AHFS Class:

• HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors 8:18.08.20

Generic Name(s):

• Tenofovir Disoproxil Fumarate

Tenofovir disoproxil fumarate (tenofovir DF), an antiretroviral agent, is a human immunodeficiency virus (HIV) nucleotide reverse transcriptase inhibitor that is active against HIV and hepatitis B virus (HBV).1,2,3,200

Treatment of HIV Infection

Tenofovir disoproxil fumarate (tenofovir DF) is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, adolescents, and pediatric patients 2 years of age or older weighing ≥10 kg.1 Tenofovir DF is commercially available as a single-entity preparation and in various fixed-combination preparations that contain 2 or 3 additional antiretrovirals; refer to separate combination product monographs for information related to the specific uses of these products.1,230,231,232,233,235,239,240 Tenofovir DF is commonly used as part of a dual-nucleoside reverse transcriptase inhibitor (NRTI) “backbone” of a fully suppressive antiretroviral regimen; consult guidelines for the most current information on recommended regimens.200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.200,201,202

Clinical Experience

Antiretroviral-naive Adults and Adolescents

Efficacy of tenofovir DF in a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen in treatment-naïve adults was evaluated in a double-blind, active-controlled study (study 903) in 600 adults (mean age 36 years, 74% male, 64% white, 20% Black, mean baseline CD4+ T-cell count 279 cells/mm³, median baseline plasma HIV-1 RNA 77,600 copies/mL).1,40 At 144 weeks, 68% of those receiving a regimen of efavirenz, tenofovir DF, and lamivudine had plasma HIV-1 RNA levels <400 copies/mL compared with 62% of those receiving a regimen of efavirenz, stavudine, and lamivudine.1 In addition, 62% of those receiving the tenofovir DF regimen had plasma HIV-1 RNA levels <50 copies/mL compared with 58% in the comparator group.1 The mean increase from baseline CD4+ T-cell count was 263 and 283 cells/mm³, respectively.1

Efficacy of an NNRTI-based regimen that included tenofovir DF (efavirenz, emtricitabine, and tenofovir DF) was evaluated in a randomized, open-label study designed to demonstrate noninferiority of this regimen compared with a regimen of efavirenz, zidovudine, and lamivudine (study 934).1,23 In this study, 511 treatment-naïve HIV-infected patients (mean age 38 years, 86% male, 59% white, 23% Black, median baseline plasma HIV-1 RNA level 5.01 log₁₀ copies/mL [range: 3.56-6.54 log₁₀ copies/mL], mean baseline CD4+ T-cell count 245 cells/mm³) were randomized to receive a once-daily regimen of efavirenz, emtricitabine, and tenofovir DF or a regimen of efavirenz once daily with the fixed combination of lamivudine and zidovudine (lamivudine/zidovudine; Combivir^®) twice daily.1,23 The primary measure used to assess noninferiority of the regimen of efavirenz, emtricitabine, and tenofovir DF to the regimen of efavirenz and lamivudine/zidovudine was plasma HIV-1 RNA levels at week 48, specifically, the number of patients with HIV-1 RNA levels <400 copies/mL.1,23 The 487 patients without baseline resistance to efavirenz who underwent randomization and received treatment were the predefined population used for the primary endpoint analysis.23

Through week 48, the regimen of efavirenz, emtricitabine, and tenofovir DF met the criteria for noninferiority to the regimen of efavirenz and lamivudine/zidovudine.23 At week 48, 84 or 80% of adults receiving the efavirenz, emtricitabine, and tenofovir DF regimen and 73 or 70% of adults receiving the efavirenz and lamivudine/zidovudine regimen had plasma HIV-1 RNA levels <400 or 50 copies/mL, respectively.1,23 At week 48, increases in CD4+ T-cell counts were greater in patients receiving the efavirenz, emtricitabine, and tenofovir DF regimen (mean increase of 190 cells/mm³) than in those receiving the efavirenz and lamivudine/zidovudine regimen (mean increase of 158 cells/mm³).1,23 Virologic failure (i.e., individuals who failed to achieve virologic suppression or experienced rebound after achieving virologic suppression) was reported in 2% of those receiving efavirenz, emtricitabine, and tenofovir DF and in 4% of those receiving efavirenz and lamivudine/zidovudine at week 48.1 At 144 weeks, 64% of adults receiving the efavirenz, emtricitabine, and tenofovir DF regimen and 56% of those receiving the efavirenz and lamivudine/zidovudine regimen had plasma HIV-1 RNA levels <50 copies/mL.30 The mean increase in CD4+ T-cell count from baseline in these groups at 144 weeks was 312 and 271 cells/mm³, respectively.1

Antiretroviral-experienced Adults and Adolescents

In study 907, a placebo-controlled, randomized study in 550 previously treated HIV-infected adults (mean age 42 years, 85% male, 69% white, 17% Black, 12% Hispanic, mean duration of prior treatment 5.4 years, mean baseline CD4+ T-cell count 427 cells/mm³; median baseline plasma HIV-1 RNA level 2340 copies/mL), addition of tenofovir DF to the existing antiretroviral regimen resulted in decreases in plasma HIV-1 RNA levels and increases in CD4+ T-cell counts.1,8 At 24 weeks, plasma HIV-1 RNA levels were <400 copies/mL in 40% of those receiving tenofovir DF compared with 11% of those receiving placebo; in addition, 19% of those receiving tenofovir DF had levels <50 copies/mL compared with 1% of those receiving placebo.1,8 After 24 weeks of blinded study, all patients received open-label tenofovir DF for an additional 24 weeks.1,8 At week 48, 28% of those who received tenofovir DF for the entire duration had plasma HIV-1 RNA levels <400 copies/mL.4

