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tenofovir disoproxil fumarate 300 mg tablet generic viread

Out of Stock Manufacturer MACLEODS PHARMA 33342009607
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Uses

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.

For purposes of therapeutic decisions, tenofovir DF is grouped with HIV nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral agents. Tenofovir DF usually is used in multiple-drug regimens that include another NRTI (dual NRTIs) and an HIV integrase strand transfer inhibitor (INSTI), HIV nonnucleoside reverse transcriptase inhibitor (NNRTI), or HIV protease inhibitor (PI) in INSTI-, NNRTI-, or PI-based regimens. Single-entity tenofovir DF is labeled by FDA for use in conjunction with other antiretrovirals in adults, adolescents, and children 2 years of age or older. Tenofovir DF also is commercially available in various fixed-combination preparations that contain emtricitabine with or without a third antiretroviral. These fixed combinations can be used in specific patient groups to decrease pill burden and improve compliance.

If the dual NRTI option of tenofovir DF and emtricitabine is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection, a fixed-combination preparation containing both drugs (emtricitabine/tenofovir DF; Truvada) is commercially available and can be used in adults, adolescents, and children weighing at least 17 kg. Emtricitabine/tenofovir DF must be used in conjunction with other antiretrovirals for treatment of HIV-1.

If an HIV NNRTI-based regimen of efavirenz, emtricitabine, and tenofovir DF is used for the treatment of HIV-1 infection, a fixed-combination preparation containing all 3 drugs (efavirenz/emtricitabine/tenofovir DF; Atripla) is commercially available and can be used in adults and adolescents 12 years of age or older weighing at least 40 kg. Efavirenz/emtricitabine/tenofovir DF can be used alone as a complete treatment regimen or in conjunction with other antiretrovirals.

If an HIV NNRTI-based regimen of rilpivirine, emtricitabine, and tenofovir DF is used for the treatment of HIV-1 infection, a fixed-combination preparation containing all 3 drugs (emtricitabine/rilpivirine/tenofovir DF; Complera) is commercially available and can be used in antiretroviral-naive adults and adolescents 12 years of age or older weighing at least 35 kg with baseline plasma HIV-1 RNA levels of 100,000 copies/mL or less. Emtricitabine/rilpivirine/tenofovir DF also can be used to replace a stable antiretroviral regimen in certain antiretroviral-experienced (previously treated) patients who are virologically suppressed (i.e., plasma HIV-1 RNA levels less than 50 copies/mL). Emtricitabine/rilpivirine/tenofovir DF is used alone as a complete treatment regimen.

A fixed-combination preparation containing elvitegravir, cobicistat, emtricitabine, and tenofovir DF (EVG/c/FTC/TDF; Stribild) also is commercially available for use alone as a complete regimen for the treatment of HIV-1 in adults. For information on EVG/c/FTC/TDF, see

Tenofovir DF has been used in triple NRTI regimens, and some experts state that a regimen of tenofovir DF, zidovudine, and lamivudine may be considered in certain situations. However, triple NRTI regimens containing tenofovir DF, abacavir, and lamivudine or tenofovir DF, didanosine, and lamivudine are not recommended because of a high rate of virologic failure.(See All-NRTI Regimens under Treatment of HIV Infection: Antiretroviral-naive Adults and Adolescents, in Uses.)

The most appropriate antiretroviral regimen cannot be defined for each clinical scenario and selection of specific antiretroviral agents for use in multiple-drug regimens should be individualized based on information regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the patient. For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens,

Antiretroviral-naive Adults and Adolescents

Dual NRTI Options

For initial treatment in HIV-infected adults and adolescents, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that the dual tenofovir DF and emtricitabine (or lamivudine) is a recommended dual NRTI option for use in most INSTI-, NNRTI-, and PI-based regimens. This recommendation is based on safety and efficacy data from clinical trials, long-term clinical experience, and availability of fixed-combination preparations containing tenofovir DF and emtricitabine.

Because all 3 drugs have activity against both HIV and hepatitis B virus (HBV), tenofovir DF and emtricitabine or tenofovir DF and lamivudine are preferred dual NRTI options for antiretroviral regimens used in HIV-infected patients coinfected with HBV.

A dual NRTI option of didanosine and tenofovir DF should not be used at any time because such regimens are associated with early virologic failure, rapid selection of resistant mutants, potential for immunologic nonresponse or decline in CD4 T-cell counts, and increased didanosine concentrations and toxicities. Clinicians caring for patients who are clinically stable on a regimen containing didanosine and tenofovir DF should consider altering the NRTIs.

All-NRTI Regimens

Tenofovir DF has been included in NRTI regimens that include 3 or 4 NRTIs (without any drugs from another class). However, triple and quadruple NRTI regimens generally are not recommended for initial treatment in HIV-infected adults or adolescents because such regimens have inferior virologic efficacy or have not been adequately studied.

A triple NRTI regimen of zidovudine, lamivudine, and tenofovir DF has been used and has been shown to have antiretroviral activity; however, this regimen is not routinely recommended because of limited data comparing it with other options.

A quadruple NRTI regimen of abacavir, lamivudine, tenofovir DF, and zidovudine is not recommended for initial therapy in antiretroviral-naive HIV-infected adults and adolescents because of inferior virologic efficacy.

Study 903

Safety and efficacy of tenofovir DF in an NNRTI-based regimen in treatment-naive adults was evaluated in a double-blind, active-controlled study (study 903) in 600 adults (mean age 36 years, 74% male, 64% white, 20% African American, mean baseline CD4 T-cell count 279 cells/mm, median baseline plasma HIV-1 RNA 77,600 copies/mL). At 144 weeks, 68% of those receiving a regimen of efavirenz, tenofovir DF, and lamivudine had plasma HIV-1 RNA levels less than 400 copies/mL compared with 62% of those receiving a regimen of efavirenz, stavudine, and lamivudine. In addition, 62% of those receiving the tenofovir DF regimen had plasma HIV-1 RNA levels less than 50 copies/mL compared with 58% in the comparator group. The mean increase from baseline CD4 T-cell count was 263 or 283 cells/mm, respectively.

Efavirenz, Emtricitabine, and Tenofovir DF

Safety and 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). In this study, 511 treatment-naive 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/mm) 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. 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 less than 400 copies/mL. The 487 patients without baseline resistance to efavirenz who underwent randomization and received treatment were the predefined population used for the primary endpoint analysis.

Through week 48, the regimen of efavirenz, emtricitabine, and tenofovir DF met the criteria for noninferiority to the regimen of efavirenz and lamivudine/zidovudine. 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 less than 400 or 50 copies/mL, respectively. 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/mm) than in those receiving the efavirenz and lamivudine/zidovudine regimen (mean increase of 158 cells/mm). 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.

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 less than 50 copies/mL. The mean increase in CD4 T-cell count from baseline in these groups at 144 weeks was 312 and 271 cells/mm, respectively.

Antiretroviral-experienced Adults and Adolescents

Study 907

In study 907, a placebo-controlled, randomized study in 550 previously treated HIV-infected adults (mean age 42 years, 85% male, 69% white, 17% African American, 12% Hispanic, mean duration of prior treatment 5.4 years, mean baseline CD4 T-cell count 427 cells/mm; 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. At 24 weeks, plasma HIV-1 RNA levels were less than 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 less than 50 copies/mL compared with 1% of those receiving placebo. After 24 weeks of blinded study, all patients received open-label tenofovir DF for an additional 24 weeks. At week 48, 28% of those who received tenofovir DF for the entire duration had plasma HIV-1 RNA levels less than 400 copies/mL.

Efavirenz, Emtricitabine, and Tenofovir DF

Efficacy of the fixed combination efavirenz/emtricitabine/tenofovir DF (Atripla) was evaluated in a randomized, open-label study (study 073) in antiretroviral-experienced patients who had been receiving a suppressive regimen consisting of at least 2 NRTIs and a PI or NNRTI (mean age 43 years [range 22-73 years]), 88% male, 68% white, 29% black, median CD4 T-cell count 516 cells/mm). Patients had plasma HIV-1 RNA levels less than 200 copies/mL for at least 12 weeks on their existing regimen (96% had plasma HIV-1 RNA levels less than 50 copies/mL), no known HIV-1 substitutions conferring resistance to the components of the fixed combination, and no history of virologic failure; patients were randomized to either switch to the fixed combination of efavirenz/emtricitabine/tenofovir DF or continue their existing (baseline) regimen. At 48 weeks, 89 and 87% of those switched to efavirenz/emtricitabine/tenofovir DF had plasma HIV-1 RNA levels less than 200 and 50 copies/mL, respectively, compared with 88 and 85% of those who remained on their baseline regimen. This difference was not statistically significant. There was no change in CD4 T-cell count from baseline in either group.

