These Highlights Do Not Include All The Information Needed To Use Truvada Safely And Effectively. See Full Prescribing Information For Truvada.

Treatment of HIV-1 Infection

Table 2 provides dosage interval adjustment for patients with renal impairment. No dosage adjustment is necessary for HIV-1 infected patients with mild renal impairment (creatinine clearance 50–80 mL/min). The safety and effectiveness of the dosing interval adjustment recommendations in patients with moderate renal impairment (creatinine clearance 30–49 mL/min) have not been clinically evaluated; therefore, clinical response to treatment and renal function should be closely monitored in these patients [see Warnings and Precautions (5.3)].

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

Store at 25 °C (77 °F), excursions permitted to 15 °C–30 °C (59 °F–86 °F) (see USP Controlled Room Temperature).

• Keep container tightly closed.
• Dispense only in original container.

If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

TRUVADA tablets are fixed-dose combination tablets containing emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). FTC is a synthetic nucleoside analog of cytidine. TDF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Both FTC and tenofovir exhibit inhibitory activity against HIV-1 reverse transcriptase.

Clinical trials of FTC, TDF, or TRUVADA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

TRUVADA for HIV-1 PrEP is contraindicated in individuals with unknown or positive HIV-1 status [see Warnings and Precautions (5.2)].

The following adverse reactions are discussed in other sections of the labeling:

• Severe Acute Exacerbations of Hepatitis B in Patients with HBV Infection [see Warnings and Precautions (5.1)].
• New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.3)].
• Immune Reconstitution Syndrome [see Warnings and Precautions (5.4)].
• Bone Loss and Mineralization Defects [see Warnings and Precautions (5.5)].
• Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.6)].

• Tenofovir disoproxil fumarate increases didanosine concentrations. Dose reduction and close monitoring for didanosine toxicity are warranted. (7.2)
• Coadministration decreases atazanavir concentrations. When coadministered with TRUVADA, use atazanavir given with ritonavir. (7.2)
• Coadministration of TRUVADA with certain HIV-1 protease inhibitors or certain drugs to treat HCV increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. (7.2)
• Consult Full Prescribing Information prior to and during treatment for important drug interactions. (7.2)

HIV-1 Treatment (1.1)

TRUVADA is a two-drug combination of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), both HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated:

• in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg.

HIV-1 PrEP (1.2):

• TRUVADA is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Individuals must have a negative HIV-1 test immediately prior to initiating TRUVADA for HIV-1 PrEP.

TRUVADA is a fixed-dose combination of antiviral drugs FTC and TDF [see Microbiology (12.4)].

• Comprehensive management to reduce the risk of acquiring HIV-1 when TRUVADA is used for HIV-1 PrEP: Use as part of a comprehensive prevention strategy including other prevention measures; strictly adhere to dosing schedule. (5.2)
• Management to reduce the risk of acquiring HIV-1 drug resistance when TRUVADA is used for HIV-1 PrEP: refer to full prescribing information for additional detail. (5.2)
• New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering TRUVADA with concurrent or recent use of nephrotoxic drugs. (5.3)
• Immune reconstitution syndrome during treatment of HIV-1 infection: May necessitate further evaluation and treatment. (5.4)
• Decreases in bone mineral density (BMD): Consider assessment of BMD in individuals with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. (5.5)
• Lactic acidosis/severe hepatomegaly with steatosis: Discontinue TRUVADA in individuals who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. (5.6)

• Testing: Prior to or when initiating TRUVADA test for hepatitis B virus infection. Prior to initiation and during use of TRUVADA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals. In individuals with chronic kidney disease, also assess serum phosphorus. (2.1)
• HIV-1 Screening: Screen all individuals for HIV-1 infection immediately prior to initiating TRUVADA for HIV-1 PrEP and at least once every 3 months while taking TRUVADA, and upon diagnosis of any other sexually transmitted infections (STIs). (2.2)

Treatment of HIV-1 Infection

• Recommended dosage in adults and pediatric patients weighing at least 35 kg: One TRUVADA tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food. (2.3)
• Recommended dosage in pediatric patients weighing at least 17 kg: One TRUVADA low-strength tablet (100 mg/150 mg, 133 mg/200 mg, or 167 mg/250 mg based on body weight) once daily taken orally with or without food. (2.4)
• Recommended dosage in renally impaired HIV-1 infected adult patients:
  • Creatinine clearance (CrCl) 30−49 mL/min: 1 tablet every 48 hours. (2.6)
  • CrCl below 30 mL/min or hemodialysis: TRUVADA is not recommended. (2.6)

HIV-1 Pre-Exposure Prophylaxis (PrEP)

• Recommended dosage in HIV-1 uninfected adults and adolescents weighing at least 35 kg: One TRUVADA tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food. (2.5)
• Recommended dosage in renally impaired HIV-uninfected individuals: TRUVADA is not recommended in HIV-uninfected individuals if CrCl is below 60 mL/min. (2.6)

TRUVADA tablets are available in four dose strengths.