Pediatric Patients

Efficacy of tenofovir DF in pediatric patients has been evaluated in a randomized study in 92 HIV-1-infected antiretroviral-experienced children 2 to less than 12 years of age (study 352).1,38 Patients had been receiving a suppressive regimen containing stavudine or zidovudine and were randomized to receive tenofovir DF instead of stavudine or zidovudine or to continue their original regimen.1,2,38 At 48 weeks, 89% of patients randomized to receive tenofovir DF and 90% of those who continued their original regimen had plasma HIV-1 RNA levels <400 copies/mL.8

In a study in 87 antiretroviral-experienced pediatric patients 12 to less than 18 years of age (study 321) with mean baseline plasma HIV-1 RNA level of 4.6 log₁₀ copies/mL and mean baseline CD4+ T-cell count of 374 cells/mm³ (90% harbored HIV-1 with NRTI resistance-associated substitutions at baseline), patients received tenofovir DF or placebo with an optimized background regimen (OBR) for 48 weeks.39 Overall, there was no difference in virologic response between the groups; subgroup analysis suggested that the lack of difference in virologic response may be attributable to imbalances between the treatment arms in baseline virus susceptibility to tenofovir DF and the OBR.1 Although changes in HIV-1 RNA were less than anticipated in this trial, the comparability of the pharmacokinetic and safety data to that observed in adults supports the use of tenofovir DF in pediatric patients 12 years of age or older who weigh at least 35 kg and whose HIV-1 isolate is expected to be sensitive to tenofovir DF.1

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy (ART) is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of ART are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 NRTIs administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), an NNRTI, or a protease inhibitor (PI) with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), antiretroviral regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200

Tenofovir DF, an NRTI, is commonly used as part of a dual-NRTI “backbone” of a fully suppressive antiretroviral regimen.200 In the 2022 HHS adult and adolescent HIV treatment guideline, tenofovir DF is included in various regimens.200 Some of these tenofovir DF-containing regimens are listed among recommended initial regimens for most people with HIV, and include the following: dolutegravir/tenofovir DF/emtricitabine; dolutegravir/tenofovir DF/lamivudine.200 Additional tenofovir DF-containing regimens are listed among recommended initial regimens in certain clinical situations.200 Regimens containing tenofovir DF/emtricitabine or tenofovir DF/lamivudine are recommended in patients co-infected with HBV, as these drugs have activity against both viruses.200

In the 2022 HHS pediatric HIV treatment guideline, tenofovir DF is included in various regimens.201 Tenofovir DF plus lamivudine or emtricitabine is recommended as an alternative dual-NRTI combination for children aged ≥2 to 12 years.201

In the 2022 HHS perinatal HIV treatment guideline, tenofovir DF is included in various regimens.202 Tenofovir DF plus lamivudine or emtricitabine is recommended as one of the preferred dual-NRTI backbones.202 Preferred antiretroviral regimens for initial ART in pregnancy include a preferred dual-NRTI backbone plus one of the following: dolutegravir, raltegravir, atazanavir/ritonavir, or darunavir/ritonavir.202

Preexposure Prophylaxis for Prevention of HIV-1 Infection

Tenofovir DF is used in combination with emtricitabine for preexposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in at-risk HIV-negative adults and adolescents; refer to the fixed-combination product monograph for detailed information on this use.230,1001

Clinical Perspective

In the 2021 CDC HIV PrEP guideline, several PrEP regimens are recommended based on an individual patient's characteristics to reflect the populations evaluated in pivotal clinical studies.1001 Options for PrEP include oral emtricitabine/tenofovir DF in sexually active adults and adolescents and men and women who inject drugs, oral emtricitabine/tenofovir alafenamide in men and transgender women who have sex with men, and intramuscular cabotegravir in adults and adolescents.1001

Postexposure Prophylaxis following Occupational Exposure to HIV

Tenofovir DF is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel and other individuals 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

Clinical Perspective

The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).199 These experts recommend several alternative regimens that include an INSTI, NNRTI, or PI and 2 NRTIs (dual NRTIs).199 The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir^®), or zidovudine and emtricitabine.199 Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Tenofovir DF is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when that exposure represents a substantial risk for HIV transmission.198

Clinical Perspective

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).198 The alternative nPEP regimen recommended in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF (Truvada^®).198

Consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if an antiretroviral regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals.198 However, initiation of nPEP should not be delayed while waiting for expert consultation.198

Chronic Hepatitis B Virus Infection

Tenofovir DF is used for the treatment of chronic HBV infection in adults and pediatric patients ≥2 years of age weighing ≥10 kg.1 Tenofovir DF is a preferred initial treatment option when chronic HBV treatment is indicated; choice of antiviral medication should be individualized based on patient characteristics and comorbidities, treatment tolerability, and cost.97

Clinical Experience

HBeAg-Positive Adults

Efficacy of tenofovir DF for treatment of HBeAg-positive chronic HBV infection was evaluated in a phase 3, randomized, double-blind, active-controlled study (study 0103) in mainly nucleoside-naïve adults with compensated liver function (mean baseline serum HBV DNA level 8.7 log₁₀ copies/mL, mean serum ALT 147 IU/mL, mean baseline total Knodell Histology Activity Index [HAI] score 8.4).1,26 Patients received tenofovir DF 300 mg once daily or adefovir dipivoxil 10 mg once daily.1,26 Sixty-nine percent of patients in the study were male, 36% were Asian and 52% were Caucasian, 16% had received prior treatment with interferon alfa, and less than 5% had received treatment with a nucleoside.1 After 48 weeks of treatment, all patients were eligible to receive open-label tenofovir DF with no interruption in treatment.1

