Emtricitabine

Class: HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
VA Class: AM800
Chemical Name: 5-Fluoro-1-(2R, 5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine
Molecular Formula: C8H10FN3O3S
CAS Number: 143491-57-0
Brands: Atripla, Complera, Emtriva, Stribild, Truvada

Warning(s)

  • Lactic Acidosis and Hepatomegaly with Steatosis
  • Lactic acidosis and severe hepatomegaly with steatosis, including fatalities, reported in patients receiving HIV nucleoside reverse transcriptase inhibitors (NRTIs) in conjunction with other antiretrovirals.1 230 232 233 (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

  • HBV Infection
  • Single entity and fixed combinations containing emtricitabine not labeled by FDA for treatment of chronic HBV infection; safety and efficacy not established in HIV-infected patients coinfected with HBV.1 230 232 233

  • Severe, acute exacerbations of HBV reported following discontinuance of emtricitabine or tenofovir disoproxil fumarate (tenofovir DF) in patients coinfected with HIV-1 and HBV.1 230 232 233 Monitor hepatic function closely with both clinical and laboratory follow-up for at least several months after emtricitabine or a fixed combination containing emtricitabine is discontinued in coinfected patients.1 230 232 233 If appropriate, initiation of HBV treatment may be warranted.1 230 232 233

  • HIV-1 Preexposure Prophylaxis (PrEP)
  • Prescribe emtricitabine/tenofovir DF (Truvada) for HIV-1 PrEP only for individuals confirmed to be HIV-1-negative immediately prior to initiation of PrEP; confirm HIV-1-negative status periodically (at least every 3 months) during PrEP.230

  • Drug-resistant HIV-1 variants have been identified when emtricitabine/tenofovir DF PrEP was used following undetected acute HIV-1 infection.230 Do not initiate PrEP if signs or symptoms of acute HIV-1 infection are present, unless negative infection status is confirmed.230 (See Precautions Related to HIV-1 Preexposure Prophylaxis under Cautions.)

REMS:

FDA approved a REMS for emtricitabine to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of emtricitabine and consists of the following: medication guide and elements to assure safe use. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Antiretroviral; HIV nucleoside reverse transcriptase inhibitor (NRTI).1 200

Uses for Emtricitabine

Treatment of HIV Infection

Treatment of HIV-1 infection in adults, adolescents, and pediatric patients; used in conjunction with other antiretrovirals.1 200 201 202

Used with another NRTI (dual NRTIs) in conjunction with an HIV integrase strand transfer inhibitor (INSTI), HIV nonnucleoside reverse transcriptase inhibitor (NNRTI), or HIV protease inhibitor (PI) in INSTI-, NNRTI-, or PI-based regimens.200 201

For initial treatment in HIV-infected adults and adolescents, experts state that tenofovir DF and emtricitabine (or lamivudine) is the recommended dual NRTI option for use in most INSTI-, NNRTI-, and PI-based regimens.200 The dual NRTI option of abacavir and lamivudine (or emtricitabine) also is recommend for some initial treatment regimens, but use only in those negative for human leukocyte antigen (HLA)-B*5701.200

For initial treatment in antiretroviral-naive pediatric patients, experts state that the preferred dual NRTI options to use with a recommended NNRTI or PI are zidovudine and either lamivudine or emtricitabine (use in pediatric patients of any age) or abacavir and either lamivudine or emtricitabine (use only in those ≥3 months of age who are negative for HLA-B*5701).201 For adolescents at Tanner stage 4 or 5, these experts recommend the dual NRTI options of abacavir and either lamivudine or emtricitabine (use only in those who are negative for HLA-B*5701), tenofovir DF and either lamivudine or emtricitabine, or zidovudine and either lamivudine or emtricitabine.201

Tenofovir DF and emtricitabine (or lamivudine) is the preferred dual NRTI option for antiretroviral regimens in HIV-infected patients coinfected with HBV.200 All 3 NRTIs (tenofovir DF, emtricitabine, lamivudine) have activity against both HIV and HBV; dual NRTI options that contain only 1 of these 3 NRTIs not recommended in coinfected patients.200

Slideshow: Flashback: FDA Drug Approvals 2013

Emtricitabine/tenofovir DF fixed combination (Truvada) can be used in adults, adolescents, and children ≥12 years of age weighing ≥35 kg to decrease pill burden and improve adherence;200 230 used in conjunction with other antiretrovirals for treatment of HIV-1 infection.230

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

Emtricitabine/rilpivirine/tenofovir DF fixed combination (Complera) can be used alone as a complete treatment regimen in antiretroviral-naive adults with baseline plasma HIV-1 RNA levels ≤100,000 copies/mL to decrease pill burden and improve adherence;233 also may be used to replace a stable antiretroviral regimen in certain antiretroviral-experience adults who are virologically suppressed (i.e., plasma HIV-1 RNA levels <50 copies/mL).233

