TRUVADA (Brand for EMTRICITABINE-TENOFOVIR DISOP)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-May be administered with or without food.
-Tablets must be swallowed whole.

Adverse events observed in pediatric emtricitabine; tenofovir trials were consistent with those observed in clinical trials in adults.

Lactic acidosis and severe hepatomegaly with steatosis, sometimes fatal, have been reported with the use of nucleoside/nucleotide analogs, including emtricitabine and tenofovir, alone or in combination with other antiretroviral therapy. Adult females appear to be at a higher risk for lactic acidosis; it is not clear whether this increased risk also applies to pediatric females. Obesity and prolonged nucleoside exposure are also risk factors. Discontinue emtricitabine; tenofovir disoproxil fumarate (DF) if a patient develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity, including hepatomegaly and steatosis even in the absence of marked elevated transaminases. Elevated hepatic enzymes, including AST (3%), ALT (2%), and alkaline phosphatase (1%), and hyperbilirubinemia (up to 3%) were reported in adult clinical trials in patients receiving emtricitabine; tenofovir DF. Severe acute hepatitis B exacerbation (including hepatic decompensation and hepatic failure) has been reported in hepatitis B virus (HBV)-infected patients who have discontinued treatment with emtricitabine or tenofovir DF. In HBV-infected patients who discontinue emtricitabine; tenofovir DF, closely monitor hepatic function with both clinical and laboratory follow-up for at least several months. If appropriate, treatment for hepatitis B infection may be warranted. Prior to initiating emtricitabine; tenofovir DF therapy, it is recommended that all patients be tested for the presence of chronic HBV.

Renal impairment and renal failure (unspecified), which may include hypophosphatemia and acute interstitial nephritis, have been reported with tenofovir disoproxil fumarate (DF) use. Assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients prior to initiating therapy, and as indicated during treatment. Additionally, patients at risk for or with a history of renal dysfunction should have serum phosphorus assessed prior to therapy initiation and periodically during therapy. In pediatric trials of tenofovir (n = 89), 4 patients discontinued tenofovir therapy due to proximal renal tubulopathy; 3 of these patients presented with hypophosphatemia. Tenofovir should be avoided in those patients with concurrent or recent use of nephrotoxic agents (e.g., non-steroidal anti-inflammatory drugs [NSAIDs]). Cases of acute renal failure, requiring hospitalization and renal replacement therapy, have been reported in HIV-infected patients at high-risk for renal impairment, who appeared stable on tenofovir, after initiation of high-dose or multiple dose NSAIDs. Hematuria was noted in 3% of patients receiving tenofovir in combination with emtricitabine and efavirenz during clinical trials. Other adverse reactions that have been reported during the postmarketing period with tenofovir DF include elevated serum creatinine, Fanconi syndrome, hypokalemia, nephrogenic diabetes insipidus, proteinuria, proximal renal tubulopathy, renal insufficiency, interstitial nephritis, polyuria, and acute renal tubular necrosis. Worsening pain in bones or extremities, fractures and/or muscular pain or weakness may also be manifestations of proximal renal tubulopathy; promptly evaluate renal function in patients experiencing these symptoms.