At 48 weeks, 67% of patients receiving tenofovir DF had serum HBV DNA levels <400 copies/mL and histologic improvement (defined as a reduction of at least 2 points in the Knodell necroinflammatory score with no concurrent worsening of the Knodell fibrosis score) compared with 12% of those receiving adefovir.1,26 HBeAg seroconversion occurred in about 20 or 16% of those receiving tenofovir DF or adefovir, respectively; loss of hepatitis B surface antigen (HBsAg) occurred in 3 or 0% of those who received tenofovir DF or adefovir, respectively.1

Through 384 weeks, 49% of patients originally randomized to tenofovir DF who subsequently received open-label tenofovir DF had HBV DNA levels <400 copies/mL, 42% had ALT normalization, 20% had HBeAg loss, and 13% had HBeAg seroconversion.1 In patients originally randomized to adefovir who subsequently received open-label tenofovir DF, 56% had HBV DNA levels <400 copies/mL, 50% had ALT normalization, 28% had HBeAg loss, and 19% had HBeAg seroconversion through 384 weeks.1 Rates of HBsAg loss and seroconversion were 11 and 8%, respectively, at week 384 in those initially randomized to tenofovir DF and 12 and 10%, respectively, in those initially randomized to adefovir.1

Liver biopsies were obtained at baseline, 48 weeks, and 240 weeks from 328 patients in studies 102 (HBeAg-negative adults) and 103 (HBeAg-positive adults) who received continuing open-label treatment with tenofovir DF.1 The observed histological response rates in these patients were 80 and 88% at week 48 and 240, respectively.1 In patients with cirrhosis at baseline, 97 and 99% had improvement or no change in fibrosis score at week 48 and 240, respectively; 29 and 72% experienced regression of cirrhosis by week 48 and 240, respectively.1

A total of 203 patients from studies 102 and 103 continued to receive open-label tenofovir DF for up to 10 years; at 10 years, tenofovir DF maintained tolerability and efficacy without development of resistance.45

HBeAg-Negative Adults

Efficacy of tenofovir DF for treatment of HBeAg-negative chronic HBV infection was evaluated in a phase 3, randomized, double-blind, active-controlled study (study 0102) in adults with compensated liver function (mean baseline serum HBV DNA level 6.9 log₁₀ copies/mL, mean serum ALT 140 IU/mL, mean baseline total Knodell Histology Activity Index [HAI] score 7.8).1,26 Patients received tenofovir DF 300 mg once daily or adefovir dipivoxil 10 mg once daily for 48 weeks.1,26 Seventy-seven percent of patients in the study were male, 25% were Asian and 65% were Caucasian, 17% had received prior treatment with interferon alfa, and 18% had received treatment with a nucleoside (16% had received lamivudine).1 After 48 weeks of treatment, all patients were eligible to receive open-label tenofovir DF with no interruption in treatment.1

At 48 weeks, 71% of patients receiving tenofovir DF had serum HBV DNA levels <400 copies/mL and histologic improvement (defined as a reduction of at least 2 points in the Knodell necroinflammatory score with no concurrent worsening of the Knodell fibrosis score) compared with 49% of those receiving adefovir.1,26

At 384 weeks, 73% of patients originally randomized to tenofovir DF who subsequently received open-label tenofovir DF had HBV DNA levels <400 copies/mL and 63% had ALT normalization.1 In patients originally randomized to adefovir who subsequently received open-label tenofovir DF, 80% had HBV DNA levels <400 copies/mL and 70% had ALT normalization at 384 weeks.1 HBsAg loss and seroconversion rates were approximately 1% in both treatment groups at week 384.

Lamivudine-resistant Chronic HBV

Efficacy of tenofovir DF for treatment of chronic HBV infection in adults with persistent viremia and genotypic evidence of lamivudine resistance was evaluated in a randomized, double-blind, active-controlled trial.1 43 Of the 141 adults randomized to receive tenofovir DF, mean age was 47 years, 74% were male, 59% were white, 37% were Asian, and mean baseline plasma HBV DNA was 6.4 log₁₀ copies/mL.1 At baseline, 54% were HBeAg-negative, 46% were HBeAg-positive, and 56% had abnormal ALT.1 At 96 weeks, 89% of patients receiving tenofovir DF had HBV DNA levels less than 400 copies/mL, which was similar to comparator groups; 62% of patients with abnormal ALT at baseline experienced normalization.1 Of the 65 patients who were HBeAg-positive at baseline, 15% experienced HbeAg loss and 11% developed antibodies to HBsAg (anti-HBs) through week 96.1 Efficacy of tenofovir DF was maintained for up to 240 weeks.44

Across the combined chronic HBV treatment trials, there were insufficient data to establish efficacy in patents with adefovir resistance-associated substitutions.1

Decompensated Liver Disease

Efficacy of tenofovir DF for treatment of chronic HBV infection in adults with decompensated liver disease was evaluated in a small, randomized, double-blind, active-controlled trial (study 0108).1,41 The primary objective of the study was to assess safety; efficacy outcomes were examined as secondary endpoints.41 A total of 45 patients were assigned to the tenofovir DF treatment arm.1,41 At baseline, 69% of patients were HBeAg-negative and 31% were HBeAg-positive; patients had a mean Child-Pugh score of 7, mean Model for End-stage Liver Disease (MELD) score of 12, mean HBV DNA level of 5.8 log₁₀ copies/mL, and mean serum ALT concentration of 61 IU/mL.1

At 48 weeks, 70% of patients receiving tenofovir DF had HBV DNA levels <400 copies/mL and 46% had ALT normalization.1 The study was not designed to evaluate treatment effect on clinical end points such as progression of liver disease, need for liver transplantation, or death.1

