Tenofovir Disoproxil Fumarate

Pronunciation

Class: HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
VA Class: AM800
Chemical Name: Bis(1 - methyl - ethyl)ester - (R) - 5 - [[2 - (6 - Amino - 9H - purin - 9 - yl) - 1 - methylethoxy]methyl] - 2,4,6,8 - tetraoxa - 5 - phosphanonanedioic acid 5-oxide (E)-2-butenedioate
Molecular Formula: C9H14N5O4P•H2O
CAS Number: 202138-50-9
Brands: Atripla, Complera, Stribild, Truvada, Viread

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 7 230 232 233 (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

  • HBV Infection
  • Fixed combinations containing tenofovir disoproxil fumarate (tenofovir DF) not labeled by FDA for treatment of chronic HBV infection; safety and efficacy not established in HIV-infected patients coinfected with HBV.230 232 233

  • Severe, acute exacerbations of HBV reported following discontinuance of tenofovir DF HIV-infected in patients coinfected with HBV.1 230 232 233 Monitor hepatic function closely with both clinical and laboratory follow-up for at least several months after tenofovir DF or fixed combination containing tenofovir DF is discontinued in coinfected patients.1 230 232 233 If appropriate, initiation or resumption 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 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 [PrEP] under Cautions.)

REMS:

FDA approved a REMS for tenofovir DF to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of tenofovir DF 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 nucleotide reverse transcriptase inhibitor; also has antiviral activity against HBV.1 2 3 200

Uses for Tenofovir Disoproxil Fumarate

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 transferase 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

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 either lamivudine or emtricitabine is an alternative (not preferred) dual NRTI option for initial treatment regimens in children and adolescents at Tanner stage 3; use in prepubertal children ≥2 years of age or adolescents at Tanner stage 1 or 2 only in special circumstances.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: Debunking The Myths - HIV/Aids Unravelled

Emtricitabine/tenofovir DF fixed combination (Truvada) can be used in adults, adolescents, and children ≥12 years 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;200 232 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;200 233 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;235 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 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

Chronic HBV Infection

Treatment of chronic HBV infection in adults and children ≥12 years of age.1

Used in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative adults with compensated liver disease who had not previously received a nucleoside antiviral (nucleoside-naive) and in treatment-experienced adults with documented resistance to lamivudine.1 26

Only limited data in patients with decompensated liver disease.1

Insufficient data in patients with adefovir-associated substitutions at baseline.1

Do not use for treatment of chronic HBV infection in HIV-infected individuals who are not currently receiving antiretroviral therapy.1 97 155 156 200

Treatment of chronic HBV infection is complex and rapidly evolving and should be directed by clinicians familiar with the disease; consult a specialist to obtain the most up-to-date information.97

Tenofovir Disoproxil Fumarate Dosage and Administration

Administration

Oral Administration

Tenofovir DF (Viread): Administer orally once daily without regard to meals.1 Use in conjunction with other antiretrovirals for treatment of HIV-1 infection;1 can be used alone for treatment of chronic HBV infections.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

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

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

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 fixed combination is used in conjunction with other antiretrovirals.230 232 233 (See Precautions Related to Use of Fixed Combinations under Cautions.)

Oral Powder (Viread)

Measure dosage using only the scoop provided by the manufacturer.1

Mix required number of scoops of oral powder with 2–4 ounces of soft food that can be swallowed without chewing (e.g., applesauce, baby food, yogurt);1 immediately ingest entire mixture to avoid a bitter taste.1

Do not administer the powder in liquid since powder may float to the top, even after stirring.1

Dosage

Available as tenofovir DF; dosage expressed in terms of tenofovir DF.1

Dosage of tenofovir DF (Viread) oral powder is expressed as number of scoops of powder.1 The oral powder contains 40 mg of tenofovir DF per g;1 scoop provided by the manufacturer delivers 1 g of powder for each level scoop.1

Pediatric Patients

Treatment of HIV Infection
Oral

Tenofovir DF (Viread) in children ≥2 to <12 years of age: 8 mg/kg (up to 300 mg) once daily as a tablet or oral powder.1 In those weighing ≥17 kg who can reliably swallow tablets, use a single tablet containing appropriate dosage (see Table 1).1 When oral powder is used, use required number of scoops of powder (see Table 2).1