• 100 mg/150 mg Tablets: 100 mg of emtricitabine (FTC) and 150 mg of tenofovir disoproxil fumarate (TDF) (equivalent to 123 mg of tenofovir disoproxil): blue, oval shaped, film coated, debossed with "GSI" on one side and with "703" on the other side.
• 133 mg/200 mg Tablets: 133 mg of FTC and 200 mg of TDF (equivalent to 163 mg of tenofovir disoproxil): blue, rectangular shaped, film coated, debossed with "GSI" on one side and with "704" on the other side.
• 167 mg/250 mg Tablets: 167 mg of FTC and 250 mg of TDF (equivalent to 204 mg of tenofovir disoproxil): blue, modified capsule shaped, film coated, debossed with "GSI" on one side and with "705" on the other side.
• 200 mg/300 mg Tablets: 200 mg of FTC and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil): blue, capsule shaped, film coated, debossed with "GILEAD" on one side and with "701" on the other side.

The following adverse reactions have been identified during postapproval use of TDF. No additional adverse reactions have been identified during postapproval use of FTC. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders

allergic reaction, including angioedema

Metabolism and Nutrition Disorders

lactic acidosis, hypokalemia, hypophosphatemia

Respiratory, Thoracic, and Mediastinal Disorders

dyspnea

Gastrointestinal Disorders

pancreatitis, increased amylase, abdominal pain

Hepatobiliary Disorders

hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)

Skin and Subcutaneous Tissue Disorders

rash

Musculoskeletal and Connective Tissue Disorders

rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy

Renal and Urinary Disorders

acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria

General Disorders and Administration Site Conditions

asthenia

The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

Lactation: Mothers infected with HIV-1 or suspected of having acquired HIV-1 infection should be instructed not to breastfeed due to the potential for HIV transmission. (8.2)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

TRUVADA is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg [see Clinical Studies (14)].

The efficacy and safety of TRUVADA have been evaluated in the studies summarized in Table 13.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including TRUVADA. During the initial phase of combination antiretroviral treatment, HIV-1 infected patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) 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 treatment.

FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion [see Clinical Pharmacology (12.3)]. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of TRUVADA with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.3)]. Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir.

TRUVADA tablets are available in bottles containing 30 tablets with child-resistant closure as follows:

• 100 mg of FTC and 150 mg of TDF (equivalent to 123 mg of tenofovir disoproxil) tablets are blue, oval shaped, film coated, debossed with "GSI" on one side and with "703" on the other side (NDC 61958-0703-1).
• 133 mg of FTC and 200 mg of TDF (equivalent to 163 mg of tenofovir disoproxil) tablets are blue, rectangular shaped, film coated, debossed with "GSI" on one side and with "704" on the other side (NDC 61958-0704-1).
• 167 mg of FTC and 250 mg of TDF (equivalent to 204 mg of tenofovir disoproxil) tablets are blue, modified capsule shaped, film coated, debossed with "GSI" on one side and with "705" on the other side (NDC 61958-0705-1).
• 200 mg of FTC and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil) tablets are blue, capsule shaped, film coated, debossed with "GILEAD" on one side and with "701" on the other side (NDC 61958-0701-1).

TRUVADA is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Individuals must have a negative HIV-1 test immediately prior to initiating TRUVADA for HIV-1 PrEP [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Tenofovir and TDF administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.

Evidence of renal toxicity was noted in four animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

Emtricitabine and tenofovir are principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF, a component of TRUVADA [see Adverse Reactions (6.2)].

Prior to initiation and during use of TRUVADA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals. In individuals with chronic kidney disease, also assess serum phosphorus.

TRUVADA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.1)]. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in individuals at risk of renal dysfunction.

Table 7 provides a listing of established or clinically significant drug interactions. The drug interactions described are based on studies conducted with either TRUVADA, the components of TRUVADA (FTC and TDF) as individual agents and/or in combination, or are predicted drug interactions that may occur with TRUVADA [see Clinical Pharmacology (12.3)].

The iPrEx trial was a randomized, double-blind, placebo-controlled multinational study evaluating TRUVADA in 2,499 HIV-seronegative men or transgender women who have sex with men and with evidence of high-risk behavior for HIV-1 infection. Evidence of high-risk behavior included any one of the following reported to have occurred up to six months prior to study screening: no condom use during anal intercourse with an HIV-1 positive partner or a partner of unknown HIV status; anal intercourse with more than 3 sex partners; exchange of money, gifts, shelter, or drugs for anal sex; sex with male partner and diagnosis of sexually transmitted infection; no consistent use of condoms with sex partner known to be HIV-1 positive.