Emtricitabine, Rilpivirine, and Tenofovir DF

The fixed combination emtricitabine/rilpivirine/tenofovir DF can be used to replace a stable antiretroviral regimen for treatment of HIV-1 infection in antiretroviral-experienced adults and adolescents 12 years of age or older weighing at least 35 kg who have been virologically suppressed (i.e., plasma HIV-1 RNA levels less than 50 copies/mL) on their current regimen for at least 6 months, are currently receiving only their first or second antiretroviral regimen, have no history of virologic failure, and have no current evidence or history of resistance to emtricitabine, rilpivirine, or tenofovir DF.

The efficacy and safety of emtricitabine/rilpivirine/tenofovir DF (Complera) have been evaluated in a randomized, open-label study (study 106) in 476 virologically suppressed HIV-infected adults (mean age 42 years, 88% male, 77% white, 17% black, 17% Hispanic, mean baseline CD4 T-cell count 584 cells/mm). Patients were receiving their first or second antiretroviral regimen with no history of virologic failure; had no history of resistance to emtricitabine, rilpivirine, or tenofovir DF; and were virologically suppressed (plasma HIV-1 RNA levels less than 50 copies/mL) for at least 6 months. Patients were randomized in a 2:1 ratio to switch to emtricitabine/rilpivirine/tenofovir DF for 48 weeks or to continue receiving their baseline antiretroviral regimen containing a ritonavir-boosted HIV PI for 24 weeks and then switch to emtricitabine/rilpivirine/tenofovir DF for an additional 24 weeks. In patients initially switched to emtricitabine/rilpivirine/tenofovir DF, 89% maintained plasma HIV-1 RNA levels less than 50 copies/mL at 48 weeks; 90% of those who continued to receive their baseline regimen maintained plasma HIV-1 RNA levels less than 50 copies/mL at 24 weeks.

Pediatric Patients

Tenofovir DF is used in conjunction with other antiretroviral agents for treatment of HIV-1 infection in pediatric patients 2 years of age or older. Tenofovir DF is not recommended in children younger than 2 years of age because decreased bone mineral density (BMD) has been reported in adults and children.(See Bone Effects under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

The fixed combination emtricitabine/rilpivirine/tenofovir DF can be used alone as a complete regimen for the treatment of HIV-1 infection in adolescents 12 years of age or older weighing at least 35 kg.

For initial treatment of HIV-infected pediatric patients, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a PI-, NNRTI-, or INSTI-based regimen that includes 2 NRTIs (dual NRTIs).

For use in initial treatment regimens, the HHS panel states that tenofovir DF and emtricitabine is an alternative dual NRTI option for antiretroviral-naive children and adolescents with sexual maturity rating (SMR) 3; however, because decreased BMD has been reported in adults and children receiving tenofovir DF, the panel states that the dual option of tenofovir DF and emtricitabine should be used in children 2 years or age or older or adolescents at SMR 1 or 2 only in special circumstances after weighing the potential risk of decreased BMD versus the benefits of the dual NRTI option.

The dual NRTI option of tenofovir DF and abacavir is not recommended for use in initial treatment regimens in antiretroviral-naive pediatric patients because of insufficient data.

The dual NRTI option of tenofovir DF and didanosine is not recommended for use in initial treatment regimens in antiretroviral-naive pediatric patients because of a high rate of virologic failure.

Antiretroviral regimens containing only NRTIs are not recommended for initial treatment in antiretroviral-naive pediatric patients because of inferior virologic efficacy.

A triple NRTI regimen that includes abacavir, tenofovir DF, and either lamivudine or emtricitabine or a triple NRTI regimen that includes tenofovir DF, didanosine, and either lamivudine or emtricitabine should not be used at any time in pediatric patients because of the high rate of early virologic failure reported in antiretroviral-naive adults.

For further information on treatment of HIV infection in pediatric patients,

Clinical Experience

Efficacy and safety of tenofovir DF in pediatric patients have been evaluated in a randomized study in 92 HIV-1-infected antiretroviral-experienced children 2 to less than 12 years of age (study 352). 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. 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 less than 400 copies/mL.

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/mm (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. 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.

Preexposure Prophylaxis for Prevention of HIV-1 Infection

The fixed combination containing emtricitabine and tenofovir DF (emtricitabine/tenofovir DF; Truvada) is used for preexposure prophylaxis (PrEP) in conjunction with safer sex practices to reduce the risk of sexually acquired HIV-1 infection in HIV-1-negative adults at high risk. The manufacturer states that this indication is based on clinical trials in men who have sex with men (MSM) at high risk for HIV-1 infection and in heterosexual HIV-serodiscordant couples.

Adults at high risk for HIV-1 infection 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 or more 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.

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

For additional information on PrEP,

Clinical Experience

Efficacy and safety of a once-daily regimen of emtricitabine/tenofovir DF for HIV-1 PrEP were evaluated in a multinational, randomized, double-blind, placebo-controlled, phase 3 trial (Preexposure Prophylaxis Initiative [iPrEx trial]; NCT00458393) that included 2499 HIV-seronegative men or transgender women (male at birth) who have sex with men and have evidence of high-risk behavior for HIV-1 infection. Study participants (mean age 27 years [range 18-67 years], 5% Asian, 9% black, 18% white, 72% Hispanic/Latino) were randomized to receive emtricitabine/tenofovir DF (single tablet containing 200 mg of emtricitabine and 300 mg of tenofovir DF once daily) or placebo in conjunction with usual prevention strategies (i.e., monthly HIV-1 testing, risk-reduction counseling, condoms, diagnosis and management of sexually transmitted infections) and were followed for 4237 person-years. The primary outcome measure was the incidence of documented HIV seroconversion. There was a 42% reduction in the risk of HIV-1 seroconversion in the group receiving emtricitabine/tenofovir DF (48 individuals receiving emtricitabine/tenofovir DF and 83 individuals receiving placebo seroconverted). Results of a post-hoc case-control study of plasma and intracellular drug concentrations in about 10% of study participants indicated that efficacy of emtricitabine/tenofovir DF PrEP is strongly correlated with adherence since risk reduction appeared to be greatest in those with detectable intracellular tenofovir.

Efficacy and safety of emtricitabine/tenofovir DF for PrEP in HIV-1-seronegative partners of serodiscordant heterosexual couples were evaluated in a randomized, double-blind, placebo-controlled, 3-arm trial (Partners Preexposure Prophylaxis [PrEP] trial; NCT00557245) that included 4758 serodiscordant couples in Kenya and Uganda. The infected partners had median plasma HIV-1 RNA levels of 3.9 log10 copies/mL and median CD4 T-cell counts of 495 cells/mm (80% had CD4 T-cell counts of 350 cells/mm or higher). The uninfected partners (mean age 33-34 years, 61-64% male) were randomized to receive emtricitabine/tenofovir DF (single tablet containing 200 mg of emtricitabine and 300 mg of tenofovir DF once daily), tenofovir DF (300 mg of tenofovir DF once daily), or placebo (once daily). Study participants received monthly HIV-1 testing, adherence evaluations, sexual behavior assessments, and safety evaluations. Women received monthly pregnancy tests; if pregnancy occurred, the study drug was interrupted during pregnancy and breast-feeding. After 7827 person-years of follow-up, there were a total of 82 emergent HIV-1 seroconversions (overall observed seroincidence rate of 1.05 per 100 person-years). The risk reduction for the emtricitabine/tenofovir DF group relative to the placebo group was 75%. There were 13 seroconversions in partners randomized to emtricitabine/tenofovir DF and 52 seroconversions in partners randomized to placebo (2 and 3 seroconversions, respectively, occurred during interruption of PrEP for pregnancy). Results of a post-hoc case-control study of plasma and drug concentrations in about 10% of study participants indicated that efficacy of emtricitabine/tenofovir DF PrEP is strongly correlated with adherence since risk reduction appeared to be greatest in those with detectable plasma tenofovir.