Elvitegravir, cobicistat, emtricitabine, and tenofovir DF fixed combination (EVG/COBI/TDF/FTC; Stribild) also commercially available for use alone as a complete regimen in antiretroviral-naive adults; do not use in conjunction with other antiretrovirals.200 235 For initial treatment in antiretroviral-naive adults, experts state that EVG/COBI/TDF/FTC is a recommended INSTI-based regimen that can be used regardless of baseline viral load or CD4+ T-cell count, but use only in patients with baseline estimated Clcr ≥70 mL/minute.200

Preexposure Prophylaxis for Prevention of HIV-1 Infection

Emtricitabine/tenofovir DF (Truvada) used for preexposure prophylaxis (PrEP) in conjunction with safer sex practices to reduce the risk of sexually acquired HIV-1 in HIV-1-negative adults at high risk.197 230 450 457 463

Adults at high risk include those with partner(s) known to be infected with HIV-1 or those engaging in sexual activity within a high prevalence area or social network and with ≥1 of the following factors: inconsistent or no condom use, diagnosis of sexually transmitted infections, exchange of sex for commodities (e.g., money, food, shelter, drugs), use of illicit drugs, alcohol dependence, incarceration, or partner(s) of unknown HIV-1 status with any of these risk factors.230

PrEP with emtricitabine/tenofovir DF not always effective in preventing acquisition of HIV-1 infection; must be used as part of a comprehensive prevention strategy that includes safer sex practices.230 (See Precautions Related to HIV-1 Preexposure Prophylaxis [PrEP] under Cautions.)

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 Several alternative regimens that include an INSTI, NNRTI, or PI and 2 NRTIs (dual NRTIs) also recommended.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 Fixed combination of EVG/COBI/TDF/FTC used alone is one of several alternative regimens for PEP.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 that exposure represents a substantial risk for HIV transmission.198 Used in conjunction with other antiretrovirals.198

Emtricitabine Dosage and Administration

Administration

Oral Administration

Emtricitabine (Emtriva): Administer orally once daily without regard to meals.1 Use in conjunction with other antiretrovirals.1

Emtricitabine/tenofovir DF (Truvada): Administer orally once daily without regard to meals.230 Use in conjunction with other antiretrovirals for treatment of HIV-1;230 use alone as a complete regimen for PrEP for prevention of sexually transmitted HIV-1.197 230

Efavirenz/emtricitabine/tenofovir DF (Atripla): Administer orally once daily on an empty stomach, preferably at bedtime.232 Use alone as a complete regimen or in conjunction with other antiretrovirals for treatment of HIV-1 infection.232

Emtricitabine/rilpivirine/tenofovir DF (Complera): Administer orally once daily with a meal.233 Use alone as a complete regimen for treatment of HIV-1 infection.233

Elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild): Administer orally once daily with food.235 Prior to initiating, determine estimated Clcr and test for HBV infection, urine glucose, and urine protein.235

Because antiretrovirals contained in the fixed combinations also are available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated when a fixed combination is used in conjunction with other antiretrovirals.230 232 233 (See Precautions Related to Use of Fixed Combinations under Cautions.)

Dosage

Emtricitabine (Emtriva) capsules and oral solution are not bioequivalent.1 (See Bioavailability under Pharmacokinetics.)

Pediatric Patients

Treatment of HIV Infection
Oral

Emtricitabine (Emtriva oral solution containing 10 mg/mL) in infants 0–3 months of age: 3 mg/kg once daily.1

Emtricitabine (Emtriva oral solution containing 10 mg/mL) in children 3 months to 17 years of age: 6 mg/kg (up to a maximum of 240 mg) once daily.1

Emtricitabine (Emtriva capsules) in children weighing >33 kg who can swallow intact capsule: 200 mg once daily.1

Emtricitabine/tenofovir DF (Truvada) in children ≥12 years of age weighing ≥35 kg: 1 tablet (emtricitabine 200 mg and tenofovir DF 300 mg) once daily.230

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

Adults

Treatment of HIV Infection
Oral

Emtricitabine (Emtriva): 200-mg capsule once daily.1 Alternatively, 240 mg (24 mL) as the oral solution containing 10 mg/mL once daily.1

Emtricitabine/tenofovir DF (Truvada): 1 tablet (emtricitabine 200 mg and tenofovir DF 300 mg) once daily.230

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

Emtricitabine/rilpivirine/tenofovir DF (Complera): 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) once daily.233

Elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild): 1 tablet (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir DF 300 mg) once daily.235

Preexposure Prophylaxis for Prevention of HIV-1 Infection
HIV-1-negative Adults at High Risk
Oral

Emtricitabine/tenofovir DF (Truvada): 1 tablet (emtricitabine 200 mg and tenofovir DF 300 mg) once daily.230

Use PrEP only in high-risk adults confirmed to be HIV-1-negative; do not initiate if signs or symptoms of acute HIV-1 infection are present and recent (<1 month) exposure to HIV-1 is suspected.230 (See Precautions Related to HIV-1 Preexposure Prophylaxis [PrEP] under Cautions.)

