from emtricitabine-containing to non-emtricitabine-containing regimens.

Resistance

The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://www.iasusa.org/resistance_mutations/index.html) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/pages/GRIP/FTC.html).

Pediatric Use

Approval
Emtricitabine is Food and Drug Administration (FDA)-approved for once-daily administration in children starting at birth. Owing to its once-daily dosing, minimal toxicity, and pediatric pharmacokinetic (PK) data, emtricitabine is commonly used as part of a dual-NRTI backbone in combination antiretroviral therapy.

Efficacy and Pharmacokinetics

Pharmacokinetics
A single-dose PK study of emtricitabine liquid solution and capsules was performed in 25 HIV-infected children aged 2 to 17 years.1 Emtricitabine was found to be well absorbed following oral administration, with a mean elimination half-life of 11 hours (range 9.7 to 11.6 hours). Plasma concentrations in children receiving the 6 mg/kg emtricitabine once-daily dose were approximately equivalent to those in adults receiving the standard 200-mg dose.

A study in South Africa evaluated the PKs of emtricitabine in 20 HIV-exposed infants aged <3 months, given emtricitabine as 3 mg/kg once daily for two, 4-day courses, separated by an interval of ≥2 weeks.2 Emtricitabine exposure (area under the curve [AUC]) in neonates receiving 3 mg/kg emtricitabine once daily was in the range of pediatric patients aged >3 months receiving the recommended emtricitabine dose of 6 mg/kg once daily and adults receiving the once-daily recommended 200-mg emtricitabine dose (AUC approximately 10 hr*ug/mL). Over the first 3 months of life, emtricitabine AUC decreased with increasing age, correlating with an increase in total body clearance of the drug. In a small group of neonates (N = 6) receiving a single dose of emtricitabine 3 mg/kg after a single maternal dose of 600 mg during delivery, the AUC exceeded that seen in adults and older children, but the half-life (9.2 hours) was similar.3 Extensive safety data are lacking in this age range.

Efficacy
Based on the aforementioned dose-finding study,1 emtricitabine was studied at a dose of 6 mg/kg once daily in combination with other antiretroviral (ARV) drugs in 116 patients aged 3 months to 16 years.4,5 PK results were similar, and follow-up data extending to Week 96 indicated that 89% of the ARV-naive and 76% of the ARV-experienced children maintained suppression of plasma HIV RNA <400 copies/mL (75% of ARV-naive children and 67% of ARV-experienced children at <50 copies/mL). Minimal toxicity was observed in this trial. In PACTG P1021,4 emtricitabine at a dose of 6 mg/kg (maximum 240 mg/day as liquid or 200 mg/day as capsules) in combination with didanosine and efavirenz, all given once daily, was studied in 37 ARV-naive HIV-infected children aged 3 months to 21 years. Eighty-five percent of children achieved HIV RNA <400 copies/mL and 72% maintained HIV RNA suppression to <50 copies/mL through 96 weeks of therapy. The median CD4 T lymphocyte count rose by 329 cells/mm3 at Week 96.

Both emtricitabine and lamivudine have antiviral activity and efficacy against hepatitis B. For a comprehensive review of this topic, hepatitis C, and tuberculosis during HIV co-infection, please see the Pediatric Opportunistic Infections Guidelines

References 

  1. Wang LH, Wiznia AA, Rathore MH, et al. Pharmacokinetics and safety of single oral doses of emtricitabine in human immunodeficiency virus-infected children. Antimicrob Agents Chemother. Jan 2004;48(1):183-191. Available at http://www.ncbi.nlm.nih.gov/pubmed/14693538.
  2. Blum M, Ndiweni D, Chittick G, et al. Steady state pharmacokinetic evaluation of emtricitabine in neonates exposed to HIV in utero. Paper presented at: 13th Conference on Retroviruses and Opportunistic Infections (CROI); February 5–9 2006; Denver, CO.
  3. Flynn PM, Mirochnick M, Shapiro DE, et al. Pharmacokinetics and safety of single-dose tenofovir disoproxil fumarate and emtricitabine in HIV-1-infected pregnant women and their infants. Antimicrob Agents Chemother. Dec 2011;55(12):5914-5922. Available at http://www.ncbi.nlm.nih.gov/pubmed/21896911.
  4. McKinney RE, Jr., Rodman J, Hu C, et al. Long-term safety and efficacy of a once-daily regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive children and adolescents: Pediatric AIDS Clinical Trials Group Protocol P1021. Pediatrics. Aug 2007;120(2):e416-423. Available at http://www.ncbi.nlm.nih.gov/pubmed/17646352.
  5. Saez-Llorens X, Violari A, Ndiweni D, et al. Long-term safety and efficacy results of once-daily emtricitabine-based highly active antiretroviral therapy regimens in human immunodeficiency virus-infected pediatric subjects. Pediatrics. Apr 2008;121(4):e827-835. Available at http://www.ncbi.nlm.nih.gov/pubmed/18332076.

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