Tenofovir DF (Viread) in children ≥12 years of age weighing ≥35 kg: 300 mg (one 300-mg tablet) once daily.1 In those unable to swallow the tablet, use 300 mg once daily as the oral powder (7.5 scoops of powder).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

Table 1. Tenofovir DF Dosage (Viread Tablets) for Treatment of HIV-1 Infection in Pediatric Patients ≥2 Years of Age Weighing ≥17 kg1

Weight (kg)

Dosage (as Tablets) Once Daily

17 to <22

150 mg

22 to <28

200 mg

28 to <35

250 mg

≥35

300 mg

Table 2. Tenofovir DF Dosage (Viread Oral Powder) for Treatment of HIV-1 Infection in Pediatric Patients ≥2 Years of Ag

Weight (kg)

Dosage (as Oral Powder) Once Daily (40 mg of Tenofovir DF per Scoop)

10 to <12

80 mg (2 scoops)

12 to <14

100 mg (2.5 scoops)

14 to <17

120 mg (3 scoops)

17 to <19

140 mg (3.5 scoops)

19 to <22

160 mg (4 scoops)

22 to <24

180 mg (4.5 scoops)

24 to <27

200 mg (5 scoops)

27 to <29

220 mg (5.5 scoops)

29 to <32

240 mg (6 scoops)

32 to <34

260 mg (6.5 scoops)

34 to < 35

280 mg (7 scoops)

≥35

300 mg (7.5 scoops)

Chronic HBV Infection
Oral

Tenofovir DF (Viread) in children ≥12 years of age weighing ≥35 kg: 300 mg once daily.1 Optimal duration of treatment unknown.1

Adults

Treatment of HIV Infection
Oral

Tenofovir DF (Viread): 300-mg tablet once daily.1 Alternatively, in those unable to swallow tablets, 7.5 scoops of oral powder (300 mg) 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

Tenofovir DF (Viread): 300 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

Tenofovir DF (Viread): 300 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) and continue for 28 days.198

Chronic HBV Infection
Oral

Tenofovir DF (Viread): 300 mg once daily.1

Optimal duration of treatment unknown.1

Special Populations

Hepatic Impairment

Treatment of HIV Infection
Oral

Tenofovir DF (Viread): Dosage adjustments not needed.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

Treatment of Chronic HBV Infection
Oral

Tenofovir DF (Viread): Dosage adjustments not needed.1

Renal Impairment

Treatment of HIV Infection
Oral

Tenofovir DF (Viread): Adjust dosage if Clcr <50 mL/minute (see Table 3).1 Dosage adjustments not needed in those with Clcr 50–80 mL/minute; however, monitor calculated Clcr, serum phosphorus, urine glucose, and urine protein.1 Dosage recommendations not available for patients with Clcr <10 mL/minute who are not undergoing hemodialysis.1

Table 3. Tenofovir DF (Viread) Dosage for Treatment of HIV-1 Infection in Adults with Renal Impairment1

Clcr (mL/minute)

Dosage

30–49

300 mg once every 48 hours

10–29

300 mg once every 72–96 hours

Hemodialysis patients

300 mg once every 7 days or after a total of approximately 12 hours of hemodialysis (assuming 3 hemodialysis sessions/week each lasting approximately 4 hours); give dose after hemodialysis

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

Treatment of Chronic HBV Infection
Oral

Tenofovir DF (Viread): Adjust dosage if Clcr <50 mL/minute (see Table 3).1 Dosage adjustments not needed in adults with Clcr 50–80 mL/minute; however, monitor calculated Clcr, serum phosphorus, urine glucose, and urine protein.1 Dosage recommendations not available for adults with Clcr <10 mL/minute who are not undergoing hemodialysis.1

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 Tenofovir Disoproxil Fumarate

Contraindications

  • Tenofovir DF: Manufacturer states none.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 under Cautions.)