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.

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). These experts recommend several alternative regimens that include an INSTI, NNRTI, or PI and 2 NRTIs (dual NRTIs). 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.

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. However, initiation of PEP should not be delayed while waiting for expert consultation.

For information on types of occupational exposure to HIV and associated risk of infection, management of occupational exposure to HIV, efficacy and safety of postexposure prophylaxis, and recommendations regarding PEP,

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.

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). The alternative nPEP regimen recommended in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF (Truvada).

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. However, initiation of nPEP should not be delayed while waiting for expert consultation.

For additional information on nonoccupational exposure to HIV and recommendations regarding postexposure prophylaxis,

Chronic Hepatitis B Virus Infection

Tenofovir DF is used for the treatment of chronic HBV infection in adults and adolescents 12 years of age or older. This indication is based principally on data from adults with hepatitis B e antigen (HBeAg)-positive or -negative chronic HBV infection with compensated liver function who had not previously received a nucleoside antiviral (nucleoside-naive) or were treatment experienced with documented resistance to lamivudine.

Tenofovir DF has been evaluated in only a limited number of patients with chronic HBV infection and decompensated liver disease. Data are insufficient to evaluate efficacy of tenofovir DF in patients with adefovir resistance-associated substitutions at baseline.

The goal of antiviral therapy in patients with chronic HBV infection is to decrease the morbidity and mortality related to the infection (e.g., cirrhosis, hepatic failure, hepatocellular carcinoma). Sustained suppression of HBV replication has been associated with normalization of serum ALT concentrations, loss of hepatitis B e antigen (HBeAg) with or without detection of antibody to HBeAg (anti-HBe), and improvement in liver histology. Currently available therapies for chronic HBV infection (e.g., adefovir, entecavir, lamivudine, telbivudine, tenofovir DF, interferon alfa, peginterferon alfa) are used in an attempt to provide an immunologic cure (HBsAg loss and sustained HBV DNA suppression), but cannot provide a virologic cure (eradication of HBV).

Treatment of chronic HBV infection is complex and evolving, and specialized references should be consulted. Information from the American Association for the Study of Liver Diseases (AASLD) regarding management of chronic HBV infection is available at http://www.aasld.org.

HBeAg-Positive Adults

Study 0103

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-naive 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). Patients received tenofovir DF 300 mg once daily or adefovir dipivoxil 10 mg once daily. 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. After 48 weeks of treatment, all patients were eligible to receive open-label tenofovir DF with no interruption in treatment.

At 48 weeks, 67% of patients receiving tenofovir DF had serum HBV DNA levels less than 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. 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.

Through 384 weeks, 49% of patients originally randomized to tenofovir DF who subsequently received open-label tenofovir DF had HBV DNA levels less than 400 copies/mL, 42% had ALT normalization, 20% had HBeAg loss, and 13% had HBeAg seroconversion. In patients originally randomized to adefovir who subsequently received open-label tenofovir DF, 56% had HBV DNA levels less than 400 copies/mL, 50% had ALT normalization, 28% had HBeAg loss, and 19% had HBeAg seroconversion through 384 weeks. 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.

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. The observed histological response rates in these patients were 80 and 88% at week 48 and 240, respectively. 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.

HBeAg-Negative Adults

Study 0102

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). Patients received tenofovir DF 300 mg once daily or adefovir dipivoxil 10 mg once daily for 48 weeks. 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). After 48 weeks of treatment, all patients were eligible to receive open-label tenofovir DF with no interruption in treatment.

At 48 weeks, 71% of patients receiving tenofovir DF had serum HBV DNA levels less than 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.

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

Lamivudine-resistant Chronic HBV

Study 121

Efficacy and safety of tenofovir DF for treatment of chronic HBV infection in adults with persistent viremia and genotypic evidence of lamivudine resistance were evaluated in a randomized, double-blind, active-controlled trial. Of the 141 adults randomized to receive tenofovir DF, mean age was 47 years, 74% were male, 59% were Caucasian, 37% were Asian, and mean baseline plasma HBV DNA was 6.4 log10 copies/mL. At baseline, 54% were HBeAg-negative, 46% were HBeAg-positive, and 56% had abnormal ALT. 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. 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.

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

Decompensated Liver Disease

Study 0108

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). At baseline, 69% of patients were HBeAg-negative and 31% were HBeAg-positive and 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.

At 48 weeks, 70% of patients receiving tenofovir DF had HBV DNA levels less than 400 copies/mL and 46% had ALT normalization. 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.

HIV-infected Individuals

Because of the risk of development of HIV-1 resistance, tenofovir DF should not be used for treatment of chronic HBV infection in HIV-infected individuals who are not currently receiving antiretroviral therapy.

HIV-infected patients coinfected with HBV often have higher HBV viral loads and are more likely to have detectable HBeAg, lower rates of HBeAg seroconversion, and an increased risk for and more rapid progression to cirrhosis, end-stage liver disease, and/or hepatocellular carcinoma compared with individuals not infected with HIV. Decisions to initiate HBV treatment in patients coinfected with HIV and HBV and the most appropriate drugs for HBV treatment in such patients depend on various factors, including the possible effects on replication of both HIV and HBV and whether the patient is currently receiving antiretroviral therapy. Specialized references should be consulted for specific information regarding the evaluation and management of chronic HBV infection in HIV-infected patients.

Dosage and Administration

Administration

Tenofovir disoproxil fumarate (tenofovir DF) is administered orally once daily without regard to meals.

Single-entity tenofovir DF (Viread) is commercially available as tablets or oral powder.

Tenofovir DF oral powder contains 40 mg of tenofovir DF per g. The appropriate dosage of the oral powder should be measured using only the scoop provided by the manufacturer. The required number of scoops of the powder should be mixed with 2-4 ounces of soft food that can be swallowed without chewing (e.g., applesauce, baby food, yogurt), and the entire mixture immediately ingested to avoid a bitter taste. The oral powder should not be administered in a liquid since the powder may float to the top, even after stirring.

Single-entity tenofovir DF should not be used concomitantly with any other tenofovir-containing preparation.

Fixed Combinations Containing Tenofovir

Tenofovir DF is commercially available in fixed-combination tablets containing emtricitabine and tenofovir DF (emtricitabine/tenofovir DF; Truvada), fixed-combination tablets containing efavirenz, emtricitabine, and tenofovir DF (efavirenz/emtricitabine/tenofovir DF; Atripla), and fixed-combination tablets containing emtricitabine, rilpivirine, and tenofovir DF (emtricitabine/rilpivirine/tenofovir DF; Complera). In addition, tenofovir DF is commercially available in fixed-combination tablets containing elvitegravir, cobicistat, emtricitabine, and tenofovir DF (EVG/c/FTC/TDF; Stribild). For information on EVG/c/FTC/TDF), see

Emtricitabine/tenofovir DF (Truvada) tablets are administered orally once daily without regard to meals. A fixed-combination tablet containing 200 mg of emtricitabine and 300 mg of tenofovir DF is bioequivalent to a 200-mg capsule of emtricitabine and a 300-mg tablet of tenofovir DF given simultaneously. For the treatment of human immunodeficiency virus type 1 (HIV-1) infection, emtricitabine/tenofovir DF is used in conjunction with other antiretrovirals. For preexposure prophylaxis (PrEP) for prevention of HIV-1 infection, emtricitabine/tenofovir DF is used alone without any other antiretroviral.

Efavirenz/emtricitabine/tenofovir DF (Atripla) tablets are administered orally once daily on an empty stomach, preferably at bedtime. Administration at bedtime may make efavirenz-related adverse CNS effects more tolerable. A fixed-combination tablet containing 600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir DF is bioequivalent to a 600-mg tablet of efavirenz, 200-mg capsule of emtricitabine, and 300-mg tablet of tenofovir DF when taken in the fasting state. The fixed combination can be used alone as a complete regimen or used in conjunction with other antiretrovirals.

Emtricitabine/rilpivirine/tenofovir DF (Complera) tablets are administered orally once daily with a meal. A fixed-combination tablet containing 200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir DF taken with a meal is bioequivalent to a 200-mg emtricitabine capsule, 25-mg rilpivirine tablet, and 300-mg tenofovir DF tablet taken simultaneously with a meal. The fixed combination can be used alone as a complete treatment regimen.