Postexposure Prophylaxis following Occupational Exposure to HIV
Oral

Emtricitabine (Emtriva capsules): 200 mg once daily.199 Use in conjunction with other antiretrovirals (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).199

Emtricitabine/tenofovir DF (Truvada): 1 tablet (emtricitabine 200 mg and tenofovir DF 300 mg) once daily.199 Use in conjunction with a recommended INSTI, NNRTI, or PI (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).199

Emtricitabine/rilpivirine/tenofovir DF (Complera): 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) once daily.233 Use as a complete regimen for PEP.233

Elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild): 1 tablet (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir DF 300 mg) once daily.235

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

Postexposure Prophylaxis following Nonoccupational Exposure to HIV
Oral

Emtricitabine (Emtriva capsules): 200 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

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection
Oral

Emtricitabine (Emtriva) in children 3 months to 17 years of age: Maximum 240 mg (as the oral solution) once daily.1

Special Populations

Hepatic Impairment

Treatment of HIV Infection

Emtricitabine not metabolized by liver enzymes; not specifically studied, but clinically important changes in metabolism not expected in patients with hepatic impairment.1

Emtricitabine/tenofovir DF (Truvada): Not studied in hepatic impairment.230

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

Emtricitabine/rilpivirine/tenofovir DF (Complera): Use usual dosage in adults with mild or moderate hepatic impairment (Child-Pugh class A or B);233 not studied in those with severe hepatic impairment (Child-Pugh class C).233

Elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild): Dosage adjustments not necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A or B);200 235 do not use in patients with severe hepatic impairment (Child-Pugh class C).200 235

Renal Impairment

Treatment of HIV Infection
Oral

Emtricitabine (Emtriva): Reduce dosage in adults with Clcr <50 mL/minute (see Table 1).1

Emtricitabine (Emtriva): Data insufficient to make specific emtricitabine dosage recommendations for pediatric patients with renal impairment; consider reducing dose and/or increasing dosing interval.1

Table 1. Emtricitabine (Emtriva) Dosage for Treatment of HIV-1 Infection in Adults with Renal Impairment1200

Clcr (mL/minute)

Dosage of Capsules

Dosage of Oral Solution

30–49

200 mg every 48 hours

120 mg every 24 hours

15–29

200 mg every 72 hours

80 mg every 24 hours

<15

200 mg every 96 hours

60 mg every 24 hours

Hemodialysis patients

200 mg every 96 hours; on day of dialysis, give dose after the procedure

60 mg every 24 hours; on day of dialysis, give dose after the procedure

Emtricitabine/tenofovir DF (Truvada): Dosage adjustments not needed in adults with Clcr 50–80 mL/minute; however, monitor calculated Clcr, serum phosphorus, urine glucose, and urine protein.230 In adults with Clcr 30–49 mL/minute, reduce dosage to 1 tablet (emtricitabine 200 mg and tenofovir DF 300 mg) once every 48 hours; monitor clinical response and renal function since dosage not evaluated clinically.230 Do not use in adults with Clcr <30 mL/minute (including hemodialysis patients).230 Data insufficient to make dosage recommendations for treatment of HIV-1 infection in pediatric patients with renal impairment.230

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

Emtricitabine/rilpivirine/tenofovir DF (Complera): Do not use if Clcr <50 mL/minute or dialysis required.233

Elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild): Do not initiate in patients with estimated Clcr <70 mL/minute.200 235 Discontinue if estimated Clcr decreases to <50 mL/minute during treatment.200 235

Preexposure Prophylaxis for Prevention of HIV-1 Infection
Oral

Emtricitabine/tenofovir DF (Truvada): Use usual dosage in adults with Clcr ≥60 mL/minute; however, monitor calculated Clcr, serum phosphorus, urine glucose, and urine protein.230 If Clcr decreases, evaluate potential causes and reassess potential risks and benefits of continued use.230 Do not use if Clcr <60 mL/minute.230

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 230 232 233

Cautions for Emtricitabine

Contraindications

  • Known hypersensitivity to emtricitabine or any ingredient in the formulation.1

  • Emtricitabine/tenofovir DF: Do not use alone for treatment of HIV-1 infection; do not use for preexposure prophylaxis of HIV-1 infection in individuals with unknown or positive HIV-1 status.230 (See Precautions Related to HIV-1 Preexposure Prophylaxis [PrEP] under Cautions.)