  • Tenofovir DF 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

Possible lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) reported in patients receiving HIV NRTIs, including tenofovir DF, in conjunction with other antiretrovirals.1 230 232 233 Reported mostly 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-infected patients for presence of HBV before initiating antiretroviral therapy.1 230 232 233

Test all HBV-infected patients for HIV before initiating tenofovir DF.1

Use tenofovir DF with other highly active antiretroviral agents in individuals coinfected with HBV and HIV.1

Severe acute exacerbations of HBV reported following discontinuance of HBV therapy in patients with HBV infection.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 tenofovir DF or fixed combinations containing tenofovir DF are discontinued.1 230 232 233 If appropriate, initiation or resumption 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 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

Renal Toxicity

Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with hypophosphatemia) reported with tenofovir DF.1 230 232 233

Calculate Clcr in all patients prior to and as clinically indicated during therapy.1 230 232 233 Routinely monitor calculated Clcr, serum phosphorus, urine glucose, and urine protein prior to and periodically during therapy in all patients at risk for renal impairment, including those who had adverse renal effects while receiving adefovir.1 230 232 233

Avoid tenofovir DF or fixed combinations containing tenofovir DF in patients who are receiving or recently received nephrotoxic drugs (e.g., high-dose or multiple nonsteroidal anti-inflammatory agents [NSAIAs]).1 230 232 233 In patients at risk for renal dysfunction, promptly evaluate renal function if manifestations of proximal renal tubulopathy are present (i.e., persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness).1 230 232 233

Bone Effects

Decreases from baseline in bone mineral density (BMD) at lumbar spine and hip, increases in biochemical markers of bone metabolism, increased serum parathyroid hormone, and increased 1,25 vitamin D levels reported in adults receiving tenofovir DF with lamivudine and efavirenz.1 230 232 233 Similar effects observed in pediatric patients with HIV-1 or HBV infection; however, skeletal growth appeared to be unaffected.1 230 232

Clinical importance of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and fracture risk are unknown.1 230 232 233 Consider BMD monitoring in adults and pediatric patients with history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.1 230 232 233 Effect of calcium and vitamin D supplementation not studied, but may be beneficial for all patients.1 230 232 233 If bone abnormalities suspected, obtain appropriate consultation.1 230 232 233

Osteomalacia associated with proximal renal tubulopathy, which may contribute to fractures, reported; arthralgias and muscle pain or weakness also reported in patients with proximal renal tubulopathy.1 230 232 233 Consider hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms.1 230 232 233

Early Virologic Failure in HIV Infection

Triple NRTI regimens associated with early virologic failure and high rates of resistance.1 Use with caution; closely monitor and consider modifying the regimen.1

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 tenofovir DF-containing preparations concomitantly.1 230 232 233

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

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance.1 230 232 233 Mechanisms and long-term consequences of adipogenic effects unknown;1 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]); 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

Tenofovir DF (Viread): Category B.1 230 232

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-1 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

Tenofovir distributed into human milk in low concentrations.1 34 202

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

Pediatric Use

Tenofovir DF (Viread): Safety and efficacy for treatment of HIV-1 infection not established in children <2 years of age.1 Safety and efficacy for treatment of HBV infection not established in children <12 years of age weighing <35 kg.1

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; select dosage with caution.1 230 232 233

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

Hepatic Impairment

Tenofovir DF (Viread): Limited data indicate dosage adjustments not needed in patients with hepatic impairment.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

Tenofovir DF (Viread): Principally eliminated by kidneys; pharmacokinetics likely to be affected.1 Monitor Clcr and serum phosphorus in patients with mild renal impairment.1 Adjust dosage in those with moderate or severe 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 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

HIV-1 infection: Nausea, diarrhea, rash, headache, pain, depression, asthenia.1

HBV infection: GI effects (abdominal pain, nausea, vomiting, diarrhea), headache, insomnia, dizziness, fatigue, rash, pruritus, nasopharyngitis, back pain, fever.1

Interactions for Tenofovir Disoproxil Fumarate

Tenofovir and its prodrug are not substrates of CYP enzymes;1 tenofovir does not inhibit CYP3A4, 2D6, 2C9, or 2E1, but may have a slight inhibitory effect on 1A.1

The following drug interactions are based on studies using tenofovir DF.1 When fixed combinations containing tenofovir 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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions with drugs that are inhibitors or substrates of hepatic microsomal enzymes unlikely.1

Drugs Affecting or Affected by P-glycoprotein Transport System

Substrate of the P-glycoprotein (P-gp) transport system.1 Pharmacokinetic interactions possible with inhibitors of P-gp (increased absorption of tenofovir DF).1