Because the antiretroviral agents contained in the fixed combination preparations also may be available in single-entity or other fixed-combination preparations, care should be taken to ensure that therapy is not duplicated if a fixed combination is used in conjunction with other antiretrovirals.(See Precautions Related to Use of Fixed Combinations under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Dosage

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

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

Adult Dosage

Treatment of HIV Infection

For the treatment of HIV-1 infection in adults, the usual dosage of tenofovir DF (Viread) is 300 mg (one 300-mg tablet) once daily. Adults unable to swallow tablets can receive 300 mg once daily as the oral powder containing 40 mg of tenofovir DF per g (7.5 scoops of the powder using the scoop supplied by the manufacturer).

When emtricitabine/tenofovir DF (Truvada) is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection, adults should receive 1 tablet (200 mg of emtricitabine and 300 mg of tenofovir DF) once daily.

When efavirenz/emtricitabine/tenofovir DF (Atripla) is used for the treatment of HIV-1 infection, adults should receive 1 tablet (600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir DF) once daily.

When emtricitabine/rilpivirine/tenofovir DF (Complera) is used for the treatment of HIV-1 infection, adults should receive 1 tablet (200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir DF) once daily.

Preexposure Prophylaxis for Prevention of HIV-1 Infection

When emtricitabine/tenofovir DF (Truvada) is used for preexposure prophylaxis (PrEP) for prevention of HIV-1 infection in HIV-1-negative adults at high risk, the recommended dosage is 1 tablet (200 mg of emtricitabine and 300 mg of tenofovir DF) once daily.

PrEP should only be used in high-risk adults (see Uses: Preexposure Prophylaxis for Prevention of HIV-1 Infection) with confirmed HIV-1-negative status. PrEP should not be initiated if signs or symptoms of acute HIV-1 infection are present and recent (within the past month) exposure to HIV-1 is suspected.(See Precautions Related to HIV-1 Preexposure Prophylaxis [PrEP] under Cautions: Warnings/Precautions.)

Postexposure Prophylaxis following Occupational Exposure to HIV

For postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel or other individuals, the recommended dosage of tenofovir DF (Viread) is 300 mg once daily. Tenofovir DF usually is used with emtricitabine or lamivudine in conjunction with a recommended HIV integrase strand transferase inhibitor (INSTI), HIV nonnucleoside reverse transcriptase inhibitor (NNRTI), or HIV protease inhibitor (PI).(See Uses: Postexposure Prophylaxis following Occupational Exposure to HIV.)

When emtricitabine/tenofovir DF (Truvada) is used as the dual NRTI option in PEP regimens, adults should receive 1 tablet (200 mg of emtricitabine and 300 mg of tenofovir DF) once daily in conjunction with a recommended INSTI, NNRTI, or PI.(See Uses: Postexposure Prophylaxis following Occupational Exposure to HIV.)

When emtricitabine/rilpivirine/tenofovir DF (Complera) is used as a complete regimen for PEP, adults should receive 1 tablet (200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir DF) once daily.

The PEP regimen should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 4 weeks, if tolerated.

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

For postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP) when the exposure represents a substantial risk for HIV transmission, the usual adult dosage of tenofovir DF (Viread) is 300 mg once daily in conjunction with other antiretrovirals. Tenofovir DF usually is used in conjunction with emtricitabine and a recommended or alternative INSTI, PI, or NNRTI.(See Uses: Postexposure Prophylaxis following Nonoccupational Exposure to HIV.)

When emtricitabine/tenofovir DF (Truvada) is used as the dual NRTI option in nPEP regimens, adults should receive 1 tablet (200 mg of emtricitabine and 300 mg of tenofovir DF) once daily in conjunction with a preferred or alternative INSTI, PI, or NNRTI.

When emtricitabine/rilpivirine/tenofovir DF (Complera) is used as a complete regimen for nPEP, adults should receive 1 tablet (200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir DF) once daily.

The nPEP regimen should be initiated as soon as possible (within 72 hours) following nonoccupational exposure to HIV and continued for 28 days. If the exposed individual seeks care more than 72 hours after the exposure, nPEP is not recommended.

Chronic Hepatitis B Virus Infection

For the treatment of chronic hepatitis B virus (HBV) infection in adults, the usual dosage of tenofovir DF is 300 mg once daily. The optimum duration of tenofovir DF therapy in patients with chronic HBV infection is not known.

Pediatric Dosage

Treatment of HIV Infection

For the treatment of HIV-1 infection in pediatric patients 2 to less than 12 years of age, the usual dosage of tenofovir DF (Viread) is 8 mg/kg (up to 300 mg) once daily as a tablet or oral powder. In pediatric patients 2 years of age or older weighing 17 kg or more who can reliably swallow tablets, a single tablet containing the appropriate dosage should be given once daily (see Table 1). When the oral powder is used, the required number of scoops of the powder should be administered once daily (see Table 2).

For the treatment of HIV-1 infection in adolescents 12 years of age or older weighing at least 35 kg, the usual dosage of tenofovir DF is 300 mg (one 300-mg tablet) once daily. Patients unable to swallow tablets can receive 300 mg once daily as the oral powder containing 40 mg of tenofovir DF per g (7.5 scoops of the powder using the scoop supplied by the manufacturer).

Table 1. Tenofovir DF Dosage (Viread® Tablets) for Treatment of HIV-1 Infection in Pediatric Patients 2 Years of Age or Older Weighing 17 kg or More[1 ]
Weight (kg) Dosage (as Tablets) Once Daily
17 to less than 22 150 mg
22 to less than 28 200 mg
28 to less than 35 250 mg
35 or more 300 mg
Table 2. Tenofovir DF Dosage (Viread® Oral Powder) for Treatment of HIV-1 Infection in Pediatric Patients 2 Years of Age or Older[1 ]
Weight (kg) Dosage (as Oral Powder) Once Daily (40 mg of Tenofovir DF per Scoop)
10 to less than 12 80 mg (2 scoops)
12 to less than 14 100 mg (2.5 scoops)
14 to less than 17 120 mg (3 scoops)
17 to less than 19 140 mg (3.5 scoops)
19 to less than 22 160 mg (4 scoops)
22 to less than 24 180 mg (4.5 scoops)
24 to less than 27 200 mg (5 scoops)
27 to less than 29 220 mg (5.5 scoops)
29 to less than 32 240 mg (6 scoops)
32 to less than 34 260 mg (6.5 scoops)
34 to less than 35 280 mg (7 scoops)
35 or more 300 mg (7.5 scoops)

When emtricitabine/tenofovir DF (Truvada) is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection in children weighing at least 35 kg, the recommended dosage is 1 tablet (200 mg of emtricitabine and 300 mg of tenofovir DF) once daily. When emtricitabine/tenofovir DF is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection in children weighing 17 to less than 35 kg who are able to swallow a tablet, recommended dosage is based on weight and a low-strength fixed-combination tablet of the drug should be used.(See Table 3.)

Table 3. Emtricitabine/Tenofovir DF (Truvada®) Dosage for Treatment of HIV-1 Infection in Children Weighing 17 kg or More[230 ]
Weight (kg) Dosage of Emtricitabine/Tenofovir DF Given Once Daily
17 to less than 22 kg 1 tablet (100 mg of emtricitabine and 150 mg of tenofovir DF)
22 to less than 28 kg 1 tablet (133 mg of emtricitabine and 200 mg of tenofovir DF)
28 to less than 35 kg 1 tablet (167 mg of emtricitabine and 250 mg of tenofovir DF)
35 kg or more 1 tablet (200 mg of emtricitabine and 300 mg of tenofovir DF)

When efavirenz/emtricitabine/tenofovir DF (Atripla) is used for the treatment of HIV-1 infection in adolescents 12 years of age or older weighing at least 40 kg, the recommended dosage is 1 tablet (600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir DF) once daily.

When emtricitabine/rilpivirine/tenofovir DF (Complera) is used for the treatment of HIV-1 infection in adolescents 12 years of age or older weighing at least 35 kg, the usual dosage is 1 tablet (200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir DF) once daily.

Chronic Hepatitis B Virus Infection

For the treatment of chronic hepatitis B virus (HBV) infection in adolescents 12 years of age or older weighing at least 35 kg, the usual dosage of tenofovir DF is 300 mg once daily. The optimum duration of tenofovir DF therapy in patients with chronic HBV infection is not known.