All subjects received monthly HIV-1 testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. Of the 2,499 enrolled subjects, 1,251 received TRUVADA and 1,248 received placebo. The mean age of subjects was 27 years; 5% were Asian, 9% Black, 18% White, and 72% Hispanic/Latino.

Subjects were followed for 4,237 person-years. The primary outcome measure was the incidence of documented HIV seroconversion. At the end of treatment, emergent HIV-1 seroconversion was observed in 131 subjects, of which 48 occurred in the TRUVADA group and 83 occurred in the placebo group, indicating a 42% (95% CI: 18–60%) reduction in risk. Risk reduction was found to be higher (53%; 95% CI: 34–72%) among subjects who reported previous unprotected anal intercourse (URAI) at screening (732 and 753 subjects reported URAI within the last 12 weeks at screening in the TRUVADA and placebo groups, respectively). In a post-hoc case control study of plasma and intracellular drug levels in about 10% of study subjects, risk reduction appeared to be greatest in subjects with detectable intracellular tenofovir diphosphate concentrations. Efficacy was therefore strongly correlated with adherence.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including FTC and TDF, components of TRUVADA, alone or in combination with other antiretrovirals. Treatment with TRUVADA should be suspended in any individual who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

The concomitant use of TRUVADA and other drugs may result in known or potentially significant drug interactions, some of which may lead to possible clinically significant adverse reactions from greater exposures of concomitant drugs [see Drug Interactions (7.2)].

See Table 7 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with TRUVADA; review concomitant medications during therapy with TRUVADA; and monitor for adverse reactions associated with the concomitant drugs.

The Partners PrEP trial was a randomized, double-blind, placebo-controlled 3-arm trial conducted in 4,758 HIV-1 serodiscordant heterosexual couples in Kenya and Uganda to evaluate the efficacy and safety of TDF (N=1,589) and FTC/TDF (N=1,583) versus (parallel comparison) placebo (N=1,586) in preventing HIV-1 acquisition by the uninfected partner.

All uninfected partner subjects received monthly HIV-1 testing, evaluation of adherence, assessment of sexual behavior, and safety evaluations. Women were also tested monthly for pregnancy. Women who became pregnant during the trial had study drug interrupted for the duration of the pregnancy and while breastfeeding. The uninfected partner subjects were predominantly male (61–64% across study drug groups) and had a mean age of 33–34 years.

Following 7,827 person-years of follow-up, 82 emergent HIV-1 seroconversions were reported, with an overall observed seroincidence rate of 1.05 per 100 person-years. Of the 82 seroconversions, 13 and 52 occurred in partner subjects randomized to TRUVADA and placebo, respectively. Two of the 13 seroconversions in the TRUVADA arm and 3 of the 52 seroconversions in the placebo arm occurred in women during treatment interruptions for pregnancy. The risk reduction for TRUVADA relative to placebo was 75% (95% CI: 55–87%). In a post-hoc case control study of plasma drug levels in about 10% of study subjects, risk reduction appeared to be greatest in subjects with detectable plasma tenofovir concentrations. Efficacy was therefore strongly correlated with adherence.

NDC 61958-0703-1

Truvada^®

(emtricitabine and

tenofovir disoproxil

fumarate) tablets

100 mg/150 mg

30 tablets

Rx only

DISPENSER: Each time Truvada is dispensed

give the patient the attached Medication Guide.

NDC 61958-0704-1

Truvada^®

(emtricitabine and

tenofovir disoproxil

fumarate) tablets

133 mg/200 mg

30 tablets

Rx only

DISPENSER: Each time Truvada is dispensed

give the patient the attached Medication Guide.

NDC 61958-0705-1

Truvada^®

(emtricitabine and

tenofovir disoproxil

fumarate) tablets

167 mg/250 mg

30 tablets

Rx only

DISPENSER: Each time Truvada is dispensed

give the patient the attached Medication Guide.

NDC 61958-0701-1

Truvada^®

(emtricitabine and

tenofovir disoproxil

fumarate) tablets

200 mg / 300 mg

30 tablets

Rx only

DISPENSER: Each time Truvada is dispensed

give the patient the attached Medication Guide.

Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing FTC+TDF administered in combination with efavirenz (EFV) versus zidovudine (AZT)/lamivudine (3TC) fixed-dose combination administered in combination with EFV in 511 antiretroviral-naïve adult subjects. From Weeks 96 to 144 of the trial, subjects received TRUVADA with EFV in place of FTC+TDF with EFV. Subjects had a mean age of 38 years (range 18–80); 86% were male, 59% were Caucasian, and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm³ (range 2–1,191) and median baseline plasma HIV-1 RNA was 5.01 log₁₀ copies/mL (range 3.56–6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥200 cells/mm³); 41% had CD4+ cell counts <200 cells/mm³ and 51% of subjects had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have EFV resistance at baseline are presented in Table 14.