Drugs Affecting or Affected by Breast Cancer Resistance Protein

Substrate of breast cancer resistance protein (BCRP).1 Pharmacokinetic interactions possible with inhibitors of BCRP (increased absorption of tenofovir DF).1

Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion

Potential increased plasma concentrations of tenofovir or the concomitant drug when used with drugs that reduce renal function or compete for active tubular secretion (e.g., acyclovir, aminoglycosides [e.g., gentamicin], cidofovir, ganciclovir, valacyclovir, valganciclovir, high-dose or multiple nonsteroidal anti-inflammatory agents [NSAIAs]).1 Monitor for dose-related toxicities.200

Specific Drugs

Drug

Interaction

Comments

Abacavir

Pharmacokinetic interaction unlikely1

No in vitro evidence of antagonistic antiretroviral effects1

Adefovir

Do not use concomitantly1

Atazanavir

Atazanavir: Decreased plasma concentrations and AUC of atazanavir (minimum concentrations decreased 40%); increased plasma concentrations and AUC of tenofovir1 10 200 203

Ritonavir-boosted atazanavir: Decreased plasma concentrations and AUC of atazanavir (minimum concentrations decreased 23%); increased plasma concentrations and AUC of tenofovir;1 200

No in vitro evidence of antagonistic antiretroviral effects203

Atazanavir (without low-dose ritonavir): Do not use concomitantly1 200

Ritonavir-boosted atazanavir: Use atazanavir 300 mg, ritonavir 100 mg, and tenofovir DF 300 mg once daily with food;1 200 203 monitor for tenofovir toxicity;1 200 203 discontinue tenofovir DF if tenofovir-associated adverse effects occur203

Ritonavir-boosted atazanavir: If used concomitantly with tenofovir DF and a histamine H2-receptor antagonist in antiretroviral-experienced adults, use atazanavir 400 mg, ritonavir 100 mg, and tenofovir DF 300 mg once daily with food200 203

Antiretroviral-experienced pregnant women in second or third trimester receiving ritonavir-boosted atazanavir and tenofovir DF: Use atazanavir 400 mg and ritonavir 100 mg once daily with food203

Dosage recommendations not available for antiretroviral-experienced pregnant women receiving ritonavir-boosted atazanavir and both tenofovir DF and a histamine H2-receptor antagonist203

Boceprevir

No clinically important pharmacokinetic interactions185 200

Dosage adjustments not needed200

Buprenorphine

No clinically important pharmacokinetic interactions200

Dosage adjustments not needed200

Darunavir

Ritonavir-boosted darunavir: Increased tenofovir concentrations and AUC;200 204 increased darunavir concentrations and AUC204

No in vitro evidence of antagonistic antiretroviral effects204

Clinical importance unknown;200 monitor for tenofovir toxicity200

Manufacturer of darunavir states usual dosage of ritonavir-boosted darunavir and tenofovir DF can be used204

Delavirdine

No in vitro evidence of antagonistic antiretroviral effects1

Didanosine

Buffered or delayed-release didanosine: Increased didanosine concentrations and AUC; no effect on tenofovir pharmacokinetics1 200

Early virologic failure, rapid selection of resistant mutations, potential for immunologic nonresponse or decline in CD4+ T-cell counts reported;200 possible increased risk of didanosine-associated adverse effects (e.g., pancreatitis, lactic acidosis, neuropathy)1

No in vitro evidence of antagonistic antiretroviral effects1

Experts state concomitant use of didanosine and tenofovir DF not recommended at any time200

Manufacturers state use concomitantly with caution and reduced didanosine dosage; closely monitor for didanosine-associated adverse effects; discontinue didanosine if necessary1

In adults or adolescents weighing ≥60 kg with Clcr ≥60 mL/minute, reduce didanosine dosage to 250 mg once daily; in those weighing <60 kg with Clcr ≥60 mL/minute, reduce didanosine dosage to 200 mg once daily1 200 217

If using didanosine delayed-release capsules, administer didanosine and tenofovir DF at same time without food or with a light meal;217 if using didanosine pediatric oral solution, administer didanosine and tenofovir DF at same time without food or administer didanosine on an empty stomach (i.e., ≥30 minutes before or 2 hours after food) if tenofovir DF is taken with food19