Special Populations

Hepatic Impairment

Dosage adjustments are not necessary when tenofovir DF (Viread) is used for the treatment of HIV-1 infection or treatment of chronic HBV infection in patients with hepatic impairment.

Emtricitabine/tenofovir DF (Truvada) has not been studied in patients with hepatic impairment.

When efavirenz/emtricitabine/tenofovir DF (Atripla) is used for the treatment of HIV-1 infection, usual dosage can be used in patients with mild hepatic impairment; however, caution is advised. The fixed combination is not recommended in those with moderate or severe hepatic impairment.

When emtricitabine/rilpivirine/tenofovir DF (Complera) is used for the treatment of HIV-1 infection in patients with mild or moderate hepatic impairment (Child-Pugh class A or B), usual dosage can be used; the fixed combination has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

When tenofovir DF (Viread) is used for the treatment of HIV-1 infection in adults, dosage adjustments are not necessary in those with mild renal impairment (creatinine clearance 50-80 mL/minute), but calculated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be monitored. Dosage of the drug should be adjusted in adults with creatinine clearances less than 50 mL/minute (see Table 4). Because safety and efficacy of these dosages have not been evaluated in clinical studies, clinical response to treatment and renal function should be closely monitored. The manufacturer states that dosage recommendations cannot be made for adults with creatinine clearances less than 10 mL/minute who are not undergoing hemodialysis since the pharmacokinetics of the drug have not been studied in such patients. The manufacturer states that data are not available to make to dosage recommendations for pediatric patients with renal impairment.

Table 4. Tenofovir DF (Viread®) Dosage for Treatment of HIV-1 Infection in Adults with Renal Impairment[1 ]
Creatinine Clearance (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

When emtricitabine/tenofovir DF (Truvada) is used for the treatment of HIV-1 infection in adults, usual dosage can be used in those with mild renal impairment (creatinine clearance 50-80 mL/minute), but calculated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be monitored. If the fixed combination is used in adults with creatinine clearance of 30-49 mL/minute, dosage should be reduced to 1 tablet (200 mg of emtricitabine and 300 mg of tenofovir DF) once every 48 hours; clinical response and renal function should be monitored since dosage has not been evaluated clinically. Emtricitabine/tenofovir DF should not be used in adults with creatinine clearances less than 30 mL/minute (including hemodialysis patients). Data are insufficient to make dosage recommendations for the fixed combination for treatment of HIV-1 infection in pediatric patients with renal impairment.

When emtricitabine/tenofovir DF is used for PrEP for prevention of HIV-1 infection in HIV-1-negative adults at high risk, usual dosage can be used in those with creatinine clearances of 60 mL/minute or greater, but calculated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be monitored. If creatinine clearance decreases while emtricitabine/tenofovir DF is being used for PrEP, potential causes should be evaluated and potential risks and benefits of continued use should be reassessed. Emtricitabine/tenofovir DF should not be used for PrEP in adults with creatinine clearances less than 60 mL/minute.

When efavirenz/emtricitabine/tenofovir DF (Atripla) is used for the treatment of HIV-1 infection, usual dosage can be used in patients with creatinine clearances of 50 mL/minute or greater. The fixed combination should not be used in those with moderate or severe renal impairment (estimated creatinine clearances less than 50 mL/minute).

Emtricitabine/rilpivirine/tenofovir DF (Complera) should not be used in patients with renal impairment that is moderate, severe, or end-stage (estimated creatinine clearance less than 50 mL/minute) or requires dialysis.

Cautions

Contraindications

The manufacturer states that there are no known contraindications to the use of tenofovir disoproxil fumarate (tenofovir DF).

The fixed combination containing emtricitabine and tenofovir DF (emtricitabine/tenofovir DF; Truvada) should not be used alone for treatment of human immunodeficiency virus type 1 (HIV-1) infection and should not be used for preexposure prophylaxis of HIV-1 infection in individuals with unknown or positive HIV-1 status.(See Precautions Related to HIV-1 Preexposure Prophylaxis under Warnings/Precautions: Warnings, in Cautions.)

The fixed combination containing efavirenz, emtricitabine, and tenofovir DF (efavirenz/emtricitabine/tenofovir DF; Atripla) is contraindicated in patients who have had a clinically important hypersensitivity reaction (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic skin eruption) to efavirenz; because of the efavirenz component, concomitant use of this fixed combination and voriconazole is contraindicated.

Concomitant use of the fixed combination containing emtricitabine, rilpivirine, and tenofovir DF (emtricitabine/rilpivirine/tenofovir DF; Complera) and certain drugs that induce cytochrome P-450 isoenzyme 3A (CYP3A) or drugs that elevate gastric pH is contraindicated because of the rilpivirine component; substantially decreased plasma concentrations of rilpivirine may occur and may result in loss of virologic response and development of resistance to rilpivirine and/or class resistance to human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitors (NNRTIs).

When emtricitabine/tenofovir DF, efavirenz/emtricitabine/tenofovir DF, or emtricitabine/rilpivirine/tenofovir DF is used, the contraindications associated with each of the individual components should be considered.(See Precautions Related to Use of Fixed Combinations under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Warnings/Precautions

Warnings

Hepatic Effects and Lactic Acidosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported in patients receiving HIV nucleoside reverse transcriptase inhibitors (NRTIs), including tenofovir DF, in conjunction with other antiretroviral agents. Most reported cases have involved women; obesity and long-term therapy with an NRTI also may be risk factors.

Caution should be observed when NRTIs are used in patients with known risk factors for liver disease; however, lactic acidosis and severe hepatomegaly with steatosis have been reported in patients with no known risk factors. Tenofovir DF (single-entity or fixed-combination preparations) should be discontinued in any patient with clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (signs of hepatotoxicity include hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).

Individuals with Hepatitis B Virus Infection

Prior to initiating tenofovir DF (single-entity or fixed-combination preparations) for treatment of HIV-1 infection, the patient should be tested for chronic hepatitis B virus (HBV).

Prior to initiation of tenofovir DF for treatment of chronic hepatitis B virus (HBV) infection, all patients should be offered HIV-1 testing.

In HIV-infected patients coinfected with HBV, tenofovir DF should be used in conjunction with other highly active antiretroviral agents. When selecting components of an antiretroviral regimen for HIV-infected patients coinfected with HBV, some experts state that tenofovir DF and emtricitabine (or lamivudine) are preferred dual NRTI options in such patients since these antiretrovirals have activity against both HIV and HBV.

Severe acute exacerbations of hepatitis have occurred following discontinuance of HBV therapy, including tenofovir DF therapy, in patients with HBV infection.

Hepatic function should be closely monitored with clinical and laboratory follow-up for at least several months after tenofovir DF is discontinued. If appropriate, resumption of anti-HBV therapy may be warranted.

Precautions Related to HIV-1 Preexposure Prophylaxis

Emtricitabine/tenofovir DF (Truvada) should be used for HIV-1 PrEP only in HIV-1-negative adults at high risk.

A negative HIV-1 test should be confirmed immediately prior to initiation of emtricitabine/tenofovir DF for HIV-1 PrEP and screening for HIV-1 infection should be performed at least once every 3 months during PrEP. Individuals also should be tested for HBV prior to initiation of emtricitabine/tenofovir DF PrEP.(See Individuals with Hepatitis B Virus Infection under Cautions: Warnings/Precautions.)

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

Emtricitabine/tenofovir DF PrEP must be used as part of a comprehensive HIV prevention strategy that includes other prevention measures (e.g., safer sex practices). (See REMS.) All uninfected individuals should be counseled 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). All HIV-negative individuals should be informed about and supported in their efforts to reduce sexual risk behavior.

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

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

If clinical symptoms consistent with acute viral infection are present and recent (within 1 month) exposures to HIV-1 are suspected, initiation of PrEP should be delayed for at least 1 month and HIV-1 status reconfirmed or a test approved by the US Food and Drug Administration (FDA) for use as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection, should be used.

During emtricitabine/tenofovir DF PrEP, if symptoms consistent with acute HIV-1 infection develop following a potential exposure event, the drugs should be discontinued 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.