  • Emtricitabine in fixed-combination preparations: Consider contraindications associated with each drug in the fixed combination.230 232 233

Warnings/Precautions

Warnings

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) reported in patients receiving HIV NRTIs, including emtricitabine, in conjunction with other antiretrovirals.1 230 232 233 Reported most frequently in women; obesity and long-term NRTI therapy also may be risk factors.1 230 232 233 Cases reported in patients with no known risk factors.1 230 232 233

Use with caution in patients with known risk factors for liver disease.1 230 232 233

Interrupt therapy if there are clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (e.g., hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).1 230 232 233

Individuals with HBV Infection

Test all HIV patients for presence of HBV before initiating antiretroviral therapy.1 230 232 233

Not indicated for treatment of chronic HBV infection.1 230 232 233

Safety and efficacy not established for treatment of HIV infection in patients coinfected with HBV.1 230 232 233 (See Treatment of HIV Infection under Uses.)

Severe acute exacerbations of HBV reported following discontinuance of emtricitabine.1 230 232 233 HBV exacerbations have been associated with hepatic decompensation and hepatic failure.1 230 232 233

If used in patients coinfected with HIV and HBV, closely monitor hepatic function (using both clinical and laboratory follow-up) for at least several months after emtricitabine or fixed combinations containing emtricitabine are discontinued.1 230 232 233 If appropriate, initiation of HBV treatment may be warranted.1 230 232 233

Precautions Related to HIV-1 Preexposure Prophylaxis

Use emtricitabine/tenofovir DF (Truvada) for HIV-1 PrEP only in HIV-1-negative adults at high risk.230

Confirm a negative HIV-1 test immediately prior to initiating PrEP and screen for HIV-1 infection at least once every 3 months during PrEP.230 Also test for HBV prior to initiating PrEP.230 (See Individuals with HBV Infection under Cautions.)

Emtricitabine/tenofovir DF PrEP not always effective in preventing acquisition of HIV-1 infection.230

Must be used as part of a comprehensive HIV prevention strategy that includes other prevention measures (e.g., safer sex practices).230 (See REMS.) Counsel all uninfected individuals about safer sex practices that include consistent and correct use of condoms, knowledge of their own HIV-1 status and that of their partner(s), and regular testing for other sexually transmitted infections that can facilitate HIV-1 transmission (e.g., syphilis, gonorrhea).230 Inform and support uninfected individuals regarding efforts to reduce sexual risk behavior.230

Because emtricitabine/tenofovir DF alone does not constitute a complete antiretroviral regimen for treatment of HIV-1 infection, HIV-1 resistance-associated mutations may emerge if emtricitabine/tenofovir DF PrEP is used in individuals with undetected HIV-1 infection.230 Drug-resistant HIV-1 variants have been identified in such individuals.230

Many HIV-1 tests (e.g., rapid tests) detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection.230 Prior to initiating PrEP, evaluate HIV-negative individuals for current or recent signs or symptoms consistent with acute viral infections (e.g., fever, fatigue, myalgia, rash) and ask about any potential exposure events within the last month (e.g., unprotected sex, condom broke during sex with HIV-infected partner).230

If clinical symptoms consistent with acute viral infection are present and recent (<1 month) exposures to HIV-1 are suspected, delay initiating PrEP for at least 1 month and reconfirm HIV-1 status or use a test approved by FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection.230

During PrEP, if symptoms consistent with acute HIV-1 infection develop following a potential exposure event, discontinue the drugs until negative infection status is confirmed using a test approved by FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection.230

Counsel uninfected individuals to strictly adhere to recommended emtricitabine/tenofovir DF dosage schedule.230 (See Preexposure Prophylaxis [PrEP] for Prevention of HIV-1 Infection under Dosage and Administration.) Effectiveness in reducing risk of acquiring HIV-1 is strongly correlated with adherence.230

Adverse effects similar to those reported in HIV-infected patients receiving the drugs for treatment of HIV-1 infection.230

Other Warnings/Precautions

Precautions Related to Use of Fixed Combinations

Emtricitabine/tenofovir DF, efavirenz/emtricitabine/tenofovir DF, emtricitabine/rilpivirine/tenofovir DF, elvitegravir/cobicistat/emtricitabine/tenofovir DF: Consider cautions, precautions, contraindications, and interactions associated with each drug in the fixed combination.230 232 233 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug.230 232 233

Because the antiretrovirals contained in the fixed-combination preparations also may be available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated when a fixed combination is used in conjunction with other antiretrovirals.230 232 233

Do not use multiple emtricitabine-containing preparations concomitantly.1 230 232 233

Because of similarities between emtricitabine and lamivudine, do not use emtricitabine (single entity or fixed-combination preparations) concomitantly with any preparation containing lamivudine.1 200 232 233

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.1 230 232 233 Mechanisms and long-term consequences of adipogenic effects unknown; causal relationship not established.1 230 232 233

Immune Reconstitution Syndrome

During initial treatment, HIV-infected 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]);1 this may necessitate further evaluation and treatment.1 230 232 233