Dolutegravir

No clinically important effect on tenofovir or dolutegravir pharmacokinetics236

Dosage adjustments not needed200

Efavirenz

No effect on concentrations or AUCs of either drug1 213

No in vitro evidence of antagonistic antiretroviral effects1

Dosage adjustments not needed213

Emtricitabine

No clinically important pharmacokinetic interactions1

In vitro evidence of additive to synergistic antiretroviral effects218

No in vitro evidence of antagonistic antiviral effects against HBV1

Entecavir

No evidence of clinically important pharmacokinetic interaction1

No in vitro evidence of antagonistic antiviral effects against HBV1

Estrogens/Progestins

Hormonal contraceptives: No clinically important pharmacokinetic interaction1

Etravirine

Decreased etravirine concentrations and AUC; no clinically important effect on tenofovir concentrations and AUC214

No in vitro evidence of antagonistic antiretroviral effects214

Dosage adjustments not needed for either drug214

Ganciclovir, valganciclovir

Possible increased concentrations of tenofovir or ganciclovir200

Monitor for dose-related toxicities200

Histamine H2-receptor antagonists

Alterations in atazanavir concentrations possible with concomitant use of a histamine H2-receptor antagonist, tenofovir DF, and atazanavir (with or without ritonavir)203

If used concomitantly with atazanavir and a histamine H2-receptor antagonist in treatment-experienced patients, a regimen of atazanavir 400 mg, tenofovir DF 300 mg, and ritonavir 100 mg once daily with food is recommended203

Indinavir

Slight increase in tenofovir concentrations and decrease in indinavir concentrations; no effect on AUC of either drug1

No in vitro evidence of antagonistic antiretroviral effects1

Lamivudine

Decreased lamivudine concentrations; no effect on lamivudine AUC or tenofovir concentrations or AUC1

No in vitro evidence of antagonistic antiretroviral effects1

No in vitro evidence of antagonistic antiviral effects against HBV1

Lopinavir/ritonavir

Increased tenofovir concentrations and AUC; no clinically important effect on lopinavir concentrations and AUC1 200

Clinical importance unknown200

Monitor for tenofovir toxicity;1 200 discontinue tenofovir DF if such effects occur1

Maraviroc

No effect on maraviroc pharmacokinetics224

No in vitro evidence of antagonistic antiretroviral effects224

Methadone

No clinically important pharmacokinetic interactions1 200

Dosage adjustments not needed200

Nelfinavir

No effect on pharmacokinetics of either drug1

No in vitro evidence of antagonistic antiretroviral effects1

Nevirapine

No in vitro evidence of antagonistic antiretroviral effects1

Nonnucleoside reverse transcriptase inhibitors (NNRTIs)

No evidence of pharmacokinetic interaction with efavirenz1

No in vitro evidence of antagonistic antiretroviral effects with delavirdine, efavirenz, or nevirapine1

Raltegravir

Increased raltegravir concentrations and AUC; no clinically important effect on tenofovir concentrations200 225

In vitro evidence of additive to synergistic antiretroviral effects225

Not considered clinically important;225 dosage adjustments not needed200

Ribavirin

No clinically important pharmacokinetic interactions1

Rilpivirine

Increased tenofovir concentrations and AUC; no clinically important effect on rilpivirine concentrations or AUC226

No in vitro evidence of antagonistic antiretroviral effects226

Dosage adjustments not needed226

Ritonavir

No in vitro evidence of antagonistic antiretroviral effects1

Saquinavir

Ritonavir-boosted saquinavir (saquinavir 1 g twice daily and ritonavir 100 mg twice daily): No clinically important change in saquinavir concentrations with tenofovir DF 300 mg once daily1

No in vitro evidence of antagonistic antiretroviral effects1

Ritonavir-boosted saquinavir: Dosage adjustments not needed 1

Simeprevir

No clinically important effect on tenofovir pharmacokinetics; slightly decreased simeprevir concentrations and AUC187

Dosage adjustments not needed for either drug187

Sofosbuvir

No clinically important effect on tenofovir or sofosbuvir pharmacokinetics188

Dosage adjustments not needed for either drug188

Stavudine

No in vitro evidence of antagonistic antiretroviral effects1

Tacrolimus

No evidence of clinically important pharmacokinetic interaction1

Telaprevir

Increased tenofovir concentrations and AUC; no clinically important effect on telaprevir concentrations and AUC184 200