Pediatric Patients

Efficacy of tenofovir DF for the treatment of chronic HBV in patients 12 to <18 years of age was evaluated in a double-blind, randomized, controlled trial (study 115).1,42 In the trial, 106 patients received treatment with tenofovir DF or placebo for 72 weeks.1,42 Most patients (91%) were HBeAg-positive at baseline.1 At trial entry, patients had a mean HBV DNA level of 8.1 log₁₀ copies/mL and mean ALT of 101 IU/L.1 At week 72, 88% of patients receiving tenofovir DF and 0% of patients receiving placebo had HBV DNA <400 copies/mL.1 Among subjects with abnormal ALT at baseline, normalization of ALT was achieved in 74% of tenofovir DF-treated patients and 31% of patients who received placebo.1,42

Efficacy of tenofovir DF for the treatment of chronic HBV in patients 2 to <12 years of age was evaluated in a placebo-controlled trial (study 144).32 Most of the 89 patients enrolled in the trial were HBeAg-positive at baseline (96%).1 Patients received tenofovir DF or placebo for 48 weeks.1 At baseline, patients had a mean HBV DNA level of 8.1 log₁₀ copies/mL and mean ALT of 123 IU/L.1 At week 48, 77% of patients receiving tenofovir DF and 7% of patients receiving placebo had HBV DNA <400 copies/mL.1 Normalization of ALT was achieved in 66% of tenofovir DF-treated patients and 15% of patients who received placebo.1 The proportion of patients achieving HBeAg loss or seroconversion was similar across treatment groups.1

Clinical Perspective

The American Association for the Study of Liver Diseases (AASLD) recommends antiviral therapy for adults with immune-active chronic HBV to decrease the risk of liver-related complications.97 Immune-active chronic HBV is characterized by an elevation of ALT ≥2 times the upper limit of normal or evidence of significant histologic disease plus elevated HBV DNA (>2000 IU/mL if HBeAg negative or >20,000 IU/mL if HBeAg positive).97 Recommended initial antiviral options for adults with immune-active chronic HBV include peginterferon alfa-2a, entecavir, tenofovir DF, and tenofovir alafenamide.97 Selection of a specific antiviral medication should be individualized based on patient characteristics and comorbidities, treatment tolerability, and cost; consult the AASLD guideline for more details.97 Antiviral therapy is also recommended for HBeAg-positive children 2 years of age and older with both elevated ALT and measurable HBV DNA levels; the goal of therapy is to achieve sustained HBeAg seroconversion.97 Preferred initial treatment options for pediatric patients include interferon alfa-2b, entecavir, and tenofovir DF.97

General

• Tenofovir DF is commercially available as a single entity and in various fixed-combination preparations that contain additional antiretrovirals.1,230,231,232,233,235,239,240 Refer to the full prescribing information for specific, distinct uses of the combination products.230,231,232,233,235,239,240 Since the antiretroviral agents contained in the fixed combination preparations also may be available in single-entity or other fixed-combination preparations, exercise care to ensure that therapy is not duplicated if a fixed combination is used in conjunction with other antiretrovirals.230,231,232,233,235,239,240

Pretreatment Screening

• Perform testing for hepatitis B virus (HBV) infection and human immunodeficiency virus type 1 (HIV-1) infection prior to or when initiating tenofovir disoproxil fumarate (tenofovir DF).1
• Assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein on a clinically appropriate schedule prior to initiation of tenofovir DF.1 In patients with chronic kidney disease, also assess serum phosphorus.1

Patient Monitoring

• Assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein on a clinically appropriate schedule during treatment with tenofovir DF.1 In patients with chronic kidney disease, also assess serum phosphorus.1
• Monitor weight periodically during treatment with tenofovir DF and adjust dosage accordingly.1

Administration

Single-entity tenofovir DF is commercially available as tablets or oral powder.1

Tenofovir DF tablet is administered orally once daily without regard to meals.1

Tenofovir DF oral powder is administered once daily.1 Measure the appropriate dosage of the oral powder using only the scoop provided by the manufacturer.1 One level scoop delivers 1 g of powder, which contains 40 mg of tenofovir DF.1 Mix the required number of scoops of the powder with 2-4 ounces of soft food that can be swallowed without chewing (e.g., applesauce, baby food, yogurt), and ingest the entire mixture immediately to avoid a bitter taste.1 Do not administer the oral powder in a liquid since the powder may float to the top of the liquid, even after stirring.1

Store tenofovir DF oral power and tablets at 25ºC (excursions permitted to 15-30ºC).1 Dispense in the original container, and keep the container tightly closed.1

Dosage

Although tenofovir DF is a prodrug that requires metabolism for activation, dosage of the drug is expressed in terms of the prodrug diester (i.e., tenofovir DF).1

Dosage of tenofovir DF oral powder containing 40 mg/g is expressed as the number of scoops of powder.1

Adults

Treatment of HIV Infection

For the treatment of HIV-1 infection, the recommended dosage of tenofovir DF oral tablet in adults weighing ≥35 kg is 300 mg once daily.1 The dosage of tenofovir DF oral tablet in adults weighing <35 kg is based on weight (see Table 1); monitor weight periodically and adjust dosage accordingly.1 In adults who are unable to swallow tablets, the recommended dosage of tenofovir DF oral powder is 8 mg/kg (up to a maximum of 300 mg) once daily with food (see Table 2); monitor weight periodically and adjust dosage accordingly.1