Through Week 48, 84% and 73% of subjects in the FTC+TDF group and the AZT/3TC group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks is largely due to the higher number of discontinuations due to adverse events and other reasons in the AZT/3TC group in this open-label trial. In addition, 80% and 70% of subjects in the FTC+TDF group and the AZT/3TC group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm³ in the FTC+TDF group and 158 cells/mm³ in the AZT/3TC group at Week 48 (312 and 271 cells/mm³ at Week 144).

Through 48 weeks, 7 subjects in the FTC+TDF group and 5 subjects in the AZT/3TC group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).

Screen all individuals for HIV-1 infection immediately prior to initiating TRUVADA for HIV-1 PrEP and at least once every 3 months while taking TRUVADA, and upon diagnosis of any other sexually transmitted infections (STIs) [see Indications and Usage (1.2), Contraindications (4), and Warnings and Precautions (5.2)].

If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection [see Warnings and Precautions (5.2), Use in Specific Populations (8.4), and Clinical Studies (14.3 and 14.4)].

All individuals should be tested for the presence of chronic hepatitis B virus (HBV) before or when initiating TRUVADA [see Dosage and Administration (2.1)].

Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in HBV-infected individuals who have discontinued TRUVADA. Individuals infected with HBV who discontinue TRUVADA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in individuals with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure. HBV-uninfected individuals should be offered vaccination.

The dosage of TRUVADA for HIV-1 PrEP is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food in HIV-1 uninfected adults and adolescents weighing at least 35 kg [see Clinical Pharmacology (12.3)].

Prior to or when initiating TRUVADA, test individuals for hepatitis B virus infection [see Warnings and Precautions (5.1)].

Prior to initiation, and during use of TRUVADA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals. In individuals with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.3)].

TRUVADA is a two-drug fixed dose combination product containing emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The recommended dosage of TRUVADA in adults and in pediatric patients weighing at least 35 kg is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food [see Clinical Pharmacology (12.3)].

The recommended oral dosage of TRUVADA for pediatric patients weighing at least 17 kg and who can swallow a tablet is presented in Table 1. Tablets should be taken once daily with or without food. Weight should be monitored periodically and the TRUVADA dose adjusted accordingly.

Use TRUVADA for HIV-1 PrEP to reduce the risk of HIV-1 infection as part of a comprehensive prevention strategy that includes other prevention measures, including adherence to daily administration and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs). The time from initiation of TRUVADA for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown.

Risk for HIV-1 acquisition includes behavioral, biological, or epidemiologic factors including but not limited to condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network.

Counsel individuals on the use of other prevention measures (e.g., consistent and correct condom use, knowledge of partner(s)' HIV-1 status, including viral suppression status, regular testing for STIs that can facilitate HIV-1 transmission). Inform uninfected individuals about and support their efforts in reducing sexual risk behavior.

Use TRUVADA to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV-negative. HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking only TRUVADA, because TRUVADA alone does not constitute a complete regimen for HIV-1 treatment [see Microbiology (12.4)]; therefore, care should be taken to minimize the risk of initiating or continuing TRUVADA before confirming the individual is HIV-1 negative.

• Some HIV-1 tests only detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection. Prior to initiating TRUVADA for HIV-1 PrEP, ask seronegative individuals about recent (in past month) potential exposure events (e.g., condomless sex or condom breaking during sex with a partner of unknown HIV-1 status or unknown viremic status, or a recent STI), and evaluate for current or recent signs or symptoms consistent with acute HIV-1 infection (e.g., fever, fatigue, myalgia, skin rash).
• If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection.

While using TRUVADA for HIV-1 PrEP, HIV-1 testing should be repeated at least every 3 months, and upon diagnosis of any other STIs.

• If an HIV-1 test indicates possible HIV-1 infection, or if symptoms consistent with acute HIV-1 infection develop following a potential exposure event, convert the HIV-1 PrEP regimen to an HIV treatment regimen until negative infection status is confirmed using a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection.

Counsel HIV-1 uninfected individuals to strictly adhere to the once daily TRUVADA dosing schedule. The effectiveness of TRUVADA in reducing the risk of acquiring HIV-1 is strongly correlated with adherence, as demonstrated by measurable drug levels in clinical trials of TRUVADA for HIV-1 PrEP. Some individuals, such as adolescents, may benefit from more frequent visits and counseling to support adherence [see Use in Specific Populations (8.4), Microbiology (12.4), and Clinical Studies (14.3 and 14.4)].

Severe acute exacerbations of hepatitis B (HBV) have been reported in HBV-infected individuals who have discontinued TRUVADA. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in individuals who are infected with HBV and discontinue TRUVADA. If appropriate, anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1)].

TRUVADA used for HIV-1 PrEP must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initiating and at least every 3 months during use. Drug-resistant HIV-1 variants have been identified with use of TRUVADA for HIV-1 PrEP following undetected acute HIV-1 infection. Do not initiate TRUVADA for HIV-1 PrEP if signs or symptoms of acute HIV-1 infection are present unless negative infection status is confirmed [see Warnings and Precautions (5.2)].