Greater decreases in bone mineral density (BMD) have been associated with tenofovir disoproxil fumarate (DF) relative to comparators in clinical studies. Normally, BMD increases rapidly in pediatric patients; however, in studies of tenofovir-treated pediatric patients, bone effects were similar to those noted in adult patients, suggesting increased bone turnover. Assessment of BMD is recommended in patients with a history of bone fractures or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D has not been studied, such supplementation may be considered for HIV-associated osteopenia or osteoporosis. If bone abnormalities are suspected, appropriate consultation should be obtained. One study evaluating HIV-infected children aged 2 to 12 years found total body BMD gains in recipients of tenofovir to be lower than the gains observed in patients receiving either stavudine or zidovudine. Additionally, at treatment week 48, 1 tenofovir-treated patient experienced significant (more than 4%) BMD loss in the lumbar spine; significant BMD losses were not observed in the stavudine or zidovudine treatment groups. In another study involving adolescents aged 12 to 17 years, the mean rate of BMD gain was less in the tenofovir-treated patients compared to the placebo group. Six tenofovir treated adolescents and 1 placebo treated adolescent had significant (more than 4%) lumbar spine BMD loss in 48 weeks. A third study involving pediatric patients ages 12 to 17 years with chronic hepatitis B also observed smaller gains in lumbar and total body BMD for those patients receiving tenofovir (+ 5% and + 3%, respectively) compared to the placebo group (+ 8% and + 5%, respectively). After 72 weeks of treatment, significant (more than 4%) lumbar spine BMD losses occurred in 3 tenofovir patients and 2 placebo patients. In all 3 pediatric studies, the skeletal growth height appeared to be unaffected. Osteomalacia has also been reported with tenofovir DF use (postmarketing), including cases associated with proximal renal tubulopathy. Worsening pain in bones or extremities, bone fractures and/or muscular pain or weakness may also be manifestations of proximal renal tubulopathy; promptly evaluate renal function in patients experiencing these symptoms.

Gastrointestinal (GI) adverse reactions are common with antiretroviral agents. During adult clinical trials with emtricitabine; tenofovir disoproxil fumarate (DF), the most common GI adverse reactions occurring in 10% or more of patients (any severity) were diarrhea (grade 2 to 4, 9%) and nausea (grade 2 to 4, 9%). Abdominal pain (4%), weight loss (3%), and vomiting (2%) were also noted in clinical trials. Other GI reactions seen in patients treated with emtricitabine and/or tenofovir in adult clinical trials include anorexia, dyspepsia, and flatulence. There have been postmarketing reports of pancreatitis in patients receiving emtricitabine; tenofovir DF. Hyperamylasemia (more than 175 units/L; 8%) was noted in clinical trials.

Emtricitabine; tenofovir disoproxil fumarate has been associated with the development of adverse reactions that affect the nervous system and the body as a whole. During adult HIV clinical trials, the most common adverse reactions occurring in 10% or more of patients (any severity) included headache (grade 2 to 4, 6%), dizziness (grade 2 to 4, 8%), depression (grade 2 to 4, 9%), insomnia (grade 2 to 4, 5%), abnormal dreams, and fatigue (grade 2 to 4, 9%). Anxiety, fever, paresthesias, peripheral neuropathy (including peripheral neuritis and neuropathy) have also been reported with emtricitabine and/or tenofovir in clinical trials.

Elevated creatinine kinase was noted in 9% of patients during clinical trials with emtricitabine; tenofovir disoproxil fumarate (DF). Arthralgia, asthenia, back pain, chest pain (unspecified), myalgia, pain, paresthesias, and peripheral neuropathy (including peripheral neuritis and neuropathy) have also been reported with emtricitabine and/or tenofovir in clinical trials. Rhabdomyolysis, myopathy, and muscular weakness have been noted during postmarketing surveillance. Worsening bone pain, pain in extremities, fractures and/or muscular pain or myasthenia may also be manifestations of proximal renal tubulopathy; promptly evaluate renal function in patients experiencing these symptoms.

In clinical trials, skin discoloration was reported in patients treated with emtricitabine. This discoloration, manifested as skin hyperpigmentation on the palms of the hands and/or soles of the feet, was generally mild and asymptomatic, and was predominantly reported in non-Caucasian patients. The mechanism and clinical significance are unknown. According to the manufacturer, the incidence of hyperpigmentation was higher in pediatric patients (32%) than in adults. Skin rash was reported in 7% of patients who received emtricitabine; tenofovir disoproxil fumarate (DF) in adult clinical trials. Reports of rash included exfoliative rash, maculopapular rash, vesicular rash, pustular rash, pruritus, and urticaria. Angioedema and dyspnea have been reported during postmarketing use of tenofovir DF. Due to the voluntary nature of postmarketing reports, neither a frequency nor definitive causal relationship with tenofovir DF can be established.

