Class: 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, Truvada, Viread

Introduction

Antiretroviral with antiviral activity against hepatitis B virus (HBV); nucleotide reverse transcriptase inhibitor.^{1 2 3 200}

Uses for Tenofovir Disoproxil Fumarate

Treatment of HIV Infection

Treatment of HIV-1 infection in conjunction with other antiretrovirals.^{1 200}

Used with another NRTI (dual NRTIs) in conjunction with a nonnucleoside reverse transcriptase inhibitor (NNRTI) or HIV protease inhibitor (PI) in NNRTI- or PI-based regimens.^{200 201} Also used with another NRTI (dual NRTIs) in conjunction with an HIV integrase inhibitor or HIV entry inhibitor.²⁰⁰

For initial treatment in HIV-infected adults and adolescents, some experts state that tenofovir and either emtricitabine or lamivudine is the preferred dual NRTI option, especially in HIV-infected patients coinfected with HBV.²⁰⁰

Emtricitabine/tenofovir fixed combination (Truvada) used in conjunction with other antiretrovirals.²³⁰ Can be used to decrease pill burden,²⁰⁰ but should not be used as a component of a triple NRTI regimen.²³⁰

Efavirenz/emtricitabine/tenofovir fixed combination (Atripla) used alone or in conjunction with other antiretrovirals.²³² Used to decrease pill burden and improve compliance.²³²

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Emtricitabine/rilpivirine/tenofovir fixed combination (Complera) can be used alone.²³³ Used to decrease pill burden and improve compliance.²³³

Preexposure Prophylaxis (PrEP) for Prevention of HIV-1 Infection

Emtricitabine/tenofovir fixed combination containing emtricitabine and tenofovir (Truvada) used for PrEP in combination with safer sex practices to reduce the risk of sexually acquired HIV-1 in HIV-1-negative adults at high risk.^{230 450 451 457 463 467}

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 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 of HIV

Postexposure prophylaxis of HIV infection† in health-care workers and others exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with risk for transmission of the virus.¹⁹⁹ Used in conjunction with other antiretrovirals.¹⁹⁹

Postexposure prophylaxis of HIV infection† in individuals who have had nonoccupational exposure 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.¹

Used in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative adults with compensated liver disease.^{26 1}

Only limited data in patients with decompensated liver disease.¹

Insufficient data in patients with lamivudine- or adefovir-associated mutations at baseline.¹

Do not use for treatment of chronic HBV infection in HIV-infected individuals who are not currently receiving antiretroviral therapy.^{1 97 190 191 200}

Tenofovir Disoproxil Fumarate Dosage and Administration

Administration

Oral Administration

Administer tenofovir or emtricitabine/tenofovir (Truvada) orally without regard to meals.^{1 230}

Administer efavirenz/emtricitabine/tenofovir (Atripla) orally once daily on an empty stomach, preferably at bedtime.²³²

Administer emtricitabine/rilpivirine/tenofovir (Complera) orally with a meal.²³³

Oral Powder

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

Mix required number of scoops of 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 disodium fumarate; dosage expressed in terms of tenofovir disodium fumarate.¹

Dosage of tenofovir oral powder is expressed as number of scoops of powder.¹ The oral powder contains 40 mg of tenofovir disoproxil fumarate per g;¹ scoop provided by the manufacturer delivers 1 g of powder.¹

Antiretroviral agents contained in Atripla, Truvada, or Complera also are available in other single-entity or fixed-combination preparations; ensure that therapy is not duplicated when Atripla, Truvada, or Complera is used in conjunction with other antiretrovirals.^{230 232 233} When selecting concomitant therapy, consider cautions and interactions for each drug in the fixed combination.^{230 232 233}

Pediatric Patients

Treatment of HIV Infection

Oral

Children ≥2 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

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

Table 1. Tenofovir Disoproxil Fumarate Dosage for Treatment of HIV-1 Infection in Pediatric Patients ≥2 Years of Age Weighing ≥17 kg (Tablets)1