Preexposure Prophylaxis for Prevention of HIV Infection

The fixed-dose combination containing emtricitabine/tenofovir DF (Truvada^®) is used for preexposure prophylaxis (PrEP) for prevention of HIV-1 infection.230 For PreP, the usual dosage of tenofovir DF is 300 mg once daily in conjunction with other antiretrovirals; see the full prescribing information for specific dosage of emtricitabine/tenofovir DF (Truvada^®). 230

Postexposure Prophylaxis following Occupational Exposure to HIV

For postexposure prophylaxis of HIV infection following occupational exposure† (PEP), the usual dosage of tenofovir DF is 300 mg once daily in conjunction with other antiretrovirals.199 Tenofovir DF usually is used with emtricitabine or lamivudine in conjunction with a recommended HIV INSTI, HIV NNRTI, or HIV PI.199 The preferred dual NRTI backbone option for use in PEP regimens is emtricitabine and tenofovir DF, commonly administered as the fixed-dose combination of emtricitabine/tenofovir DF (Truvada^®).199 See the full prescribing information for specific dosage of emtricitabine/tenofovir DF (Truvada^®).230

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

For postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP), the usual dosage of tenofovir DF is 300 mg once daily in conjunction with other antiretrovirals.198 Tenofovir DF usually is used in conjunction with emtricitabine and a recommended or alternative INSTI, PI, or NNRTI.198 The preferred dual NRTI backbone option for use in nPEP regimens is emtricitabine and tenofovir DF, commonly administered as the fixed-dose combination of emtricitabine/tenofovir DF (Truvada^®).198 See the full prescribing information for specific dosage of emtricitabine/tenofovir DF (Truvada^®).230

Treatment of Chronic HBV Infection

For the treatment of HBV infection, the recommended dosage of tenofovir DF oral tablet in adults weighing ≥35 kg is 300 mg once daily.1 The dosage of tenofovir DF oral tablet in adults weighing <35 kg is based on weight (see Table 1); monitor weight periodically and adjust dosage accordingly.1

In adults who are unable to swallow tablets, the recommended dosage of tenofovir DF oral powder is 8 mg/kg (up to a maximum of 300 mg) once daily with food (see Table 2); monitor weight periodically and adjust dosage accordingly.1

The optimum duration of tenofovir DF therapy in patients with chronic HBV infection is not known.1

Pediatric Patients

Treatment of HIV Infection

For the treatment of HIV infection in pediatric patients ≥2 years of age weighing ≥35 kg, the recommended dosage of tenofovir DF oral tablet is 300 mg once daily.1

In pediatric patients ≥2 years of age weighing ≥17 kg who are able to swallow intact tablets, the recommended dosage of tenofovir DF oral tablet is 8 mg/kg (up to a maximum of 300 mg) once daily (see Table 1).1 Monitor weight periodically and adjust dosage accordingly.1

In pediatric patients ≥2 years of age weighing ≥10 kg who are unable to swallow tablets, the recommended dosage of tenofovir DF oral powder is 8 mg/kg (up to a maximum of 300 mg) once daily (see Table 2).1 Monitor weight periodically and adjust dosage accordingly.1

Preexposure Prophylaxis for Prevention of HIV Infection

The fixed-dose combination containing emtricitabine/tenofovir DF (Truvada^®) is used for preexposure prophylaxis (PrEP) for prevention of HIV infection in adolescents weighing ≥35 kg.230 For PreP, the usual dosage of tenofovir DF is 300 mg once daily in conjunction with other antiretrovirals; see the full prescribing information for specific dosage of emtricitabine/tenofovir DF (Truvada^®).230

Chronic HBV Infection

For the treatment of chronic HBV infection in pediatric patients ≥2 years of age weighing ≥35 kg, the recommended dosage of tenofovir DF oral tablet is 300 mg once daily.1

In pediatric patients ≥2 years of age weighing ≥17 kg but less than 35 kg who are able to swallow intact tablets, the recommended dosage of tenofovir DF oral tablet is 8 mg/kg (up to a maximum of 300 mg) once daily (see Table 1).26 Monitor weight periodically and adjust dosage accordingly.1

In pediatric patients ≥2 years of age weighing ≥10 kg who are unable to swallow tablets, the recommended dosage of tenofovir DF oral powder is 8 mg/kg (up to a maximum of 300 mg) once daily (see Table 2).1 Monitor weight periodically and adjust dosage accordingly.1 The optimum duration of tenofovir DF therapy in patients with chronic HBV infection is not known.1

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1

Renal Impairment

Dosage adjustments are not necessary for patients with mild renal impairment (creatinine clearance 50-80 mL/minute).1 Administration of tenofovir DF to patients with moderate to severe renal impairment (creatinine clearance <50 mL/minute) resulted in significant increase in drug exposures.1 The recommended dosage interval adjustments in adults with creatinine clearance <50 mL/minute are outlined in Table 3.1

No data are available to make dosage recommendations in adults with creatinine clearance <10 mL/minute who are not on hemodialysis.1

No data are available to make dosage recommendations for pediatric patients with renal impairment.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1 Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Contraindications

• None.1

Warnings/Precautions

Warnings

Severe Acute Exacerbations of Hepatitis B Virus Infection

A boxed warning regarding the risk of severe acute exacerbation of hepatitis B virus (HBV) is included in the prescribing information of tenofovir disoproxil fumarate (tenofovir DF).1 Test all patients for the presence of chronic HBV before or when initiating tenofovir DF.1

Severe acute exacerbations of HBV infection may occur following discontinuance of HBV treatment, including tenofovir DF.1 Closely monitor hepatic function with clinical and laboratory follow-up for at least several months after tenofovir DF is discontinued.1 If appropriate, resumption of HBV treatment may be warranted, especially in patients with cirrhosis or advanced liver disease, since posttreatment exacerbation of HBV infection may lead to hepatic decompensation and liver failure.1