Increased clinical and laboratory monitoring warranted;184 200 discontinue tenofovir DF if tenofovir-associated toxicities occur184

Telbivudine

No in vitro evidence of antagonistic antiviral effects against HBV1

Tipranavir

Ritonavir-boosted tipranavir: Decreased tenofovir concentrations and AUC; possible decreased tipranavir concentrations and AUC200 211

In vitro evidence of additive antiretroviral effects211

Dosage adjustments not needed200

Zidovudine

No in vitro evidence of antagonistic antiretroviral effects1

Tenofovir Disoproxil Fumarate Pharmacokinetics

Absorption

Bioavailability

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

Tenofovir DF is a diester prodrug of tenofovir.1

Oral bioavailability of tenofovir from tenofovir DF is approximately 25%; peak plasma concentrations attained in about 1 hour in fasting HIV-infected patients.1

Peak plasma concentrations and AUC in pediatric patients 2 to <12 years of age receiving 8 mg/kg (up to 300 mg) once daily as an oral powder or in pediatric patients 12 to <18 years of age receiving 300 mg once daily as tablets were similar to peak plasma concentrations and AUC reported in adults receiving 300 mg once daily.1 Exposures in HBV-infected pediatric patients 12 to <18 years of age receiving 300 mg once daily as tablets were similar to those in HIV-1-infected adults and adolescents receiving 300 mg once daily.1

In nonfasting individuals, mean peak plasma concentrations were 26% lower when administered as an oral powder compared with administration as tablets; mean AUC was similar with both preparations.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, 300-mg tenofovir DF tablet, and 200-mg emtricitabine capsule given simultaneously.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 emtricitabine capsule and 300-mg tenofovir DF tablet given simultaneously.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 delays time to peak plasma tenofovir concentrations by approximately 1 hour.1 Administration with a high-fat meal increases oral bioavailability of tenofovir (14% increase in peak plasma concentrations; 40% increase in AUC);1 pharmacokinetics not appreciably affected by administration with a light meal.1

Distribution

Extent

Tenofovir distributed into semen35 and vaginal tissue and cervicovaginal fluid in low concentrations following oral administration.30 31 32 36 Very low concentrations may be distributed into saliva.33

Tenofovir crosses human placenta.32 202

Tenofovir distributed into human milk in low concentrations.1 34 202

Plasma Protein Binding

In vitro binding to plasma or serum proteins is <0.7 or 7.2%, respectively, over tenofovir concentrations of 0.01–25 mcg/mL.1

Elimination

Metabolism

Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylation by cellular enzymes to form the active tenofovir diphosphate.1

Tenofovir and its prodrug are not substrates of CYP enzymes.1

Elimination Route

Tenofovir eliminated principally by kidneys using glomerular filtration and active tubular secretion; approximately 32% of an oral dose eliminated in urine within 24 hours.1

Tenofovir removed by hemodialysis.1

Half-life

Approximately 17 hours.1

Special Populations

No substantial changes in tenofovir pharmacokinetics in individuals with moderate to severe hepatic impairment compared with those with normal hepatic function.1

Moderate to severe renal impairment results in increased tenofovir plasma concentrations and AUC; dosage adjustment necessary if Clcr <50 mL/minute.1 (See Renal Impairment under Dosage and Administration.)

Stability

Storage

Oral

Powder

Tenofovir DF (Viread): 25°C (may be exposed to 15–30°C).1

Tablets

Tenofovir DF (Viread): 25°C (may be exposed to 15–30°C).1

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

  • Tenofovir DF is a prodrug and is inactive until hydrolyzed in vivo to tenofovir which is then phosphorylated to the active metabolite (tenofovir diphosphate).1 2 3

  • Active in vitro and in vivo against HIV-11 and HBV;1 26 200 some activity against HIV-2.1

  • Inhibits replication of retroviruses, including HIV-1, by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).1 2 3

  • Inhibits HBV replication through competitive inhibition of viral reverse transcriptase.1

  • Weak inhibitor of mammalian DNA α- and β-polymerases and mitochondrial DNA γ-polymerase.1 4 Low potential to induce mitochondrial toxicity.4

  • HIV-1 resistant to tenofovir can be selected in vitro and have been reported in clinical isolates.1

  • HIV resistant to tenofovir may be cross-resistant to some NRTIs.1 Cross-resistance with HIV PIs or NNRTIs unlikely.7

  • May be active against HBV resistant to adefovir and/or lamivudine.1 26 29 Some adefovir-, entecavir-, lamivudine-, or telbivudine-resistant HBV may have reduced susceptibility to tenofovir.1

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 tenofovir DF (Viread) or emtricitabine/tenofovir DF (Truvada) in conjunction with other antiretrovirals for treatment of HIV-1—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. 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.235 232 233

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications of 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.1 200 230 232 233

  • 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 emtricitabine/tenofovir DF 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 clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, as well as concomitant medical problems such as renal or hepatic impairment.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.