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.1 230

Specific Populations

Pregnancy

Emtricitabine (Emtriva): Category B.1 230 233

Emtricitabine/tenofovir DF (Truvada), emtricitabine/rilpivirine/tenofovir DF (Complera): Category B.230 233

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

Elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild): Category B.235

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202 230 232 233

Experts state that tenofovir DF and either emtricitabine or lamivudine is a preferred dual NRTI option for use in conjunction with an NNRTI or PI for initial treatment of HIV-1 infection in antiretroviral-naive pregnant women, and is the preferred dual NRTI option in pregnant HIV-infected women coinfected with HBV.202

Experts state safety and pharmacokinetic data insufficient to recommend routine use of elvitegravir/cobicistat/emtricitabine/tenofovir DF for treatment in antiretroviral-naive pregnant women.202

Experts state that the dual NRTI option of tenofovir DF and emtricitabine in conjunction with the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) is a preferred regimen for treatment of HIV type 2 (HIV-2) infection in pregnant women.202

If HIV-negative woman receiving emtricitabine/tenofovir DF (Truvada) for HIV-1 PrEP becomes pregnant, carefully consider whether PrEP regimen should be continued, taking into account the potential increased risk of HIV-1 infection during pregnancy.230

Lactation

Emtricitabine distributed into human milk in low concentrations.1 34

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202 230 232 233

Pediatric Use

Emtricitabine (Emtriva): Safety and efficacy for treatment of HIV-1 infection in pediatric patients ≥3 months of age is supported by evidence from studies in pediatric patients.1 Adverse effects reported in children similar to adults.1 Pharmacokinetics evaluated in a limited number of neonates born to HIV-infected mothers; efficacy in preventing or treating HIV infection in these neonates not determined.1 20

Emtricitabine/tenofovir DF (Truvada): Safety and efficacy for treatment of HIV-1 infection not established in pediatric patients <12 years of age or weighing <35 kg; safety and efficacy for HIV-1 PrEP not established in pediatric patients.230

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

Emtricitabine/rilpivirine/tenofovir DF (Complera): Safety and efficacy not established in pediatric patients <18 years of age.233

Elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild): Safety and efficacy not established in pediatric patients <18 years of age.235

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1 230 232 233

Hepatic Impairment

Emtricitabine not metabolized by liver enzymes; any impact of hepatic impairment expected to be limited.1 (See Hepatic Impairment under Dosage and Administration.)

Emtricitabine/tenofovir DF (Truvada): Not studied in patients with hepatic impairment.230

Efavirenz/emtricitabine/tenofovir DF (Atripla): Do not use in those with moderate or severe hepatic impairment.232

Emtricitabine/rilpivirine/tenofovir DF (Complera): Not studied in patients with severe hepatic impairment (Child-Pugh class C).233

Elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild): Pharmacokinetic or safety data not available in patients with severe hepatic impairment (Child-Pugh class C);235 use is not recommended in such patients.235

Renal Impairment

Dosage adjustment of emtricitabine (Emtriva) necessary based on degree of renal impairment.1 Monitor clinical response and renal function in patients with renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Emtricitabine/tenofovir DF (Truvada): Do not use for treatment of HIV-1 in patients with Clcr <30 mL/minute or patients with end-stage renal disease requiring dialysis.230 Do not use for PrEP in HIV-1 uninfected adults with Clcr <60 mL.230 If Clcr decreases during emtricitabine/tenofovir DF (Truvada) PrEP, evaluate potential causes and reassess potential risks and benefits of continued use.230

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

Emtricitabine/rilpivirine/tenofovir DF (Complera): Do not use in those with Clcr <50 mL/minute or if dialysis required.233

Elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild): Do not initiate in patients with estimated Clcr <70 mL/minute.200 235 Discontinue if estimated Clcr decreases to <50 mL/minute during treatment.200 235

Common Adverse Effects

Mild to moderate headache, GI effects (diarrhea, nausea), rash.1

Interactions for Emtricitabine

Emtricitabine does not inhibit CYP1A2, 2A6,2B6, 2C9, 2C19, 2D6, or 3A4.1 Interactions with drugs metabolized by these CYP isoenzymes unlikely.1

Emtricitabine does not inhibit glucuronosyltransferase (uridine diphosphoglucuronosyltransferase, UDP-glucuronate β-d-glucuronosyltransferase [acceptor-unspecific]), an enzyme responsible for glucuronidation.1 Pharmacokinetic interactions unlikely.1

The following drug interactions are based on studies using emtricitabine.1 When fixed combinations containing emtricitabine are used, consider interactions associated with each drug in the fixed combination.230 232 233 Drug interaction studies not performed using emtricitabine/tenofovir DF, efavirenz/emtricitabine/tenofovir DF, or emtricitabine/rilpivirine/tenofovir DF.230 232 233