Other Warnings/Precautions

New Onset or Worsening Renal Impairment

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in patients receiving tenofovir DF.1 Assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein on a clinically appropriate schedule in all patients prior to or when initiating tenofovir DF, and during treatment with the drug.1 In patients with chronic kidney disease, also assess serum phosphorus.1

In patients with creatinine clearance <50 mL/min, adjust dosing interval of tenofovir DF and closely monitor renal function.1 Since no safety or efficacy data are available in patients with renal impairment who received tenofovir DF using the dosing guidelines outlined in the prescribing information, assess the potential benefit of tenofovir DF therapy against the potential risk of renal toxicity.1

Avoid use of tenofovir DF in patients who are receiving or have recently received nephrotoxic drugs (e.g., high-dose or multiple nonsteroidal anti-inflammatory agents [NSAIAs]).1 Acute renal failure has been reported after initiation of high-dose or multiple NSAIAs in HIV-infected patients with risk factors for renal dysfunction who appeared stable while receiving tenofovir DF.1 Some cases required hospitalization and renal replacement therapy.1 Consider alternatives to NSAIAs in patients at risk for renal dysfunction.1 If manifestations of proximal renal tubulopathy are present in patients at risk for renal dysfunction (i.e., persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness), promptly evaluate renal function.1

Individuals with HBV and HIV-1 Coinfection

Prior to initiating tenofovir DF for treatment of HIV-1 infection, test the patient for chronic HBV.1 Prior to initiation of tenofovir DF for treatment of chronic HBV infection, offer HIV-1 testing in all patients.1

Due to the risk of development of HIV-1 resistance, only use tenofovir DF in patients with HBV and HIV-1 coinfection as part of an appropriate antiretroviral combination regimen.1

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported in patients receiving nucleoside analogs, including tenofovir DF, alone or in conjunction with other antiretroviral agents.1

Suspend tenofovir DF in any patient with clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).1

Bone Loss and Mineralization Defects

In clinical studies of patients infected with HIV-1, tenofovir was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover in comparison with other antiretroviral agents.1 Increased serum parathyroid hormone and 1,25 vitamin D levels were also reported in HIV-infected adults receiving tenofovir DF.1

In clinical studies in pediatric patients infected with HIV-1, effects on bone in patients 2 to <18 years of age were similar to those observed in adults, suggesting increased bone turnover.1 Similar trends were observed in HBV-infected pediatric patients 2 to <18 years of age.1 In all pediatric studies, normal skeletal growth appeared to be unaffected for the duration of the study.1 The clinical importance of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and fracture risk in adults and pediatric patients are unknown.1 The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients, especially the effects of long-duration exposure in younger children, is unknown.1

Consider BMD monitoring for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.1 Although the effect of calcium and vitamin D supplementation was not studied, such supplementation may be beneficial.1 If bone abnormalities are suspected, obtain appropriate consultation.1

Osteomalacia associated with proximal renal tubulopathy, which may contribute to fractures, has been reported in patients receiving tenofovir DF; arthralgias and muscle pain or weakness have also been reported in patients with proximal renal tubulopathy.1 Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF.1

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients with HIV-1 treated with combination antiretroviral therapy, including tenofovir DF.1 During the initial phase of treatment, patients infected with HIV-1 whose immune systems 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 ]); such response may necessitate further evaluation and treatment.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1

Risk of Adverse Reactions Due to Drug Interactions

Concomitant use of tenofovir and certain drugs may result in known or potentially significant drug interactions, some of which may lead to possible clinically important adverse reactions from greater exposures of concomitant drugs.1 Consult the prescribing information for steps to prevent or manage possible and known significant drug interactions.1 Consider the potential for drug interactions before and during therapy with tenofovir, review concomitant medications during therapy, and monitor for adverse reactions associated with concomitant drugs.1

Specific Populations

Pregnancy

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to tenofovir DF during pregnancy.1 Clinicians are encouraged to register patients in the APR by calling 1-800-258-4263 or visiting [Web].1

Based on prospective data from the APR, the prevalence of birth defects in live births was 2.3% and 2.1% following first and second/third trimester exposure, respectively, to tenofovir DF-containing regimens.1 The overall risk of birth defects with first-trimester exposure for tenofovir DF was not markedly different compared to the background rate for major birth defects of 2.7% in the United States reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).1 Limitations of using an external comparator (the MACDP) include differences in populations and methodology, and confounding due to the underlying disease.1 The rate of miscarriage is not reported in the APR.1 Tenofovir crosses the human placenta.32

In published studies that included HBV-infected pregnant women treated with tenofovir DF, an increased risk of adverse pregnancy-related outcomes was not observed with use of tenofovir DF during the third trimester.1 Two stillbirths were identified, and there was 1 major birth defect (talipes) and 1 occurrence of multiple congenital abnormalities (not further specified) in infants exposed to tenofovir DF.1 No clinically relevant drug-related safety findings were found in infants exposed to tenofovir DF during late gestation.1

Animal reproduction studies did not find any adverse developmental effects when tenofovir DF was administered at doses ≥14 (tenofovir DF) and exposures 2.7 (tenofovir) times the recommended daily dose of tenofovir DF in humans.1

Lactation

Tenofovir is distributed into human milk in low concentrations.1,34 In a study of breast-feeding women (not infected with HIV) who were on a tenofovir-containing regimen started between 1-24 weeks postpartum, tenofovir was undetectable in the plasma of most infants after 7 days of treatment in mothers.1 No serious adverse events were reported in mothers or infants.1