Dyslipidemia (hypercholesterolemia, hypertriglyceridemia) is relatively common in children receiving HAART and is often associated with lipodystrophy. Hypercholesterolemia (more than 240 mg/dL; 22%) and hypertriglyceridemia (more than 750 mg/dL; 4%) were reported in patients who received emtricitabine; tenofovir in adult clinical trials. Other metabolic abnormalities reported included hyperglycemia (more than 250 mg/dL; 2% to 3%), hypoglycemia (less than 40 mg/dL; 3% or less), and glycosuria (3+ or more; less than 1%).

During adult clinical trials of emtricitabine and tenofovir disoproxil fumarate (DF), infections, including sinusitis (8%), upper respiratory tract infection (8%), and naso-pharyngitis (5%), were reported. Cough, fever, pneumonia, and rhinitis have been reported with emtricitabine and/or tenofovir DF in clinical trials.

Anemia was noted in 7% of pediatric patients during emtricitabine clinical trials. Neutropenia (less than 750/mm3) was reported in 3% of patients receiving emtricitabine; tenofovir in adult clinical trials.

Unplanned antiretroviral therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption is necessary (i.e., < 1-2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable drug concentrations of efavirenz and nevirapine ranges from < 1 week to > 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

Both emtricitabine and tenofovir are eliminated by the kidney. Avoid use of emtricitabine; tenofovir DF for treatment of HIV in patients with creatinine clearance less than 30 mL/minute or requiring hemodialysis. Although there are insufficient data to make recommendations for pediatric patients, dosage adjustments are required for adults with creatinine clearance 30 to 49 mL/minute. For HIV pre-exposure prophylaxis (PrEP), avoid use of the drug in persons with creatinine clearance less than 60 mL/minute. Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been associated with the administration of tenofovir DF. The majority of such cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents; some cases, however, occurred in patients with no identified risk factors. Obtain serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients prior to initiation and as clinically appropriate during therapy; a dosage adjustment may be necessary. In patients at risk for or with a history of renal dysfunction, also assess serum phosphorus prior to therapy initiation and periodically during therapy. Worsening bone pain, pain in extremities, bone fracture, and muscular pain or weakness may be manifestations of proximal renal tubulopathy; promptly evaluate renal function in patients experiencing these symptoms. For individuals receiving PrEP, guidelines recommend monitoring creatinine clearance at baseline and at least every 12 months thereafter. For patients with a creatinine clearance less than 90 mL/minute at baseline, assess creatinine clearance every 6 months. Avoid use of the drug concurrently with or after recent use of a nephrotoxic agent, including high-dose or multiple non-steroidal antiinflammatory drugs (NSAIDS), as cases of acute renal failure requiring hospitalization and renal replacement therapy have been reported.