Uninfected individuals should be counseled to strictly adhere to the recommended emtricitabine/tenofovir DF dosage schedule (see Preexposure Prophylaxis for Prevention of HIV-1 Infection under Dosage: Adult Dosage, in Dosage and Administration). Effectiveness of the fixed combination in reducing the risk of acquiring HIV-1 is strongly correlated with adherence as demonstrated by measurable drug concentrations in clinical trials.

Adverse effects reported in HIV-negative adults receiving emtricitabine/tenofovir DF PrEP are similar to those reported in HIV-infected patients receiving the drugs for treatment of HIV-1 infection.

Other Warnings/Precautions

Renal Toxicity

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.

Creatinine clearance should be calculated in all patients prior to and as clinically indicated during tenofovir DF therapy. Calculated creatinine clearance and serum phosphorus, urine glucose, and urine protein concentrations should be monitored prior to and periodically during tenofovir DF therapy in patients at risk for renal dysfunction, including those who had adverse renal effects while receiving adefovir dipivoxil.

Use of tenofovir DF should be avoided in patients who are receiving or have recently received nephrotoxic drugs (e.g., high-dose or multiple nonsteroidal anti-inflammatory agents [NSAIAs]). 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. Some cases required hospitalization and renal replacement therapy. Alternatives to NSAIAs should be considered in patients at risk for renal dysfunction. 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), renal function should be promptly evaluated.

Evidence of renal toxicity was reported in animal studies (increases in serum creatinine or BUN, glycosuria, proteinuria, phosphaturia, calciuria, decreases in serum phosphate); the relationship of renal abnormalities, particularly phosphaturia, to bone toxicity in animals is unknown.

Precautions Related to Use of Fixed Combinations

When emtricitabine/tenofovir DF, efavirenz/emtricitabine/tenofovir DF, or emtricitabine/rilpivirine/tenofovir DF is used, the usual cautions, precautions, contraindications, and drug interactions associated with each drug in the fixed combination must be considered. Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug. For cautionary information related to , , and , see Cautions in the individual drug monographs.

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

Multiple tenofovir-containing preparations should not be used concomitantly.

Preparations containing tenofovir DF should not be used concomitantly with adefovir dipivoxil. In addition, because of similarities between emtricitabine and lamivudine, fixed combinations containing emtricitabine should not be used concomitantly with any preparation containing lamivudine.

Bone Effects

In one clinical study (study 903), decreases from baseline in bone mineral density (BMD) at the lumbar spine, increases in levels of 4 biochemical markers of bone metabolism, increased serum parathyroid hormone levels, and increased 1,25 vitamin D levels were reported in HIV-infected adults receiving tenofovir DF concomitantly with lamivudine and efavirenz; these effects also were reported to a lesser extent in patients who received a regimen of stavudine, lamivudine, and efavirenz. With the exception of bone-specific alkaline phosphatase concentrations, these changes generally remained within the normal range. There were 4 bone fractures reported in patients receiving the regimen that contained tenofovir DF and 6 reported in those receiving the regimen that did not include tenofovir DF.

In 2 clinical studies (study 321 and study 352) in HIV-1-infected pediatric patients, effects on bone were similar to those observed in adults, suggesting increased bone turnover. Similar trends were observed in HBV-infected pediatric patients 12 to less than 18 years of age. In all pediatric studies, skeletal growth appeared to be unaffected.

The clinical importance of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and fracture risk are unknown. BMD monitoring should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of calcium and vitamin D supplementation was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected, appropriate consultation should be obtained.

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. 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.

Osteomalacia and decreases in BMD have been reported in toxicology studies in juvenile animals given high doses of tenofovir.

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (''buffalo hump''), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance, has been reported with antiretroviral therapy. The mechanisms responsible for these adipogenic effects and the long-term consequences of these effects are unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome

During the initial phase of treatment, HIV-infected patients 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.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barre 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.

Early Virologic Failure in HIV Infection

Triple NRTI regimens have less potent virologic activity than comparator HIV nonnucleoside reverse transcriptase (NNRTI)-based or HIV protease inhibitor (PI)-based regimens. Triple NRTI regimens are associated with early virologic failure and high rates of resistance. These regimens should be used with caution. Patients should be carefully monitored and consideration given to modifying the regimen.

Specific Populations

Pregnancy

Tenofovir DF (Viread): Category B.

Emtricitabine/tenofovir DF (Truvada): Category B.

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

Emtricitabine/rilpivirine/tenofovir DF (Complera): Category B.

Antiretroviral Pregnancy Registry at 800-258-4263 or http://www.APRegistry.com.

The US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that tenofovir DF and either emtricitabine or lamivudine is a preferred dual NRTI option for use in conjunction with an HIV integrase strand transferase inhibitor (INSTI), NNRTI, or PI for initial treatment of HIV-1 infection in antiretroviral-naive pregnant women, and is a preferred dual NRTI option in pregnant women coinfected with HBV.

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

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

Lactation

Tenofovir is distributed into human milk in low concentrations.

Because of the risk of adverse effects in the infant and the risk of HIV transmission, HIV-infected women should not breast-feed infants.

Pediatric Use

Safety and efficacy of tenofovir DF (Viread) have not been established in HIV-1-infected children younger than 2 years of age. Safety and efficacy of tenofovir DF (Viread) for treatment of chronic HBV infection have not been established in children younger than 12 years of age weighing less than 35 kg.

Safety and efficacy of emtricitabine/tenofovir DF (Truvada) for treatment of HIV-1 infection have not been established in pediatric patients weighing less than 17 kg; safety and efficacy of this fixed combination for HIV-1 PrEP have not been established in pediatric patients.

Efavirenz/emtricitabine/tenofovir DF (Atripla) should not be used in pediatric patients younger than 12 years of age or weighing less than 40 kg. Safety and efficacy of emtricitabine/rilpivirine/tenofovir DF (Complera) have not been established in pediatric patients younger than 12 years of age or weighing less than 35 kg.

Geriatric Use

Experience in those 65 years of age or older is insufficient to determine whether they respond differently to tenofovir DF (single-entity or fixed-combination preparations) than younger adults. Dosage should be selected with caution because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or drug therapy observed in geriatric individuals.

Hepatic Impairment

Limited data indicate that the pharmacokinetics of tenofovir are not substantially altered in patients with moderate or severe hepatic impairment.(See Hepatic Impairment under Dosage and Administration: Special Populations.)

Emtricitabine/tenofovir DF (Truvada) has not been studied in patients with hepatic impairment. Hepatic impairment does not have a substantial effect on tenofovir DF pharmacokinetics and is expected to have a minimal effect on emtricitabine pharmacokinetics.

Efavirenz/emtricitabine/tenofovir DF (Atripla) is not recommended in patients with moderate or severe hepatic impairment.

Emtricitabine/rilpivirine/tenofovir DF (Complera) has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

Tenofovir is principally eliminated by the kidney and the pharmacokinetics of the drug are likely to be affected by renal impairment. Dosage adjustments are necessary if tenofovir DF is used in patients with moderate or severe renal impairment.(See Renal Impairment under Dosage and Administration: Special Populations.)

Emtricitabine/tenofovir DF (Truvada) should not be used for treatment of HIV-1 infection in patients with creatinine clearance less than 30 mL/minute or in those with end-stage renal disease requiring dialysis; dosage adjustments are necessary when the drug is used for treatment of HIV-1 infection in those with creatinine clearance 30-49 mL/minute. Emtricitabine/tenofovir DF should not be used for PrEP in HIV-1 uninfected adults with creatinine clearances less than 60 mL/minute. If creatinine clearance decreases while emtricitabine/tenofovir DF is being used for PrEP, potential causes should be evaluated and potential risks and benefits of continued use should be reassessed.

Efavirenz/emtricitabine/tenofovir DF (Atripla) should not be used in patients with moderate or severe renal impairment (estimated creatinine clearances less than 50 mL/minute).

Emtricitabine/rilpivirine/tenofovir DF (Complera) should not be used in patients with renal impairment that is moderate, severe, or end-stage (estimated creatinine clearance less than 50 mL/minute) or requires dialysis.

Common Adverse Effects

The most common adverse effects in HIV-infected patients receiving tenofovir DF are rash, diarrhea, headache, pain, depression, asthenia, and nausea.

The most common adverse effects in patients with chronic HBV infection receiving tenofovir DF are GI effects (abdominal pain, nausea, vomiting, diarrhea), headache, insomnia, dizziness, fatigue, rash, pruritus, nasopharyngitis, back pain, and fever.