It is not known whether tenofovir DF affects human milk production or has effects on the breast-fed infant.1

If using tenofovir DF for the treatment of HIV-1 infection, women should not breast-feed infants due to the potential for the following: HIV transmission in HIV-negative infants, development of viral resistance in HIV-positive infants, and adverse reactions in the breast-fed infant similar to those observed in adults.1

If using tenofovir DF for the treatment of HBV infection, consider the developmental and health benefits of breast-feeding and the importance of tenofovir DF to the mother along with the potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1

Pediatric Use

Safety and efficacy of tenofovir DF for treatment of HIV-1 infection in pediatric patients 2 to <18 years of age are supported by data from 2 randomized controlled trials.1 Peak plasma concentrations and AUC of tenofovir in HIV-1-infected pediatric patients 2 to <18 years of age receiving 8 mg/kg of tenofovir DF (up to 300 mg) once daily as oral powder or receiving 300 mg once daily as tablets were similar to peak plasma concentrations and AUC reported in adults receiving 300 mg once daily.1 Safety and efficacy of tenofovir DF for treatment of HIV-1 infection have not been established in children <2 years of age weighing <10 kg.1

In HBV-infected pediatric patients 12 to <18 years of age receiving tenofovir DF 300 mg once daily as tablets, and pediatric patients 2 to <12 years of age receiving 8 mg/kg of tenofovir DF (up to 300 mg) once daily as tablets or oral powder, tenofovir exposures were similar to those reported in HIV-1-infected adults receiving identical doses.1

Safety and efficacy of tenofovir DF for treatment of chronic HBV infection have not been established in children <2 years of age weighing <10 kg.1

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently to tenofovir DF than younger adults.1 Select dosage in geriatric patients with caution because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or drug therapy.1 Pharmacokinetic studies have not been conducted in patients ≥65 years of age.1

Hepatic Impairment

The pharmacokinetics of tenofovir are not substantially altered in patients with moderate or severe hepatic impairment compared with those with normal hepatic function.1

Renal Impairment

Tenofovir is principally eliminated by the kidney.1 Moderate or severe renal impairment (creatinine clearance <50 mL/minute or end-stage renal disease requiring dialysis) results in increased tenofovir plasma concentrations and AUC, and dosage interval adjustments are necessary in such patients.1

Common Adverse Effects

The most common adverse effects (incidence ≥10%; grades 2-4) in HIV-infected patients receiving tenofovir DF are rash, diarrhea, headache, pain, depression, asthenia, and nausea.1

The most common adverse effect (all grades) in HBV-infected patients with compensated liver disease was nausea (9%).1

The most common adverse effects (incidence ≥10%; all grades) in HBV-infected patients with decompensated liver disease were abdominal pain, nausea, vomiting, pruritus, insomnia, dizziness, and pyrexia.1

Adverse reactions in pediatric patients were consistent with those observed in adults.1

Tenofovir disoproxil fumarate (tenofovir DF) is a substrate of the P-glycoprotein (P-gp) transport system and breast cancer resistance protein (BCRP).1 Tenofovir and its prodrug (tenofovir DF) are not substrates of cytochrome P-450 (CYP) isoenzymes; in vitro studies indicate tenofovir does not inhibit CYP isoenzymes 3A4, 2D6, 2C9, or 2E1, but may have a slight inhibitory effect on CYP1A.1

The following drug interactions are based on studies using tenofovir DF; refer to the full prescribing information for further details.1 Additional drug interactions may exist for fixed-combinations containing emtricitabine and tenofovir DF (Truvada^®); doravirine, lamivudine, and tenofovir DF (Delstrigo^®); efavirenz, emtricitabine, and tenofovir DF (Atripla^®); emtricitabine, rilpivirine, and tenofovir DF (Complera^®); elvitegravir, cobicistat, emtricitabine, and tenofovir DF (Stribild^®); and efavirenz, lamivudine, and tenofovir (Symfi^® and Symfi Lo^®).230,231,232,233,235,239,240 When a fixed combination is used, interactions associated with each drug in the fixed combination should be considered.230,231,232,233,235,239,240 See the full prescribing information for drug interactions of each combination product.230,231,232,233,235,239,240

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions between tenofovir and drugs that are inhibitors or substrates of hepatic microsomal enzymes are unlikely.1

Drugs Affecting P-glycoprotein Transport

Pharmacokinetic interactions are possible with inhibitors of P-gp.1 Concomitant use of tenofovir DF and inhibitors of P-gp may increase absorption of tenofovir DF, resulting in increased plasma concentrations of the drug.1

Drugs Affecting Breast Cancer Resistance Protein

Pharmacokinetic interactions are possible with inhibitors of BCRP.1 Concomitant use of tenofovir DF and inhibitors of BCRP may increase absorption of tenofovir DF, resulting in increased plasma concentrations of the drug.1

Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion

Concomitant use of tenofovir DF with drugs that reduce renal function or compete for active renal tubular secretion (i.e., acyclovir, aminoglycosides [e.g., gentamicin], cidofovir, ganciclovir, valacyclovir, valganciclovir, high-dose or multiple nonsteroidal anti-inflammatory agents [NSAIAs]) may increase concentrations of tenofovir and other drugs that are renally eliminated, which may increase the risk of adverse effects.1

Adefovir Dipivoxil

Concomitant use of adefovir dipivoxil and tenofovir DF may result in increased plasma concentrations of tenofovir and/or adefovir.200

Do not use tenofovir DF and adefovir dipivoxil concomitantly.1

Antiretroviral Agents

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

No in vitro evidence of antagonistic antiretroviral effects was observed between tenofovir and NNRTIs (efavirenz, nevirapine).1