Specific Drugs

Drug

Interaction

Comments

Abacavir

In vitro evidence of additive or synergistic antiretroviral effects1

Atazanavir

No in vitro evidence of antagonistic antiretroviral effects203

Darunavir

Pharmacokinetic interaction unlikely204

No in vitro evidence of antagonistic antiretroviral effects204

Delavirdine

In vitro evidence of additive or synergistic antiretroviral effects1

Didanosine

Experts state concomitant use of didanosine and emtricitabine not recommended in antiretroviral-naive adults;200 use in antiretroviral-naive children only in special circumstances201

Efavirenz

In vitro evidence of additive or synergistic antiretroviral effects1

Etravirine

No in vitro evidence of antagonistic antiretroviral effects214

Famciclovir

Pharmacokinetic interaction unlikely1

Indinavir

No effect on pharmacokinetics of either drug1

Lamivudine

In vitro evidence of additive antiretroviral effects1

Do not use concomitantly;1 200 201 no potential benefit since emtricitabine is an analog of lamivudine and has the same resistance profile and minimal additive antiretroviral effects200 201

Maraviroc

No in vitro evidence of antagonistic antiretroviral effects224

Nelfinavir

In vitro evidence of additive to synergistic antiretroviral effects1

Nevirapine

In vitro evidence of additive or synergistic antiretroviral effects1

Rilpivirine

Pharmacokinetic interactions unlikely226

No in vitro evidence of antagonistic antiretroviral effects226

Ritonavir

In vitro evidence of additive or synergistic antiretroviral effects1

Saquinavir

In vitro evidence of additive or synergistic antiretroviral effects1

Simeprevir

Clinically important interactions not expected187

Sofosbuvir

No clinically important pharmacokinetic interactions188

Dosage adjustments not needed for either drug188

Stavudine

Pharmacokinetic interaction unlikely1

In vitro evidence of additive or synergistic antiretroviral effects1

Experts state use stavudine and emtricitabine concomitantly in children only in special circumstances201

Tenofovir

Pharmacokinetic interaction unlikely1

In vitro evidence of additive to synergistic antiretroviral effects1

Tipranavir

In vitro evidence of additive antiretroviral effects211

Zidovudine

In vitro evidence of additive or synergistic antiretroviral effects1

Emtricitabine Pharmacokinetics

Absorption

Bioavailability

Pharmacokinetics in healthy individuals similar to those in individuals with HIV-1 infection.1

Rapidly and extensively absorbed; peak plasma concentrations of emtricitabine attained within 1–2 hours.1

Emtricitabine capsules: Bioavailability is 93%.1

Emtricitabine oral solution: Bioavailability is 75%.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 tablet of efavirenz, 200-mg capsule of emtricitabine, and 300-mg tablet of tenofovir DF taken simultaneously in fasting state.232

Fixed-combination tablet containing emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg (emtricitabine/rilpivirine/tenofovir DF; Complera) taken with a meal is bioequivalent to a 200-mg emtricitabine capsule, 25-mg rilpivirine tablet, and 300-mg tenofovir DF tablet taken simultaneously with a meal.233

Fixed-combination tablet containing emtricitabine 200 mg and tenofovir DF 300 mg (emtricitabine/tenofovir DF; Truvada) is bioequivalent to a 200-mg capsule of emtricitabine and 300-mg tablet of tenofovir DF.230

Following an oral dose of fixed combination containing elvitegravir, cobicistat, emtricitabine, and tenofovir DF (Stribild) with food, peak plasma concentrations of elvitegravir and cobicistat occur at 4 and 3 hours, respectively, and peak plasma concentrations of emtricitabine and tenofovir occur at 3 and 2 hours, respectively.235

Food

Food does not have a clinically important effect on emtricitabine absorption.1

Special Populations

Pharmacokinetics in pediatric patients 3 months to 17 years of age receiving recommended emtricitabine dosage (6 mg/kg daily [up to 240 mg daily] as the oral solution or 200-mg capsule once daily) similar to those reported in adults receiving 200 mg daily.1 AUC reported in neonates receiving 3 mg/kg daily for 4 days similar to that reported in children 3 months to 17 years of age receiving the recommended dosage.1

Peak plasma concentrations and AUC of emtricitabine increased in patients with renal impairment (Clcr <50 mL/minute or end-stage renal disease requiring dialysis) due to reduced renal clearance of the drug.1 Dosage adjustments needed.1 (See Renal Impairment under Dosage and Administration.)