Tenofovir Disoproxil Fumarate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Powder

40 mg per g

Viread

Gilead

Tablets, film-coated

150 mg

Viread

Gilead

200 mg

Viread

Gilead

250 mg

Viread

Gilead

300 mg

Viread

Gilead

Tenofovir Disoproxil Fumarate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

300 mg with Emtricitabine 200 mg

Truvada

Gilead

300 mg with Emtricitabine 200 mg and Efavirenz 600 mg

Atripla

Bristol-Myers Squibb and Gilead

300 mg with Emtricitabine 200 mg and Rilpivirine Hydrochloride 25 mg (of rilpivirine)

Complera

Gilead

300 mg with Emtricitabine 200 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

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

Viread 300MG Tablets (GILEAD SCIENCES): 30/$836.95 or 90/$2,387.98

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.

References

1. Gilead Sciences. Viread (tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2013 Oct.

2. Squires KE. Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2001; 45:2733-9. [IDIS 469675] [PubMed 11557462]

3. Srinivas RV, Kim C et al. Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), Bis(isopropyloxymethylcarbonyl)PMPA. Antimicrob Agents Chemother. 1998; 42:612-7. [PubMed 9517941]

4. Birkus G, Hitchcock MJM, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother. 2002; 46:716-23 [PubMed 11850253]

7. Gilead, Foster City, CA: Personal communication

8. Squires K, Pierone G, Berger D et al. Tenofovir DF: a 48-week final analysis from a phase III randomized, double blind placebo controlled study in antiretroviral experienced patients. Poster presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle, WA: 2002 Feb 24-28. Poster No. 413-W

9. Manion DJ. Dear healthcare provider letter: early virologic non-response in patients with HIV infection treated with lamivudine, abacavir, and tenofovir. GlaxoSmithKline; 2003 Jul. From FDA website.

10. Hodder S. Dear healthcare provider letter: important new pharmacokinetic data for Reyataz (atazanavir sulfate) in combination with Viread (tenofovir disoproxil fumarate). Princeton, NJ: Bristol-Myers Squibb; 2003 Aug 8.

12. Toole J. Dear healthcare provider letter: high rate of virologic failure in patients with HIV infection treated with once-daily triple NRTI regimen containing didanosine, lamivudine, and tenofovir. Foster City, CA; 2003 Oct 14. From FDA website.

19. Bristol-Myers Squibb. Videx (didanosine) pediatric powder for oral solution prescribing information. Princeton, NJ; 2011 Nov.

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]

26. Marcellin P, Heathcote EJ, Buti M et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis. N Engl J Med.2008; 359:2442-55. [PubMed 19052126]

29. Delaney WE, Ray AS, Yang H et al. Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicro Agents Chemother. 2006; 50:2471-7.

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]

32. Yeh RF, Rezk NL, Kashuba AD et al. Genital tract, cord blood, and amniotic fluid exposures of seven antiretroviral drugs during and after pregnancy in human immunodeficiency virus type 1-infected women. Antimicrob Agents Chemother. 2009; 53:2367-74. [PubMed 19307360]

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]

35. Ghosn J, Chaix ML, Peytavin G et al. Penetration of enfuvirtide, tenofovir, efavirenz, and protease inhibitors in the genital tract of HIV-1-infected men. AIDS. 2004; 18:1958-61. [PubMed 15353984]

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.

97. Lok ASF, McMahon BJ. Chronic hepatitis B: Update 2009. AASLD practice guidelines. Sep 2009. From AASLD website.

106. DART Virology group and trial team. Virologic response to a triple nucleoside/nucleotide analogue regimen over 48 weeks in HIV-1 infected adults in Africa. AIDS. 2006; 20:1391-9. [PubMed 16791013]

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