Treatment of HIV-1 Infection

Table 2 provides dosage interval adjustment for patients with renal impairment. No dosage adjustment is necessary for HIV-1 infected patients with mild renal impairment (creatinine clearance 50–80 mL/min). The safety and effectiveness of the dosing interval adjustment recommendations in patients with moderate renal impairment (creatinine clearance 30–49 mL/min) have not been clinically evaluated; therefore, clinical response to treatment and renal function should be closely monitored in these patients [see Warnings and Precautions (5.3)].

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

Store at 25 °C (77 °F), excursions permitted to 15 °C–30 °C (59 °F–86 °F) (see USP Controlled Room Temperature).

• Keep container tightly closed.
• Dispense only in original container.

If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

TRUVADA tablets are fixed-dose combination tablets containing emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). FTC is a synthetic nucleoside analog of cytidine. TDF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Both FTC and tenofovir exhibit inhibitory activity against HIV-1 reverse transcriptase.

Clinical trials of FTC, TDF, or TRUVADA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

TRUVADA for HIV-1 PrEP is contraindicated in individuals with unknown or positive HIV-1 status [see Warnings and Precautions (5.2)].

The following adverse reactions are discussed in other sections of the labeling:

• Severe Acute Exacerbations of Hepatitis B in Patients with HBV Infection [see Warnings and Precautions (5.1)].
• New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.3)].
• Immune Reconstitution Syndrome [see Warnings and Precautions (5.4)].
• Bone Loss and Mineralization Defects [see Warnings and Precautions (5.5)].
• Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.6)].

• Tenofovir disoproxil fumarate increases didanosine concentrations. Dose reduction and close monitoring for didanosine toxicity are warranted. (7.2)
• Coadministration decreases atazanavir concentrations. When coadministered with TRUVADA, use atazanavir given with ritonavir. (7.2)
• Coadministration of TRUVADA with certain HIV-1 protease inhibitors or certain drugs to treat HCV increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. (7.2)
• Consult Full Prescribing Information prior to and during treatment for important drug interactions. (7.2)

HIV-1 Treatment (1.1)

TRUVADA is a two-drug combination of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), both HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated:

• in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg.

HIV-1 PrEP (1.2):

• TRUVADA is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Individuals must have a negative HIV-1 test immediately prior to initiating TRUVADA for HIV-1 PrEP.

TRUVADA is a fixed-dose combination of antiviral drugs FTC and TDF [see Microbiology (12.4)].

• Comprehensive management to reduce the risk of acquiring HIV-1 when TRUVADA is used for HIV-1 PrEP: Use as part of a comprehensive prevention strategy including other prevention measures; strictly adhere to dosing schedule. (5.2)
• Management to reduce the risk of acquiring HIV-1 drug resistance when TRUVADA is used for HIV-1 PrEP: refer to full prescribing information for additional detail. (5.2)
• New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering TRUVADA with concurrent or recent use of nephrotoxic drugs. (5.3)
• Immune reconstitution syndrome during treatment of HIV-1 infection: May necessitate further evaluation and treatment. (5.4)
• Decreases in bone mineral density (BMD): Consider assessment of BMD in individuals with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. (5.5)
• Lactic acidosis/severe hepatomegaly with steatosis: Discontinue TRUVADA in individuals who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. (5.6)

• Testing: Prior to or when initiating TRUVADA test for hepatitis B virus infection. Prior to initiation and during use of TRUVADA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals. In individuals with chronic kidney disease, also assess serum phosphorus. (2.1)
• HIV-1 Screening: Screen all individuals for HIV-1 infection immediately prior to initiating TRUVADA for HIV-1 PrEP and at least once every 3 months while taking TRUVADA, and upon diagnosis of any other sexually transmitted infections (STIs). (2.2)

Treatment of HIV-1 Infection

• Recommended dosage in adults and pediatric patients weighing at least 35 kg: One TRUVADA tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food. (2.3)
• Recommended dosage in pediatric patients weighing at least 17 kg: One TRUVADA low-strength tablet (100 mg/150 mg, 133 mg/200 mg, or 167 mg/250 mg based on body weight) once daily taken orally with or without food. (2.4)
• Recommended dosage in renally impaired HIV-1 infected adult patients:
  • Creatinine clearance (CrCl) 30−49 mL/min: 1 tablet every 48 hours. (2.6)
  • CrCl below 30 mL/min or hemodialysis: TRUVADA is not recommended. (2.6)

HIV-1 Pre-Exposure Prophylaxis (PrEP)

• Recommended dosage in HIV-1 uninfected adults and adolescents weighing at least 35 kg: One TRUVADA tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food. (2.5)
• Recommended dosage in renally impaired HIV-uninfected individuals: TRUVADA is not recommended in HIV-uninfected individuals if CrCl is below 60 mL/min. (2.6)

TRUVADA tablets are available in four dose strengths.