Efavirenz

Concomitant use of tenofovir DF and efavirenz does not result in clinically important drug interactions.1

HIV Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

No in vitro evidence of antagonistic antiretroviral effects was observed between tenofovir and NRTIs (abacavir, didanosine, lamivudine, zidovudine).1

Abacavir

Concomitant use of tenofovir DF and abacavir does not have a clinically important effect on the pharmacokinetics of abacavir.1

Didanosine

Concomitant use of didanosine enteric-coated (delayed-release) capsules and tenofovir DF results in substantially increased didanosine plasma concentrations.1 When didanosine 250 mg enteric-coated capsules were used concomitantly with tenofovir DF and a light meal (373 kcal, 8.2 g fat), peak plasma concentrations of didanosine were decreased 20% and didanosine AUC was similar to that reported when the 400-mg didanosine enteric-coated capsules are used alone in the fasted state.1

If didanosine delayed-release capsules and tenofovir DF are used concomitantly, reduce dosage of didanosine and monitor closely for didanosine-associated adverse effects.1 Higher concentrations of didanosine could lead to didanosine-associated adverse effects (e.g., pancreatitis, neuropathy); discontinue didanosine if such adverse effects occur.1 Concomitant use of tenofovir DF and didanosine 400 mg has also resulted in suppression of CD4+ cell counts.1

If didanosine delayed-release capsules are used concomitantly with tenofovir DF, reduce didanosine dosage to 250 mg once daily in patients weighing ≥60 kg or to 200 mg once daily in those weighing <60 kg.1 Patients may take didanosine delayed-release capsules and tenofovir DF at the same time with a light meal (no more than 400 kcal, no more than 20% fat) or in the fasted state.1

Concomitant use of tenofovir DF and didanosine buffered tablets does not have a clinically important effect on the pharmacokinetics of didanosine buffered tablets.1

Emtricitabine

Concomitant use of tenofovir DF and emtricitabine does not have a clinically important effect on the pharmacokinetics of emtricitabine.1

Lamivudine

Concomitant use of tenofovir DF and lamivudine does not have a clinically important effect on the pharmacokinetics of lamivudine.1

HIV Protease Inhibitors (PIs)

No in vitro evidence of antagonistic antiretroviral effects between tenofovir DF and HIV PIs (amprenavir, nelfinavir, ritonavir).1

Atazanavir

Concomitant use of tenofovir DF and atazanavir results in decreased atazanavir plasma concentrations.1

If using concomitantly with tenofovir DF, administer atazanavir 300 mg with ritonavir 100 mg.1

Monitor patients receiving tenofovir DF concomitantly with ritonavir-boosted atazanavir for tenofovir-associated adverse reactions; discontinue tenofovir DF if tenofovir-associated adverse effects occur.1

Darunavir

Monitor patients receiving tenofovir DF concomitantly with ritonavir-boosted darunavir for tenofovir-associated adverse reactions; discontinue tenofovir DF if tenofovir-associated adverse effects occur.1

Lopinavir

Coadministration of tenofovir DF and the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) resulted in increased tenofovir AUC; no change in lopinavir plasma concentrations and AUC was observed.1

Monitor patients receiving tenofovir DF concomitantly with lopinavir/ritonavir for tenofovir-associated adverse reactions; discontinue tenofovir DF if such effects occur.1

Nelfinavir

No clinically important pharmacokinetic interaction was observed between nelfinavir and tenofovir DF.1

Tipranavir

Pharmacokinetic interaction between tenofovir DF and ritonavir-boosted tipranavir results in decreased concentrations of both tenofovir DF and tipranavir; tenofovir AUC increased by 2% and tipranavir AUC decreased by 9%.1

Entecavir

No clinically important pharmacokinetic interaction was observed between entecavir and tenofovir DF.1

Estrogens and Progestins

No clinically important pharmacokinetic interaction between oral contraceptives and tenofovir DF.1

HCV Antivirals

Sofosbuvir

Concomitant use of tenofovir DF and sofosbuvir does not have a clinically important effect on the pharmacokinetics of either drug.1

Sofosbuvir and Velpatasvir

Concomitant use of tenofovir DF and the fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir) may result in increased plasma concentrations of tenofovir.1

If an antiretroviral regimen containing tenofovir DF is used concomitantly with sofosbuvir/velpatasvir, monitor the patient for tenofovir-associated adverse effects.1

Sofosbuvir, Velpatasvir, and Voxilaprevir

Concomitant use of tenofovir DF and the fixed combination of sofosbuvir, velpatasvir, and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir) may result in increased plasma concentrations of tenofovir.1

Ledipasvir and Sofosbuvir

Concomitant use of the fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) and tenofovir DF results in increased tenofovir exposure.1

Monitor patients receiving tenofovir DF concomitantly with ledipasvir/sofosbuvir without an HIV-1 PI/ritonavir or an HIV-1 PI/cobicistat combination, for tenofovir DF-associated adverse effects.1 In patients receiving tenofovir DF concomitantly with ledipasvir/sofosbuvir and an HIV-1 PI/ritonavir or an HIV-1 PI/cobicistat combination, consider an alternative hepatitis C virus (HCV) or antiretroviral therapy.1 Safety of increased tenofovir concentrations in this setting has not been established.1 If coadministration is necessary, monitor for tenofovir DF-associated adverse effects.1

Opiates and Opiate Partial Agonists

Methadone

No clinically important pharmacokinetic interaction was observed between methadone and tenofovir DF.1

Ribavirin

No clinically important pharmacokinetic interaction was observed between ribavirin and tenofovir DF.1

Tacrolimus

Pharmacokinetic interaction is unlikely.1