Bone mineral density (BMD) monitoring should be considered for patients receiving emtricitabine; tenofovir who have a history of pathologic bone fractures or are at substantial risk for osteopenia, osteoporosis, or osteomalacia; osteomalacia has been reported in association with tenofovir administration. Cases of osteomalacia associated with proximal renal tubulopathy have been reported with tenofovir therapy. Worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may also be manifestations of proximal renal tubulopathy; promptly evaluate renal function in patients experiencing these symptoms. Normally, BMD increases rapidly in children and adolescents; however, in studies of tenofovir-treated pediatric patients, bone effects were similar to those noted in adult patients. One study evaluating HIV-infected children aged 2-12 years found total body BMD gains in recipients of tenofovir to be lower than the gains observed in patients receiving either stavudine or zidovudine. Additionally, at treatment week 48, 1 tenofovir-treated patient experienced significant (> 4%) BMD loss in the lumbar spine; significant BMD losses were not observed in the stavudine or zidovudine treatment groups. In another study involving adolescents aged 12-17 years, the mean rate of BMD gain was less in the tenofovir-treated patients compared to the placebo group. Six tenofovir-treated adolescents and 1 placebo-treated adolescent had significant (> 4%) lumbar spine BMD loss in 48 weeks. A third study involving pediatric patients ages 12-17 years with chronic HBV infection also observed smaller gains in lumbar and total body BMD for those patients receiving tenofovir (+ 5% and + 3%, respectively) compared to the placebo group (+ 8% and + 5%, respectively). After 72 weeks of treatment, significant (> 4%) lumbar spine BMD losses occurred in 3 tenofovir patients and 2 placebo patients. In all 3 pediatric studies, the skeletal growth height appeared to be unaffected. Although the effect of supplementation with calcium and vitamin D has not been studied, such supplementation may be considered for HIV-associated osteopenia or osteoporosis. If bone abnormalities are suspected, appropriate consultation should be obtained.

Lactic acidosis and hepatotoxicity with steatosis, including fatal cases, have been reported after use of emtricitabine and tenofovir, both alone and in combination with other antiretroviral medications. Suspend treatment with emtricitabine; tenofovir in any patient who develops clinical or laboratory findings suggestive of hepatotoxicity or lactic acidosis, which may include hepatomegaly and steatosis even in the absence of marked elevated hepatic enzymes. Although these adverse reactions may occur in any drug recipient, some risk factors include hepatic disease (e.g., alcoholism), obesity, and prolonged nucleoside exposure. In addition, adult females appear to be at a higher risk for lactic acidosis; it is not clear whether this increased risk applies to pediatric females.

Emtricitabine; tenofovir disoproxil fumarate (DF) is not indicated for the treatment of patients with hepatitis B and HIV coinfection, although both drugs can be used together off-label for the treatment of hepatitis B virus (HBV) infection. It should be noted that only the individual tablet formulations have been studied in HBV; the combination tablet has not been studied. Perform HBV screening in all patients prior to initiating therapy with emtricitabine; tenofovir DF to assure appropriate treatment. Patients who are co-infected with HIV and HBV and require treatment for either infection should be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. The HIV guidelines recommend that coinfected pediatric patients 2 years and older receive an antiretroviral regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, another agent with anti-HBV activity should be used in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Management of HIV should be continued with the goal of maximal suppression. After discontinuation of emtricitabine; tenofovir DF in patients with HBV infection, some patients have experienced severe acute hepatitis B exacerbation; exacerbations have also been associated with liver decompensation and liver failure in patients who have discontinued emtricitabine. In patients with HBV who discontinue emtricitabine; tenofovir DF, closely monitor hepatic function with both clinical and laboratory follow-up for at least several months. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test results kept in the patient's medical record until they become clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. Emtricitabine will not likely be effective in individuals who display resistance to lamivudine, due to the similarities between the two drugs. Clinicians should not expect patients with the M184 mutation associated with lamivudine to benefit from an emtricitabine containing regimen. The M184 mutation confers high-level resistance, and emtricitabine, like lamivudine, selects for the M184 mutation. It is important that persons with detectable viral load who plan to switch therapy from lamivudine to emtricitabine have genotypic testing performed to determine whether the M184V mutation is present. A patient's treatment history is also extremely important; if lamivudine has failed in the past, the 184 is archived, thus rendering emtricitabine ineffective in this patient population. In addition, as with all other antiretroviral agents, resistance could develop if emtricitabine; tenofovir is used either alone or in combination with other agents; monotherapy with emtricitabine; tenofovir is not recommended.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy such as emtricitabine; tenofovir disoproxil fumarate. During the initial phase of HIV treatment, patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as progressive multifocal leukoencephalopathy (PML), mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, polymyositis, and autoimmune hepatitis) may also develop; the time to onset is variable and may occur months after treatment initiation.