Drug Interactions

The following drug interactions are based on studies using tenofovir disoproxil fumarate (tenofovir DF).

Drug interaction studies have also been performed using the fixed combination containing efavirenz, emtricitabine, and tenofovir DF (efavirenz/emtricitabine/tenofovir DF; Atripla) or the fixed combination containing emtricitabine, rilpivirine, and tenofovir DF (emtricitabine/rilpivirine/tenofovir DF; Complera). When a fixed combination is used, interactions associated with each drug in the fixed combination should be considered.

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. 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.

Drugs Affecting P-glycoprotein Transport

Tenofovir DF is a substrate of the P-glycoprotein (P-gp) transport system. Pharmacokinetic interactions are possible with inhibitors of P-gp (increased absorption of tenofovir DF).

Drugs Affecting Breast Cancer Resistance Protein

Tenofovir DF is a substrate of breast cancer resistance protein (BCRP). Pharmacokinetic interactions are possible with inhibitors of BCRP (increased absorption of tenofovir DF).

Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion

Potential pharmacokinetic interaction between tenofovir and drugs that reduce renal function or that may compete with tenofovir 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]); increased plasma concentrations of tenofovir and/or the concomitantly administered drug may occur.

Adefovir Dipivoxil

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

Tenofovir DF and adefovir dipivoxil should not be used concomitantly.

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Maraviroc

No in vitro evidence of antagonistic antiretroviral effects between maraviroc and tenofovir DF.

Tenofovir DF does not affect the pharmacokinetics of maraviroc.

HIV Integrase Inhibitors (INSTIs)

Dolutegravir

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

Dosage adjustments are not needed if dolutegravir is used concomitantly with tenofovir DF.

Raltegravir

In vitro evidence of additive to synergistic antiretroviral effects between raltegravir and tenofovir DF.

Pharmacokinetic interaction with raltegravir (increased raltegravir plasma concentrations and area under the concentration-time curve [AUC]; no clinically important effect on tenofovir pharmacokinetics). This interaction is not considered clinically important. Dosage adjustments are not needed if raltegravir is used concomitantly with tenofovir DF.

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

No in vitro evidence of antagonistic antiretroviral effects between tenofovir and NNRTIs (delavirdine, efavirenz, etravirine, nevirapine, rilpivirine).

Efavirenz

Concomitant use of tenofovir DF and efavirenz does not affect plasma concentrations or AUC of either drug.

Dosage adjustments are not needed if efavirenz and tenofovir DF are used concomitantly.

Etravirine

Pharmacokinetic interaction with etravirine (decreased etravirine plasma concentrations and AUC; no clinically important effect on tenofovir plasma concentrations and AUC).

Dosage adjustments are not needed for either drug if etravirine and tenofovir DF are used concomitantly.

Rilpivirine

Concomitant use of tenofovir DF and rilpivirine has resulted in increased tenofovir plasma concentrations and AUC, but did not have any clinically important effects on rilpivirine plasma concentrations or AUC.

Dosage adjustments are not needed if rilpivirine and tenofovir DF are used concomitantly.

HIV Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

In vitro evidence of additive to synergistic antiretroviral effects between tenofovir and emtricitabine. No in vitro evidence of antagonistic antiretroviral effects between tenofovir and NRTIs (abacavir, didanosine, lamivudine, stavudine, zidovudine).

Abacavir

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

Didanosine

Depending on the specific didanosine dosage used, concomitant use of buffered didanosine (Videx) or delayed-release capsules containing enteric-coated pellets of didanosine (Videx EC) and tenofovir DF results in substantially increased didanosine plasma concentrations and AUC, but does not affect tenofovir pharmacokinetics. The mechanism of this interaction is unknown. Concomitant use of the drugs potentially could lead to didanosine-associated adverse effects (e.g., pancreatitis, lactic acidosis, neuropathy); concomitant use also has been associated with early virologic failure, rapid selection of resistant mutations, and immunologic nonresponse or decline in CD4 T-cell count.

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.

Concomitant use of didanosine and tenofovir DF should be avoided, and some experts state that didanosine and tenofovir DF should not be used concomitantly at any time.(See Dual NRTI Options under Treatment of HIV Infection: Antiretroviral-naive Adults and Adolescents, in Uses.) If didanosine and tenofovir DF are used concomitantly, the manufacturers recommend that a reduced didanosine dosage be used with caution and close monitoring for didanosine-associated adverse effects; didanosine should be discontinued if didanosine-associated adverse effects occur.

If didanosine delayed-release capsules are used with tenofovir DF, didanosine dosage should be decreased to 250 mg once daily in those weighing 60 kg or more with creatinine clearances of 60 mL/minute or greater or 200 mg once daily in those weighing less than 60 kg with creatinine clearances of 60 mL/minute or greater. Didanosine delayed-release capsules and tenofovir DF should be taken at the same time with a light meal (no more than 400 kcal, no more than 20% fat) or in the fasted state. The appropriate didanosine dosage in patients with creatinine clearance less than 60 mL/minute receiving tenofovir DF has not been established.

Emtricitabine

No clinically important pharmacokinetic interactions between emtricitabine and tenofovir DF.

Lamivudine

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

HIV Protease Inhibitors (PIs)

In vitro evidence of additive antiretroviral effects between tenofovir DF and tipranavir. No in vitro evidence of antagonistic antiretroviral effects between tenofovir DF and HIV PIs (amprenavir, atazanavir, darunavir, indinavir, nelfinavir, ritonavir, saquinavir).

Atazanavir

Pharmacokinetic interaction between tenofovir DF and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (decreased atazanavir plasma concentrations and AUC; increased tenofovir plasma concentrations and AUC and possible increased risk of tenofovir-associated adverse effects, including renal disorders).

Tenofovir DF and unboosted atazanavir (without low-dose ritonavir or cobicistat) should not be used concomitantly.

If tenofovir DF and ritonavir-boosted atazanavir are used concomitantly, a regimen of atazanavir 300 mg, ritonavir 100 mg, and tenofovir DF 300 mg given once daily with food is recommended. Patients should be monitored for tenofovir toxicity; tenofovir DF should be discontinued if tenofovir-associated adverse effects occur.

If tenofovir DF and cobicistat-boosted atazanavir are used concomitantly, a regimen of atazanavir 300 mg, cobicistat 150 mg, and tenofovir DF 300 mg once daily with food is recommended. Patients should be monitored for tenofovir toxicity. Concomitant use of cobicistat-boosted atazanavir and tenofovir DF is not recommended in patients with estimated creatinine clearances less than 70 mL/minute.

If ritonavir-boosted atazanavir is used concomitantly with tenofovir DF and a histamine H2-receptor antagonist in antiretroviral-experienced adults, the recommended dosage is atazanavir 400 mg, ritonavir 100 mg, and tenofovir DF 300 mg once daily with food. Patients should be monitored for tenofovir toxicity.

If cobicistat-boosted atazanavir is used concomitantly with tenofovir DF and a histamine H2-receptor antagonist in antiretroviral-experienced adults, the recommended dosage is atazanavir 400 mg, cobicistat 150 mg, and tenofovir DF 300 mg once daily with food. Patients should be monitored for tenofovir toxicity.

Darunavir

Pharmacokinetic interactions with ritonavir-boosted darunavir (increased tenofovir plasma concentrations and AUC; increased darunavir plasma concentrations and AUC). Possible pharmacokinetic interactions with cobicistat-boosted darunavir (increased tenofovir plasma concentrations).

The manufacturer of darunavir states that the usual dosage of ritonavir-boosted darunavir can be used concomitantly with the usual dosage of tenofovir DF. Some experts state that the clinical importance of increased tenofovir DF exposures is unknown, and patients receiving ritonavir-boosted darunavir concomitantly with tenofovir DF should be monitored for tenofovir toxicity.

If tenofovir DF is used concomitantly with cobicistat-boosted darunavir, patients should be monitored for tenofovir toxicity. Concomitant use of cobicistat-boosted darunavir with tenofovir DF is not recommended in patients with estimated creatinine clearances less than 70 mL/minute.

Indinavir

Pharmacokinetic interaction with indinavir (14% increase in peak plasma concentration of tenofovir; 11% decrease in peak plasma concentration of indinavir; no change in AUC of either drug).