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 Disoproxil Fumarate Dosage for Treatment of HIV-1 Infection in Pediatric Patients ≥2 Years of Age (Oral Powder)1

Weight (kg)	Scoops of Oral Powder Once Daily
10 to <12	2
12 to <14	2.5
14 to <17	3
17 to <19	3.5
19 to <22	4
22 to <24	4.5
24 to <27	5
27 to <29	5.5
29 to <32	6
32 to <34	6.5
34 to <35	7
≥35	7.5

Adults

Treatment of HIV Infection

Oral

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

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

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

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

Preexposure Prophylaxis (PrEP) for Prevention of HIV-1 Infection

HIV-1-negative Adults at High Risk

Oral

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

Use 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 of HIV†

Occupational Exposure†

Oral

300 mg once daily.¹⁹⁹

Initiate postexposure prophylaxis as soon as possible following exposure (within hours rather than days) and continue for 4 weeks, if tolerated.¹⁹⁹

Nonoccupational Exposure†

Oral

300 mg once daily.¹⁹⁸

Initiate postexposure prophylaxis as soon as possible following exposure (preferably ≤72 hours after exposure) and continue for 28 days.¹⁹⁸

Chronic HBV Infection

Oral

300 mg once daily.¹

Optimal duration of treatment unknown.¹

Special Populations

Hepatic Impairment

Treatment of HIV Infection

Oral

Tenofovir: Dosage adjustment not needed.¹

Efavirenz/emtricitabine/tenofovir (Atripla): Dosage adjustment not needed in adults with mild hepatic impairment; however, caution advised.²³² Do not use in those with moderate or severe hepatic impairment.²³²

Emtricitabine/rilpivirine/tenofovir (Complera): Dosage adjustment not needed 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

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

Treatment of Chronic HBV Infection

Oral

Tenofovir: Dosage adjustment not needed.¹

Renal Impairment

Treatment of HIV Infection

Oral

Adjust tenofovir dosage if Cl_cr <50 mL/minute (see Table 3).¹ Dosage adjustment not needed in those with Cl_cr 50–80 mL/minute.¹ Tenofovir dosage recommendations not available for patients with Cl_cr <10 mL/minute who are not undergoing hemodialysis.¹

Table 3. Tenofovir Disoproxil Fumarate 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

Efavirenz/emtricitabine/tenofovir (Atripla): Dosage adjustment not needed in adults with Cl_cr ≥50 mL/minute;²³² do not use in those with Cl_cr< 50 mL/minute.²³²

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

Emtricitabine/tenofovir (Truvada): Dosage adjustment not needed in adults with Cl_cr 50–80 mL/minute; however, monitor calculated Cl_cr and serum phosphorus.²³⁰ In adults with Cl_cr 30–49 mL/minute, reduce dosage to 1 tablet (emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg) once every 48 hours; monitor clinical response and renal function since dosage not evaluated clinically.²³⁰ Do not use in adults with Cl_cr <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

Preexposure Prophylaxis (PrEP) for Prevention of HIV-1 Infection

Oral

Emtricitabine/tenofovir (Truvada): Dosage adjustment not needed in adults with Cl_cr ≥60 mL/minute; however, monitor calculated Cl_cr and serum phosphorus.²³⁰ If Cl_cr decreases, evaluate potential causes and reassess potential risks and benefits of continued use.²³⁰ Do not use if Cl_cr <60 mL/minute.²³⁰

Treatment of Chronic HBV Infection

Oral

Adjust tenofovir dosage if Cl_cr <50 mL/minute (see Table 3).¹ Dosage adjustment not needed in adults with Cl_cr 50–80 mL/minute.¹ Dosage recommendations not available for adults with Cl_cr <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

• Manufacturer states none with tenofovir.¹

• When used in fixed combination with other antiretrovirals (e.g., emtricitabine, efavirenz, rilpivirine), consider contraindications associated with the concomitant agent(s).^{232 233}

• Emtricitabine/tenofovir (Truvada): 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.)