Distribution

Extent

Emtricitabine distributed into saliva33 and into vaginal tissue and cervicovaginal fluid following oral administration.30 31 36

Crosses human placenta.202

Distributed into human milk in low concentrations.1 34

Plasma Protein Binding

<4 %.1

Elimination

Metabolism

Undergoes oxidation and conjugation with glucuronic acid.1

Intracellularly, emtricitabine is phosphorylated and converted by cellular enzymes to the active metabolite, emtricitabine 5′-triphosphate.1

Elimination Route

Excreted in urine (86%) and feces (14%).1 Eliminated by glomerular filtration and active tubular secretion.1

Removed by hemodialysis; not known whether removed by peritoneal dialysis.1

Half-life

10 hours.1

Special Populations

Renal impairment reduces renal clearance.1

Stability

Storage

Oral

Capsules

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

Solution

Emtricitabine (Emtriva): 2–8°C until dispensed.1 For patient use, store at 25°C (may be exposed to 15–30°C); use within 3 months.1

Tablets

Emtricitabine/tenofovir DF (Truvada), efavirenz/emtricitabine/tenofovir DF (Atripla), emtricitabine/rilpivirine/tenofovir DF (Complera), elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild): 25°C (may be exposed to 15–30°C).230 232 233 235 Store in original container; keep tightly closed.230 232 233 235

Actions and Spectrum

  • Thio analog of cytidine.1

  • Pharmacologically related to other NRTIs (e.g., abacavir, didanosine, lamivudine, stavudine, zidovudine); differs structurally from these drugs; also differs pharmacologically and structurally from other currently available antiretroviral agents.1

  • Active in vitro against HIV-1 and HIV-2.1 Also has some activity against HBV.5 7

  • Inhibits replication of HIV by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).1

  • HIV-1 with reduced susceptibility to emtricitabine have been produced in vitro and have emerged during therapy with the drug.1

  • HIV resistant to emtricitabine may be cross-resistant to some other NRTIs (e.g., lamivudine).1

  • Cross-resistance between emtricitabine and PIs is highly unlikely since the drugs have different target enzymes.200 Cross-resistance between emtricitabine and NNRTIs is considered to be low since the drugs bind at different sites on reverse transcriptase and have different mechanisms of action.200

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 230 232 233 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1 230 232 233

  • Importance of using emtricitabine (Emtriva) or emtricitabine/tenofovir DF (Truvada) in conjunction with other antiretrovirals for treatment of HIV-1 infection—not for monotherapy.1 230 Efavirenz/emtricitabine/tenofovir DF (Atripla) or emtricitabine/rilpivirine/tenofovir DF (Complera) can be used alone as a complete regimen for treatment of HIV-1 infection.232 233 Elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild) is a complete regimen for treatment of HIV-1 infection and should not be used in conjunction with other antiretroviral agents.235

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1 230 232 233

  • Advise HIV-infected patients that effective antiretroviral treatment regimens can decrease HIV-1 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.1 200 233

  • Emtricitabine/tenofovir DF (Truvada) medication guide must be provided to and reviewed with all HIV-negative individuals each time emtricitabine/tenofovir DF is dispensed for HIV-1 PrEP.37 230 (See REMS.) Advise such individuals of the importance of confirming that they are HIV-1-negative before starting PrEP, importance of regular HIV-1 testing (at least every 3 months) during PrEP, importance of strictly adhering to recommended dosage schedule and not missing any doses, and importance of using a complete prevention strategy that also includes other measures (e.g., consistent condom use, testing for other sexually transmitted infections such as syphilis and gonorrhea that may facilitate HIV-1 transmission, reducing sexual risk behavior).230 Advise uninfected individuals that PrEP does not protect all individuals from acquiring HIV-1 and to report any symptoms of acute HIV-1 infection (e.g., fever, headache, fatigue, arthralgia, vomiting, myalgia, diarrhea, pharyngitis, rash, night sweats, cervical and inguinal adenopathy) immediately to a clinician.230

  • Importance of reading patient information provided by the manufacturer.1 230 232 233

  • Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1 230 232 233

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products.1 230 232 233

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 230 232 233 Advise HIV-infected women not to breast-feed.1 230 232 233

  • Importance of advising patients of other important precautionary information.1 230 232 233 (See Cautions.)

Preparations

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

Emtricitabine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

200 mg

Emtriva

Gilead

Solution

10 mg/mL

Emtriva

Gilead

Emtricitabine Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

200 mg with Tenofovir Disoproxil Fumarate 300 mg

Truvada

Gilead

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

Atripla

Bristol-Myers Squibb and Gilead

200 mg with Tenofovir Disoproxil Fumarate 300 mg and Rilpivirine Hydrochloride 25 mg (of rilpivirine)

Complera

Gilead

200 mg with Tenofovir Disoproxil Fumarate 300 mg, Elvitegravir 150 mg, and Cobicistat 150mg

Stribild

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

Complera 200-25-300MG Tablets (GILEAD SCIENCES): 30/$1,940.02 or 90/$5,720.03

Emtriva 200MG Capsules (GILEAD SCIENCES): 30/$475.97 or 60/$890.01

Truvada 200-300MG Tablets (GILEAD SCIENCES): 30/$1,149.01 or 90/$3,406.79

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 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.