• 100 mg/150 mg Tablets: 100 mg of emtricitabine (FTC) and 150 mg of tenofovir disoproxil fumarate (TDF) (equivalent to 123 mg of tenofovir disoproxil): blue, oval shaped, film coated, debossed with "GSI" on one side and with "703" on the other side.
• 133 mg/200 mg Tablets: 133 mg of FTC and 200 mg of TDF (equivalent to 163 mg of tenofovir disoproxil): blue, rectangular shaped, film coated, debossed with "GSI" on one side and with "704" on the other side.
• 167 mg/250 mg Tablets: 167 mg of FTC and 250 mg of TDF (equivalent to 204 mg of tenofovir disoproxil): blue, modified capsule shaped, film coated, debossed with "GSI" on one side and with "705" on the other side.
• 200 mg/300 mg Tablets: 200 mg of FTC and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil): blue, capsule shaped, film coated, debossed with "GILEAD" on one side and with "701" on the other side.

The following adverse reactions have been identified during postapproval use of TDF. No additional adverse reactions have been identified during postapproval use of FTC. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders

allergic reaction, including angioedema

Metabolism and Nutrition Disorders

lactic acidosis, hypokalemia, hypophosphatemia

Respiratory, Thoracic, and Mediastinal Disorders

dyspnea

Gastrointestinal Disorders

pancreatitis, increased amylase, abdominal pain

Hepatobiliary Disorders

hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)

Skin and Subcutaneous Tissue Disorders

rash

Musculoskeletal and Connective Tissue Disorders

rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy

Renal and Urinary Disorders

acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria

General Disorders and Administration Site Conditions

asthenia

The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

Lactation: Mothers infected with HIV-1 or suspected of having acquired HIV-1 infection should be instructed not to breastfeed due to the potential for HIV transmission. (8.2)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

TRUVADA is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg [see Clinical Studies (14)].

The efficacy and safety of TRUVADA have been evaluated in the studies summarized in Table 13.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including TRUVADA. During the initial phase of combination antiretroviral treatment, HIV-1 infected patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) 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 treatment.

FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion [see Clinical Pharmacology (12.3)]. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of TRUVADA with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.3)]. Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir.

TRUVADA tablets are available in bottles containing 30 tablets with child-resistant closure as follows:

• 100 mg of FTC and 150 mg of TDF (equivalent to 123 mg of tenofovir disoproxil) tablets are blue, oval shaped, film coated, debossed with "GSI" on one side and with "703" on the other side (NDC 61958-0703-1).
• 133 mg of FTC and 200 mg of TDF (equivalent to 163 mg of tenofovir disoproxil) tablets are blue, rectangular shaped, film coated, debossed with "GSI" on one side and with "704" on the other side (NDC 61958-0704-1).
• 167 mg of FTC and 250 mg of TDF (equivalent to 204 mg of tenofovir disoproxil) tablets are blue, modified capsule shaped, film coated, debossed with "GSI" on one side and with "705" on the other side (NDC 61958-0705-1).
• 200 mg of FTC and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil) tablets are blue, capsule shaped, film coated, debossed with "GILEAD" on one side and with "701" on the other side (NDC 61958-0701-1).

TRUVADA is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Individuals must have a negative HIV-1 test immediately prior to initiating TRUVADA for HIV-1 PrEP [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Tenofovir and TDF administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.

Evidence of renal toxicity was noted in four animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

Emtricitabine and tenofovir are principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF, a component of TRUVADA [see Adverse Reactions (6.2)].

Prior to initiation and during use of TRUVADA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals. In individuals with chronic kidney disease, also assess serum phosphorus.

TRUVADA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.1)]. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in individuals at risk of renal dysfunction.

Table 7 provides a listing of established or clinically significant drug interactions. The drug interactions described are based on studies conducted with either TRUVADA, the components of TRUVADA (FTC and TDF) as individual agents and/or in combination, or are predicted drug interactions that may occur with TRUVADA [see Clinical Pharmacology (12.3)].

The iPrEx trial was a randomized, double-blind, placebo-controlled multinational study evaluating TRUVADA in 2,499 HIV-seronegative men or transgender women who have sex with men and with evidence of high-risk behavior for HIV-1 infection. Evidence of high-risk behavior included any one of the following reported to have occurred up to six months prior to study screening: no condom use during anal intercourse with an HIV-1 positive partner or a partner of unknown HIV status; anal intercourse with more than 3 sex partners; exchange of money, gifts, shelter, or drugs for anal sex; sex with male partner and diagnosis of sexually transmitted infection; no consistent use of condoms with sex partner known to be HIV-1 positive.

All subjects received monthly HIV-1 testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. Of the 2,499 enrolled subjects, 1,251 received TRUVADA and 1,248 received placebo. The mean age of subjects was 27 years; 5% were Asian, 9% Black, 18% White, and 72% Hispanic/Latino.