Warnings/Precautions

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Possible lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) reported in patients receiving NRTIs, including tenofovir, 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} Has been 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.¹

Use tenofovir 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 or fixed combinations containing tenofovir are discontinued.^{1 230 232 233} If appropriate, initiation or resumption of HBV treatment may be warranted.^{1 230 232 233}

Renal Toxicity

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

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

Avoid tenofovir or fixed combinations containing tenofovir in patients who are receiving or recently received nephrotoxic drugs.¹

Bone Effects

Decreases from baseline in bone mineral density (BMD) at lumbar spine and hip, increases in biochemical markers of bone metabolism, and increased serum parathyroid hormone reported in patients receiving tenofovir with lamivudine and efavirenz; clinical importance unclear.¹

Osteomalacia associated with proximal renal tubulopathy, which may contribute to fractures, reported.¹

Consider BMD monitoring in those 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}

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

Use of Fixed Combinations

Do not use multiple tenofovir-containing preparations concomitantly.^{1 230 232 233}

When used in fixed combination with other antiretrovirals (e.g., emtricitabine, efavirenz, rilpivirine), consider cautions, precautions, and contraindications associated with the concomitant agent(s).^{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 in the fixed combination.^{230 232 233}

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}

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 jiroveci [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}

Precautions Related to HIV-1 Preexposure Prophylaxis (PrEP)

Use emtricitabine/tenofovir (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 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 alone does not constitute a complete antiretroviral regimen for treatment of HIV-1 infection, HIV-1 resistance-associated mutations may emerge if emtricitabine/tenofovir PrEP 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 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

Specific Populations

Pregnancy

Tenofovir: Category B.^{1 230 232}

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

Some experts state that tenofovir is an alternative (not preferred) NRTI for use in multiple-drug antiretroviral regimens for treatment of HIV-1 infection in pregnant women.²⁰² These experts state that tenofovir and either emtricitabine or lamivudine is the preferred dual NRTI option for treatment in pregnant HIV-infected women coinfected with HBV.²⁰²

If HIV-negative woman receiving emtricitabine/tenofovir 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

Safety and efficacy of tenofovir for treatment of HIV-1 infection not established in children <2 years of age.¹

Safety and efficacy of tenofovir in fixed combination with efavirenz and emtricitabine (Atripla) or in fixed combination with rilpivirine and emtricitabine (Complera) not established in pediatric patients <18 years of age.^{232 233}

Safety and efficacy of tenofovir in fixed combination with emtricitabine (Truvada) 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

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

Limited data indicate tenofovir dosage adjustment not needed in patients with hepatic impairment.¹ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Tenofovir principally eliminated by kidneys; pharmacokinetics likely to be affected.¹ Monitor Cl_cr 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.)

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.¹ Drug interaction studies have not been performed using fixed combinations containing tenofovir.^{230 232 233} When used in fixed combination with other antiretrovirals, consider interactions associated with each drug in the fixed combination.^{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

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, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir).¹ Monitor for dose-related toxicities.²⁰⁰