References

1. Gilead Sciences. Emtriva (emtricitabine) capsules and oral solution prescribing information. Foster City, CA; 2012 Nov.

2. Saag M, Cahn P, Raffi F et al. A randomized, double-blind, multicenter comparison of emtricitabine QD to stavudine BID. Proceedings of ICAAC San Diego 2002. Abstract No. LB-1.

3. Sanne I, van der Horst C, Shaw A et al. Two randomized, controlled, equivalence trials of emtricitabine (FTC) to lamivudine (3TC). Poster presented at the XIV International AIDS Conference. Barcelona, Spain: 2002 Jul 7-12.

5. Seigneres B, Martin P, Werle B et al. Effects of pyrimidine and purine analog combinations in the duck hepatitis B virus infection model. Antimicrob Agents Chemother. 2003; 47:1842-52. [PubMed 12760857]

7. Gish RG, Leung NWY, Wright TL et al. Dose range study of pharmacokinetics, safety, and preliminary antiviral activity of emtricitabine in adults with hepatitis B virus infection. Antimicrob Agents Chemother. 2002; 46:1734-40. [IDIS 481640] [PubMed 12019083]

8. Gilead, Foster City, CA: Personal communication.

9. Saez-Llorens X, Violari A, Ndiweni D et al. Once daily emtricitabine (FTC) in HIV-infected pediatric patients with other antiretroviral agents. Poster presented at the 10th Conference on Retroviruses and Opportunistic Infections. Boston, MA: 2003 Feb 10-4.

20. Blum MR, Ndiweni D, Chittick G et al. Steady-state pharmacokinetic evaluation of emtricitabine in neonates exposed to HIV in utero. Poster presented at the 13th Conference on Retroviruses and Opportunistic Infections. Denver, CO: 2006 Feb 5-9.

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]

30. Dumond JB, Yeh RF, Patterson KB et al. Antiretroviral drug exposure in the female genital tract: implications for oral pre- and post-exposure prophylaxis. AIDS. 2007; 21:1899-907. [PubMed 17721097]

31. Karim SS, Kashuba AD, Werner L et al. Drug concentrations after topical and oral antiretroviral pre-exposure prophylaxis: implications for HIV prevention in women. Lancet. 2011; 378:279-81. [PubMed 21763939]

33. de Lastours V, Fonsart J, Burlacu R et al. Concentrations of tenofovir and emtricitabine in saliva: implications for preexposure prophylaxis of oral HIV acquisition. Antimicrob Agents Chemother. 2011; 55:4905-7. [PubMed 21788466]

34. Benaboud S, Pruvost A, Coffie PA et al. Concentrations of tenofovir and emtricitabine in breast milk of HIV-1-infected women in Abidjan, Cote d'Ivoire, in the ANRS 12109 TEmAA Study, Step 2. Antimicrob Agents Chemother. 2011; 55:1315-7. [PubMed 21173182]

36. Patterson KB, Prince HA, Kraft E et al. Penetration of tenofovir and emtricitabine in mucosal tissues: implications for prevention of HIV-1 transmission. Sci Transl Med. 2011; 3:112re4. [PubMed 22158861]

37. Truvada (emtricitabine/tenofovir disoproxil fumarate) risk evaluation and mitigation strategy (REMS). From FDA website.

187. Janssen. Olysio (simeprevir) capsules prescribing information. Titusville, NJ; 2013 Nov.

188. Gilead Sciences, Inc. Sovaldi (sofosbuvir) tablets prescribing information. Foster City, CA; 2013 Dec.

197. US Public Health Service. Preexposure prophylaxis for the prevention of HIV infection in the United States - 2014. A clinical practice guideline. From CDC website.

198. Center 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. Kuhar DT, Henderson DK, Struble KA et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol. 2013; 34:875-92. [PubMed 23917901]

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 (May 1, 2014). 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 (February 12, 2014). 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 (March 28, 2014). 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.

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

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

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

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

230. Gilead Sciences. Truvada (emtricitabine/tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2013 Oct.

232. Bristol-Myers Squibb and Gilead Sciences. Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA 2013 Oct.

233. Gilead Sciences. Complera (emtricitabine/rilpivirine/tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2014 Jun.

235. Gilead Sciences. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2013 Oct.

450. Grant RM, Lama JR, Anderson PL et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010; 363:2587-99. [PubMed 21091279]

457. Thigpen MC, Kebaabetswe PM, Paxton LA et al. Antiretroviral Preexposure Prophylaxis for Heterosexual HIV Transmission in Botswana. N Engl J Med. 2012; :. [PubMed 22784038]

463. Baeten JM, Donnell D, Ndase P et al. Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women. N Engl J Med. 2012; :. [PubMed 22784037]

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