Perform hepatitis C virus (HCV) screening in any child whose mother is known to have HCV infection and all HIV-infected adolescents. Treatment of HCV infection in pediatric patients younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older and adolescents with hepatitis C and HIV coinfection who have no contraindications to treatment. For antiretroviral (ARV)-naive adolescent patients with CD4 counts more than 500 cells/mm3, consideration may be given to deferring ARV therapy until the hepatitis C treatment regimen has been completed. Conversely, for adolescent patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. All HIV-infected children and adolescents, regardless of HIV and HCV status, should receive standard vaccination with hepatitis A and B vaccines. Additionally, counsel HIV/HCV-coinfected adolescents to avoid alcohol.

Due to the potential for the development of drug resistance, the use of emtricitabine; tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (PrEP) is contraindicated in individuals with positive or unknown HIV serum status. Confirm a negative HIV test immediately prior to initiating prophylaxis, at least every 3 months during therapy (prior to authorizing prescription refills), and when discontinuing PrEP. If symptoms consistent with acute HIV infection develop after a potential exposure, discontinue prophylactic therapy and reconfirm HIV status. In addition to HIV screening, all recipients of HIV PrEP should undergo testing for a sexually transmitted infection (STI) before initiating therapy and approximately every 4 to 12 months thereafter, depending on specific population and/or STI.

Description: Emtricitabine; tenofovir disoproxil fumarate (Truvada) is used for the treatment of human immunodeficiency virus (HIV) infection and for pre-exposure prophylaxis to reduce the risk of sexually acquired HIV-1 in adolescents (weighing 35 kg or more) at high risk. Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and tenofovir is an acyclic nucleotide analog (i.e., nucleotide reverse transcriptase inhibitor). Each is active against HIV and when combined exhibit synergistic antiretroviral activity in HIV-infected cells. While it belongs to the same nucleoside series as lamivudine (3TC), emtricitabine has consistently been more potent against HIV in vitro than lamivudine. Due to the similarities between the 2 drugs, emtricitabine will not likely be effective in individuals who display antimicrobial resistance to lamivudine. While emtricitabine and tenofovir also exhibit activity against hepatitis B virus (HBV), only tenofovir is indicated for this use; the combination product carries a boxed warning that severe, acute exacerbations of hepatitis B have been reported in HBV-infected patients after discontinuation of emtricitabine; tenofovir disoproxil fumarate (DF). Decreases in bone mineral density (BMD) have been reported with tenofovir therapy in children; therefore, use of tenofovir is only recommended as part of a preferred regimen in adolescents in Tanner stage 4 or 5. Tenofovir may be considered in children in lower Tanner stages as alternative treatment or in special circumstances. Emtricitabine; tenofovir DF is FDA-approved for use in pediatric patients weighing 17 kg or more.

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV treatment

-Emtricitabine; tenofovir DF is a preferred 2-nucleoside reverse transcriptase inhibitor (NRTI) backbone option for initial therapy in treatment-naive adolescents (Sexual Maturity Rating (SMR) of 4 or 5). The 2-NRTI backbone should be used in combination with an integrase strand transfer inhibitor (INSTI), which is the preferred regimen, or in combination with a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) in certain clinical situations.
-Due to decreases in bone mineral density with tenofovir, emtricitabine; tenofovir DF is an alternative dual-NRTI backbone option in children 2 to 12 years.