Specific Drugs

Drug	Interaction	Comments
Abacavir	Pharmacokinetic interaction unlikely1 In vitro evidence of additive or synergistic 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 disoproxil fumarate 300 mg once daily with food;1 200 203 monitor for tenofovir toxicity;1 200 203 discontinue tenofovir if tenofovir-associated adverse effects occur203 Ritonavir-boosted atazanavir: If used concomitantly with tenofovir and a histamine H2-receptor antagonist in antiretroviral-experienced adults, use atazanavir 400 mg, ritonavir 100 mg, and tenofovir disoproxil fumarate 300 mg once daily with food200 203 Antiretroviral-experienced pregnant women in second or third trimester receiving ritonavir-boosted atazanavir and tenofovir: 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 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 can be used204
Delavirdine	In vitro evidence of additive or synergistic 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 reported200 Increased risk of didanosine-associated adverse effects (e.g., pancreatitis, lactic acidosis, neuropathy)1 In vitro evidence of additive or synergistic antiretroviral effects1	Experts state concomitant use of didanosine and tenofovir 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 daily If using didanosine delayed-release capsules, administer didanosine and tenofovir at same time without food or with a light meal;217 if using didanosine pediatric oral solution, administer didanosine and tenofovir at same time without food or administer didanosine on an empty stomach (i.e., ≥30 minutes before or 2 hours after food) if tenofovir is taken with food19
Efavirenz	No effect on concentrations or AUCs of either drug1 213 In vitro evidence of additive to synergistic 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 containing ethinyl estradiol and norgestimate: Pharmacokinetic interaction unlikely1
Etravirine	Decreased etravirine concentrations and AUC; increased tenofovir concentrations and AUC214 No in vitro evidence of antagonistic antiretroviral effects214	Dosage adjustments not needed214
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, 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 disoproxil fumarate 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 In vitro evidence of additive to synergistic antiretroviral effects1
Lamivudine	Decreased lamivudine concentrations; no effect on lamivudine AUC or tenofovir concentrations or AUC1 In vitro evidence of additive or synergistic 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 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 concentrations or AUC of either drug1 In vitro evidence of additive to synergistic antiretroviral effects1
Nevirapine	In vitro evidence of additive or synergistic antiretroviral effects1
Nonnucleoside reverse transcriptase inhibitors (NNRTIs)	No evidence of pharmacokinetic interaction with efavirenz1 In vitro evidence of additive or synergistic 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	Pharmacokinetic interaction unlikely1
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	In vitro evidence of additive or synergistic 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 300 mg once daily1 In vitro evidence of additive or synergistic antiretroviral effects1	Ritonavir-boosted saquinavir: Dosage adjustment not needed 1
Stavudine	In vitro evidence of additive or synergistic 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 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	In vitro evidence of additive or synergistic antiretroviral effects1

Tenofovir Disoproxil Fumarate Pharmacokinetics

Absorption

Bioavailability

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

Tenofovir disoproxil fumarate is a diester prodrug of tenofovir.¹

Oral bioavailability of tenofovir from tenofovir disoproxil fumarate 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

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, tenofovir disoproxil fumarate 300 mg, and emtricitabine 200 mg (Atripla) is bioequivalent to a 600-mg efavirenz tablet, a 300-mg tenofovir disoproxil fumarate tablet, and a 200-mg emtricitabine capsule given simultaneously.²³²

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

Fixed-combination tablet containing emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg (Truvada) is bioequivalent to a 200-mg emtricitabine capsule and a 300-mg tenofovir disoproxil fumarate tablet given simultaneously.²³⁰

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} 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 disoproxil fumarate 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 or severe renal impairment results in increased tenofovir plasma concentrations and AUC; dosage adjustment necessary if Cl_cr <50 mL/minute.¹ (See Renal Impairment under Dosage and Administration.)

Stability

Storage

Oral

Tablets

Single-entity tenofovir or fixed combinations: 25°C (may be exposed to 15–30°C).^{1 230 232 233}

Actions and Spectrum

• Tenofovir disoproxil fumarate is a prodrug and is inactive until the drug is 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 or emtricitabine/tenofovir (Truvada) in conjunction with other antiretrovirals for treatment of HIV-1—not for monotherapy.^{1 230} Efavirenz/emtricitabine/tenofovir (Atripla) or emtricitabine/rilpivirine/tenofovir (Complera) can be used alone for treatment of HIV-1 infection.^{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}

• Truvada medication guide must be provided to and reviewed with all HIV-negative individuals each time emtricitabine/tenofovir 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 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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. 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