Subjects were followed for 4,237 person-years. The primary outcome measure was the incidence of documented HIV seroconversion. At the end of treatment, emergent HIV-1 seroconversion was observed in 131 subjects, of which 48 occurred in the TRUVADA group and 83 occurred in the placebo group, indicating a 42% (95% CI: 18–60%) reduction in risk. Risk reduction was found to be higher (53%; 95% CI: 34–72%) among subjects who reported previous unprotected anal intercourse (URAI) at screening (732 and 753 subjects reported URAI within the last 12 weeks at screening in the TRUVADA and placebo groups, respectively). In a post-hoc case control study of plasma and intracellular drug levels in about 10% of study subjects, risk reduction appeared to be greatest in subjects with detectable intracellular tenofovir diphosphate concentrations. Efficacy was therefore strongly correlated with adherence.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including FTC and TDF, components of TRUVADA, alone or in combination with other antiretrovirals. Treatment with TRUVADA should be suspended in any individual who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

The concomitant use of TRUVADA and other drugs may result in known or potentially significant drug interactions, some of which may lead to possible clinically significant adverse reactions from greater exposures of concomitant drugs [see Drug Interactions (7.2)].

See Table 7 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with TRUVADA; review concomitant medications during therapy with TRUVADA; and monitor for adverse reactions associated with the concomitant drugs.

The Partners PrEP trial was a randomized, double-blind, placebo-controlled 3-arm trial conducted in 4,758 HIV-1 serodiscordant heterosexual couples in Kenya and Uganda to evaluate the efficacy and safety of TDF (N=1,589) and FTC/TDF (N=1,583) versus (parallel comparison) placebo (N=1,586) in preventing HIV-1 acquisition by the uninfected partner.

All uninfected partner subjects received monthly HIV-1 testing, evaluation of adherence, assessment of sexual behavior, and safety evaluations. Women were also tested monthly for pregnancy. Women who became pregnant during the trial had study drug interrupted for the duration of the pregnancy and while breastfeeding. The uninfected partner subjects were predominantly male (61–64% across study drug groups) and had a mean age of 33–34 years.

Following 7,827 person-years of follow-up, 82 emergent HIV-1 seroconversions were reported, with an overall observed seroincidence rate of 1.05 per 100 person-years. Of the 82 seroconversions, 13 and 52 occurred in partner subjects randomized to TRUVADA and placebo, respectively. Two of the 13 seroconversions in the TRUVADA arm and 3 of the 52 seroconversions in the placebo arm occurred in women during treatment interruptions for pregnancy. The risk reduction for TRUVADA relative to placebo was 75% (95% CI: 55–87%). In a post-hoc case control study of plasma drug levels in about 10% of study subjects, risk reduction appeared to be greatest in subjects with detectable plasma tenofovir concentrations. Efficacy was therefore strongly correlated with adherence.

NDC 61958-0703-1

Truvada^®

(emtricitabine and

tenofovir disoproxil

fumarate) tablets

100 mg/150 mg

30 tablets

Rx only

DISPENSER: Each time Truvada is dispensed

give the patient the attached Medication Guide.

NDC 61958-0704-1

Truvada^®

(emtricitabine and

tenofovir disoproxil

fumarate) tablets

133 mg/200 mg

30 tablets

Rx only

DISPENSER: Each time Truvada is dispensed

give the patient the attached Medication Guide.

NDC 61958-0705-1

Truvada^®

(emtricitabine and

tenofovir disoproxil

fumarate) tablets

167 mg/250 mg

30 tablets

Rx only

DISPENSER: Each time Truvada is dispensed

give the patient the attached Medication Guide.

NDC 61958-0701-1

Truvada^®

(emtricitabine and

tenofovir disoproxil

fumarate) tablets

200 mg / 300 mg

30 tablets

Rx only

DISPENSER: Each time Truvada is dispensed

give the patient the attached Medication Guide.

Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing FTC+TDF administered in combination with efavirenz (EFV) versus zidovudine (AZT)/lamivudine (3TC) fixed-dose combination administered in combination with EFV in 511 antiretroviral-naïve adult subjects. From Weeks 96 to 144 of the trial, subjects received TRUVADA with EFV in place of FTC+TDF with EFV. Subjects had a mean age of 38 years (range 18–80); 86% were male, 59% were Caucasian, and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm³ (range 2–1,191) and median baseline plasma HIV-1 RNA was 5.01 log₁₀ copies/mL (range 3.56–6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥200 cells/mm³); 41% had CD4+ cell counts <200 cells/mm³ and 51% of subjects had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have EFV resistance at baseline are presented in Table 14.