Place in therapy for HIV pre-exposure prophylaxis (PrEP)
-Emtricitabine; tenofovir DF is approved for PrEP when used as part of a comprehensive HIV prevention program that includes safe sex practices, risk reduction counseling, counseling on medication adherence, and regular HIV testing.
-Guidelines recommend considering PrEP with emtricitabine; tenofovir DF for adolescents without HIV who report sexual behaviors or other high-risk behaviors (i.e., persons who inject drugs [PWID]) that place them at substantial ongoing risk of HIV exposure and acquisition. High-risk sexual behaviors include those who have engaged in anal or vaginal sex in the past 6 months AND any of the following: HIV-positive sexual partner (especially if partner has an unknown or detectable viral load), bacterial sexually transmitted infection in the past 6 months, or history of inconsistent or no condom use with sexual partner(s). High-risk injection behaviors for PWID include HIV-positive injecting partner or sharing injection equipment.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents:
NOTE: Children must be able to swallow whole tablets in order to use emtricitabine; tenofovir DF fixed-dose combination tablets.
Oral dosage:
Children weighing 17 to 21 kg: 1 tablet (emtricitabine 100 mg; tenofovir DF 150 mg) PO once daily.
Children weighing 22 to 27 kg: 1 tablet (emtricitabine 133 mg; tenofovir DF 200 mg) PO once daily.
Children and Adolescents weighing 28 to 34 kg: 1 tablet (emtricitabine 167 mg; tenofovir DF 250 mg) PO once daily.
Children and Adolescents weighing 35 kg or more: 1 tablet (emtricitabine 200 mg; tenofovir DF 300 mg) PO once daily.

For human immunodeficiency virus (HIV) prophylaxis:
-for HIV pre-exposure prophylaxis (PrEP) in high-risk patients without HIV to reduce the risk of sexually acquired HIV-1 and to reduce HIV acquisition risk in injection drug users*:
Oral dosage:
Adolescents weighing 35 kg or more: 200 mg emtricitabine; 300 mg tenofovir disoproxil fumarate PO once daily as part of a comprehensive HIV prevention program.
-for HIV prophylaxis* after nonoccupational exposure to HIV, including sexual assault:
NOTE: Higher risk exposures for which prophylaxis is recommended include exposure of vagina, rectum, eye, mouth, or other mucous membrane, nonintact skin, or percutaneous contact with blood, semen, vaginal secretions, rectal secretions, breast milk, or any body fluid that is visibly contaminated with blood when the source is known to be HIV-positive. Exposures to a source patient with unknown HIV status should be assessed on a case-by-case basis.
Oral dosage:
NOTE: Children must be able to swallow whole tablets to use emtricitabine; tenofovir DF fixed-dose combination tablets.
Children weighing 17 to 21 kg: 100 mg emtricitabine; 150 tenofovir disoproxil fumarate PO once daily plus raltegravir for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. Emtricitabine; tenofovir disoproxil fumarate in combination with lopinavir/ritonavir or darunavir/ritonavir (children 3 years and older) is an alternative regimen. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children weighing 22 to 27 kg: 133 mg emtricitabine; 200 tenofovir disoproxil fumarate PO once daily plus raltegravir for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. Emtricitabine; tenofovir disoproxil fumarate in combination with lopinavir/ritonavir or darunavir/ritonavir (children 3 years and older) is an alternative regimen. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children weighing 28 to 34 kg: 167 mg emtricitabine; 250 tenofovir disoproxil fumarate PO once daily plus raltegravir for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. Emtricitabine; tenofovir disoproxil fumarate in combination with lopinavir/ritonavir or darunavir/ritonavir is an alternative regimen. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children weighing 35 kg or more: 200 mg emtricitabine; 300 mg tenofovir disoproxil fumarate PO once daily plus raltegravir for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. Emtricitabine; tenofovir disoproxil fumarate in combination with lopinavir/ritonavir or darunavir/ritonavir is an alternative regimen. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Adolescents weighing 28 to 34 kg: 167 mg emtricitabine; 250 mg tenofovir disoproxil fumarate PO once daily plus raltegravir or dolutegravir for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in adolescents. Emtricitabine; tenofovir DF in combination with darunavir/ritonavir is an alternative regimen. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Adolescents weighing 35 kg or more: 200 mg emtricitabine; 300 mg tenofovir disoproxil fumarate PO once daily plus raltegravir or dolutegravir for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in adolescents. Emtricitabine; tenofovir disoproxil fumarate in combination with darunavir/ritonavir is an alternative regimen. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
weight less than 17 kg: Safety and efficacy have not been established.
weight 17 to 21 kg: 100 mg/day emtricitabine and 150 mg/day tenofovir PO.
weight 22 to 27 kg: 133 mg/day emtricitabine and 200 mg/day tenofovir PO.
weight 28 to 34 kg: 167 mg/day emtricitabine and 250 mg/day tenofovir PO.
weight 35 kg or more: 200 mg/day emtricitabine and 300 mg/day tenofovir PO.
-Adolescents
weight 28 to 34 kg: 167 mg/day emtricitabine and 250 mg/day tenofovir PO.
weight 35 kg or greater: 200 mg/day emtricitabine and 300 mg/day tenofovir PO.