Lopinavir

Pharmacokinetic interaction with the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) (increased tenofovir AUC; no change in lopinavir plasma concentrations and AUC).

Patients receiving lopinavir/ritonavir and tenofovir DF concomitantly should be monitored for tenofovir toxicity, and tenofovir DF should be discontinued if such effects occur.

Nelfinavir

No clinically important pharmacokinetic interaction between nelfinavir and tenofovir DF.

Saquinavir

Pharmacokinetic interaction with ritonavir-boosted saquinavir is not clinically important. Dosage adjustments are not needed when tenofovir DF is used with ritonavir-boosted saquinavir.

Tipranavir

Pharmacokinetic interaction with ritonavir-boosted tipranavir (decreased tipranavir concentrations and AUC; decreased tenofovir concentrations and AUC).

Dosage adjustments are not needed if tipranavir and tenofovir DF are used concomitantly.

Entecavir

No in vitro evidence of antagonistic antiviral effects between tenofovir DF and entecavir.

No clinically important pharmacokinetic interaction between entecavir and tenofovir DF.

Estrogens and Progestins

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

Ganciclovir and Valganciclovir

Concomitant use of tenofovir DF and ganciclovir or valganciclovir may result in increased plasma concentrations of tenofovir and/or ganciclovir.

If tenofovir DF is used concomitantly with ganciclovir or valganciclovir, patients should be monitored for dose-related toxicities.

HCV Antivirals

HCV Polymerase Inhibitors

Sofosbuvir

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

Dosage adjustments are not needed for either drug if sofosbuvir is used concomitantly with tenofovir DF.

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.

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

HCV Protease Inhibitors

Simeprevir

Concomitant use of tenofovir DF and simeprevir results in slightly decreased simeprevir plasma concentrations and AUC, but does not have a clinically important effect on the pharmacokinetics of tenofovir DF.

Dosage adjustments are not needed for either drug if simeprevir is used concomitantly with tenofovir DF.

HCV Replication Complex Inhibitors

Daclatasvir

Concomitant use of daclatasvir and tenofovir DF does not result in clinically important changes in the pharmacokinetics of either drug.

Elbasvir and Grazoprevir

Concomitant use of the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir) and tenofovir DF does not result in clinically important changes in the pharmacokinetics of elbasvir, grazoprevir, or tenofovir. Dosage adjustments are not needed.

Ledipasvir and Sofosbuvir

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

Concomitant use of ledipasvir/sofosbuvir and antiretroviral regimens that include tenofovir DF and certain other antiretrovirals may result in increased tenofovir concentrations (e.g., efavirenz/emtricitabine/tenofovir DF, emtricitabine/rilpivirine/tenofovir DF, dolutegravir in conjunction with emtricitabine/tenofovir DF, any regimen that includes tenofovir DF and a ritonavir-boosted PI or tenofovir DF and cobicistat). Safety of increased tenofovir concentrations in patients receiving ledipasvir/sofosbuvir has not been established.

An alternative HCV treatment regimen or alternative antiretroviral regimen should be considered if the patient is receiving ledipasvir/sofosbuvir concomitantly with an antiretroviral regimen that contains tenofovir DF and a ritonavir-boosted PI or tenofovir DF and cobicistat; if concomitant use of ledipasvir/sofosbuvir and these antiretroviral regimens is necessary, the patient should be monitored for tenofovir-associated adverse effects. Patients also should be monitored for tenofovir-associated adverse effects if ledipasvir/sofosbuvir is used concomitantly with an HIV antiretroviral regimen that contains tenofovir DF without a ritonavir-boosted HIV PI or without cobicistat.

Ombitasvir, Paritaprevir, and Ritonavir

Concomitant use of emtricitabine/tenofovir DF and the fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) with or without dasabuvir does not result in clinically important interactions.

Dosage adjustments are not needed if emtricitabine/tenofovir DF is used concomitantly with ombitasvir/paritaprevir/ritonavir with or without dasabuvir.

Opiates and Opiate Partial Agonists

Buprenorphine

No clinically important pharmacokinetic interaction between buprenorphine and tenofovir DF.

Dosage adjustments are not necessary if buprenorphine and tenofovir DF are used concomitantly.

Methadone

No clinically important pharmacokinetic interaction between methadone and tenofovir DF.

Dosage adjustments are not necessary if methadone and tenofovir DF are used concomitantly.

Ribavirin

No clinically important pharmacokinetic interaction between ribavirin and tenofovir DF.

Tacrolimus

Pharmacokinetic interaction is unlikely.

Telbivudine

No in vitro evidence of antagonistic antiviral effects between tenofovir DF and telbivudine.

Pharmacokinetics

The pharmacokinetics of tenofovir disoproxil fumarate (tenofovir DF) in healthy individuals is similar to that in individuals with human immunodeficiency virus type 1 (HIV-1) infection.

Absorption

Tenofovir DF is a diester prodrug of tenofovir. Following oral administration of tenofovir DF in fasting HIV-infected individuals, oral bioavailability of tenofovir is approximately 25% and peak plasma concentrations are attained in about 1 hour.

Pharmacokinetics are dose proportional over a tenofovir DF dosage range of 75-600 mg and are not affected by repeated dosing.

In a single-dose study in nonfasting individuals, mean peak plasma concentrations of tenofovir were 26% lower when tenofovir DF was administered as an oral powder compared with administration as tablets; however, the mean area under the concentration-time curve (AUC) of tenofovir was similar with both preparations.

A fixed-combination tablet containing efavirenz 600 mg, tenofovir DF 300 mg, and emtricitabine 200 mg (Atripla) is bioequivalent to a 600-mg efavirenz tablet, a 300-mg tenofovir DF tablet, and a 200-mg emtricitabine capsule given simultaneously.

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

A fixed-combination tablet containing emtricitabine 200 mg and tenofovir DF 300 mg (Truvada) is bioequivalent to a 200-mg emtricitabine capsule and a 300-mg tenofovir DF tablet given simultaneously.

Food

Food delays the time to peak plasma concentrations by approximately 1 hour.

Administration of 300 mg of tenofovir DF (as tablets) following a high-fat meal (approximately 700-1000 kcal containing 40-50% fat) increases oral bioavailability resulting in a 14% increase in peak plasma concentrations and 40% increase in AUC.

Administration of tenofovir DF with a light meal does not have a clinically important effect on the pharmacokinetics of tenofovir compared to administration in the fasting state.

Special Populations

Peak plasma concentrations and AUC of tenofovir in HIV-1-infected pediatric patients 2 to less than 12 years of age receiving 8 mg/kg of tenofovir DF (up to 300 mg) once daily as an oral powder or in pediatric patients 12 to less than 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. In hepatitis B virus (HBV)-infected pediatric patients 12 to less than 18 years of age receiving tenofovir DF 300 mg once daily as tablets, tenofovir exposures were similar to those reported in HIV-1-infected adults and adolescents receiving tenofovir DF 300 mg once daily.

Distribution

In vitro, tenofovir is less than 0.7 or 7.2% bound to plasma or serum proteins, respectively, over the concentration range of 0.02-25 mcg/mL.

Following oral administration of tenofovir DF, there is some evidence that tenofovir is distributed into semen and vaginal tissue and cervicovaginal fluid in low concentrations. Very low concentrations may be distributed into saliva.

Tenofovir crosses the human placenta.

Tenofovir is distributed into human milk in low concentrations.

Elimination

Metabolism

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

Tenofovir and its prodrug are not substrates of cytochrome P-450 (CYP) isoenzymes.

Elimination Route

Tenofovir is eliminated principally by the kidneys via glomerular filtration and active tubular secretion. Following multiple oral doses, approximately 32% of a dose is eliminated in urine over 24 hours.

Tenofovir is removed by hemodialysis. Following a 300-mg dose of tenofovir DF, a 4-hour hemodialysis session removes approximately 10% of the dose.

Half-life

Following a single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours.

Special Populations

Tenofovir pharmacokinetics are not substantially altered in patients with moderate to severe hepatic impairment compared with those with normal hepatic function.

Moderate or severe renal impairment (creatinine clearance less than 50 mL/minute or end-stage renal disease requiring dialysis) results in increased tenofovir plasma concentrations and AUC, and dosage adjustments are necessary in such patients.(See Renal Impairment under Dosage and Administration: Special Populations.)

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