Patients with Hepatic Impairment Dosing
No dosage adjustment required; however, due to the risk of hepatotoxicity, use caution when administering to patients with hepatic disease.

Patients with Renal Impairment Dosing
Use of emtricitabine; tenofovir disoproxil fumarate (DF) for pre-exposure prophylaxis is not recommended in adolescents with CrCl less than 60 mL/minute. For the treatment of HIV infection, there are insufficient data to make dose recommendations for pediatric patients with renal impairment; however, the following dose adjustments are recommended in adult patients with renal impairment :
CrCl 50 mL/minute or more: No dosage adjustment needed.
CrCl 30 to 49 mL/minute: 1 tablet (emtricitabine 200 mg and tenofovir DF 300 mg) PO every 48 hours.
CrCl less than 30 mL/minute: Use not recommended.

Intermittent hemodialysis
Use of emtricitabine; tenofovir is not recommended in patients requiring hemodialysis.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: In combination studies evaluating the in vitro antiviral activity of emtricitabine and tenofovir together, synergistic antiviral effects were observed.
-Emtricitabine: Emtricitabine inhibits viral reverse transcriptase and is active in vitro both on HIV-1 and HBV. Emtricitabine is similar in structure and activity to lamivudine, although its activity against HIV-1 is approximately 4-10 fold greater than that of lamivudine. Emtricitabine is a synthetic nucleoside analog of cytosine and is phosphorylated by cellular enzymes to emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA, resulting in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of polymerase alpha, beta, epsilon and mitochondrial DNA polymerase-gamma. Combination therapy targets different points in the life cycle of HIV, reducing the ability of HIV to mutate to drug-resistant strains. In combination with another NRTI and efavirenz, emtricitabine has been shown to increase CD4 cell counts and reduce plasma HIV-1 RNA levels.
-Tenofovir: Tenofovir inhibits viral reverse transcriptase and acts as a DNA chain terminator. Tenofovir disoproxil fumarate (tenofovir DF) is an acyclic nucleoside phosphonate (nucleotide) diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir. Tenofovir is then taken up by cells and undergoes phosphorylation to form tenofovir diphosphate (PMPApp). Tenofovir diphosphate competitively inhibits RNA- and DNA-directed reverse transcriptase. Tenofovir diphosphate competes with the natural substrate deoxyadenosine 5'-triphosphate (dATP) and, because it lacks a 3' hydroxyl group, causes premature DNA termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerase alpha, beta, and mitochondrial DNA polymerase-gamma.

Pharmacokinetics: Emtricitabine; tenofovir is administered orally. The steady state pharmacokinetics of emtricitabine and tenofovir are unaffected when administered together compared to each agent being administered alone.
-Emtricitabine: Emtricitabine exhibits low plasma protein binding (< 4%), and protein-binding is independent of plasma concentration. Metabolism occurs via oxidation to 3'-sulfoxide diastereomer (approximately 9% of dose) and via conjugation with glucuronic acid to 2'-O-glucuronide (approximately 4% of dose). Emtricitabine is excreted renally. The renal clearance is greater than the estimated creatinine clearance; elimination is presumed to be by both glomerular filtration and active tubular secretion, suggesting there may be competition for elimination with other compounds that are also renally eliminated. The plasma half-life is approximately 10 hours (range: 7.4-18 hours), and the metabolite, emtricitabine-triphosphate, has an intracellular half-life of approximately 39 hours.
-Tenofovir: The in vitro binding to human plasma and serum proteins is < 0.7% and 7.2%, respectively. Intracellularly, tenofovir undergoes phosphorylation to its active metabolite, tenofovir diphosphate (PMPApp). In vitro studies indicate that neither tenofovir DF nor tenofovir are substrates of cytochrome P450 enzymes. Tenofovir is eliminated by a combination of glomerular filtration and active renal tubular secretion; there may be competition for elimination with other compounds that are also renally eliminated. Approximately 70-80% is excreted as unchanged drug in the urine. The plasma half-life is approximately 17 hours (range: 12-25.7 hours) in adults, but is shorter in children.

Affected cytochrome P450 isoenzymes or drug transporters: P-gp, BCRP
Tenofovir DF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. Administration with inhibitors of these transporters may result in increased absorption of tenofovir.


-Route-Specific Pharmacokinetics
Oral Route
Emtricitabine
Emtricitabine is rapidly absorbed after oral administration with an oral bioavailability of approximately 92%. Peak plasma concentrations are achieved 1-2 hours after administration. Administration with food does not affect the systemic exposure.
Tenofovir
Due to the presence of a phosphonate group, tenofovir is negatively charged at neutral pH, which limits its bioavailability (25%). After absorption, tenofovir DF is rapidly converted to tenofovir. Peak concentrations of tenofovir are achieved approximately 1 hour after administration. Administration with food delays the Cmax by approximately 0.75 hour and increases the AUC and Cmax by approximately 35% and 15%, respectively, compared with administration under fasting conditions. However, the drug may be given without regards to food.


-Special Populations
Pediatrics
Pharmacokinetic studies for emtricitabine; tenofovir fixed-dose combination tablets have not been performed in pediatric patients. Pharmacokinetic data below is from studies with the individual components. Due to the fixed-dose combination of emtricitabine; tenofovir, use is not recommended for pediatric patients weighing less than 17 kg.
-Emtricitabine: Pharmacokinetic parameters in children and adolescents are similar to those seen in adults. In pediatric clinical studies, the mean Cmax across the age bands (n = 77) ranged from 1.9 to 2.7 mcg/mL as compared to the adult mean Cmax of 1.8 mcg/mL. The mean AUC in pediatric patients ranged from 8.7 to 12.6 mcg x hour/mL compared to 10 mcg x hour/mL in adults. The mean half-life was 8.2 to 11.3 hours in pediatric patients as compared to approximately 10 hours in adults.
-Tenofovir: Steady-state pharmacokinetics of tenofovir were evaluated in 31 HIV-infected pediatric patients (ages 2 to 17 years). Patients received either 8 mg/kg of the oral powder (up to 300 mg) or a 300 mg tablet. The exposure (AUC) in these pediatric patients was similar to that observed in adults receiving a 300 mg oral daily dose. Renal clearance is approximately 1.5-fold higher in children than in adults with a half-life of approximately 12.5 hours (range, 8 to 18 hours). Clearance increases with body weight in pediatric patients.

Hepatic Impairment
No substantial pharmacokinetic changes have been noted in patients with moderate to severe hepatic impairment after the administration of tenofovir. No information regarding the use of emtricitabine in patients with hepatic impairment is available; however, significant impact on pharmacokinetics is not expected because emtricitabine is not significantly metabolized by liver enzymes.

Renal Impairment
Emtricitabine; tenofovir is renally eliminated and clearance is reduced in patients with moderate to severe renal impairment; dosage adjustment is required. Dosage adjustment recommendations for pediatric patients with renal dysfunction are not available.