Through Week 48, 84% and 73% of subjects in the FTC+TDF group and the AZT/3TC group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks is largely due to the higher number of discontinuations due to adverse events and other reasons in the AZT/3TC group in this open-label trial. In addition, 80% and 70% of subjects in the FTC+TDF group and the AZT/3TC group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm³ in the FTC+TDF group and 158 cells/mm³ in the AZT/3TC group at Week 48 (312 and 271 cells/mm³ at Week 144).

Through 48 weeks, 7 subjects in the FTC+TDF group and 5 subjects in the AZT/3TC group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).

Screen all individuals for HIV-1 infection immediately prior to initiating TRUVADA for HIV-1 PrEP and at least once every 3 months while taking TRUVADA, and upon diagnosis of any other sexually transmitted infections (STIs) [see Indications and Usage (1.2), Contraindications (4), and Warnings and Precautions (5.2)].

If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection [see Warnings and Precautions (5.2), Use in Specific Populations (8.4), and Clinical Studies (14.3 and 14.4)].

All individuals should be tested for the presence of chronic hepatitis B virus (HBV) before or when initiating TRUVADA [see Dosage and Administration (2.1)].

Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in HBV-infected individuals who have discontinued TRUVADA. Individuals infected with HBV who discontinue TRUVADA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in individuals with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure. HBV-uninfected individuals should be offered vaccination.

The dosage of TRUVADA for HIV-1 PrEP is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food in HIV-1 uninfected adults and adolescents weighing at least 35 kg [see Clinical Pharmacology (12.3)].

Prior to or when initiating TRUVADA, test individuals for hepatitis B virus infection [see Warnings and Precautions (5.1)].

Prior to initiation, and during use of TRUVADA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals. In individuals with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.3)].

TRUVADA is a two-drug fixed dose combination product containing emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The recommended dosage of TRUVADA in adults and in pediatric patients weighing at least 35 kg is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food [see Clinical Pharmacology (12.3)].

The recommended oral dosage of TRUVADA for pediatric patients weighing at least 17 kg and who can swallow a tablet is presented in Table 1. Tablets should be taken once daily with or without food. Weight should be monitored periodically and the TRUVADA dose adjusted accordingly.

Use TRUVADA for HIV-1 PrEP to reduce the risk of HIV-1 infection as part of a comprehensive prevention strategy that includes other prevention measures, including adherence to daily administration and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs). The time from initiation of TRUVADA for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown.

Risk for HIV-1 acquisition includes behavioral, biological, or epidemiologic factors including but not limited to condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network.

Counsel individuals on the use of other prevention measures (e.g., consistent and correct condom use, knowledge of partner(s)' HIV-1 status, including viral suppression status, regular testing for STIs that can facilitate HIV-1 transmission). Inform uninfected individuals about and support their efforts in reducing sexual risk behavior.

Use TRUVADA to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV-negative. HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking only TRUVADA, because TRUVADA alone does not constitute a complete regimen for HIV-1 treatment [see Microbiology (12.4)]; therefore, care should be taken to minimize the risk of initiating or continuing TRUVADA before confirming the individual is HIV-1 negative.

• Some HIV-1 tests only detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection. Prior to initiating TRUVADA for HIV-1 PrEP, ask seronegative individuals about recent (in past month) potential exposure events (e.g., condomless sex or condom breaking during sex with a partner of unknown HIV-1 status or unknown viremic status, or a recent STI), and evaluate for current or recent signs or symptoms consistent with acute HIV-1 infection (e.g., fever, fatigue, myalgia, skin rash).
• If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection.

While using TRUVADA for HIV-1 PrEP, HIV-1 testing should be repeated at least every 3 months, and upon diagnosis of any other STIs.

• If an HIV-1 test indicates possible HIV-1 infection, or if symptoms consistent with acute HIV-1 infection develop following a potential exposure event, convert the HIV-1 PrEP regimen to an HIV treatment regimen until negative infection status is confirmed using a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection.

Counsel HIV-1 uninfected individuals to strictly adhere to the once daily TRUVADA dosing schedule. The effectiveness of TRUVADA in reducing the risk of acquiring HIV-1 is strongly correlated with adherence, as demonstrated by measurable drug levels in clinical trials of TRUVADA for HIV-1 PrEP. Some individuals, such as adolescents, may benefit from more frequent visits and counseling to support adherence [see Use in Specific Populations (8.4), Microbiology (12.4), and Clinical Studies (14.3 and 14.4)].

Severe acute exacerbations of hepatitis B (HBV) have been reported in HBV-infected individuals who have discontinued TRUVADA. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in individuals who are infected with HBV and discontinue TRUVADA. If appropriate, anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1)].

TRUVADA used for HIV-1 PrEP must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initiating and at least every 3 months during use. Drug-resistant HIV-1 variants have been identified with use of TRUVADA for HIV-1 PrEP following undetected acute HIV-1 infection. Do not initiate TRUVADA for HIV-1 PrEP if signs or symptoms of acute HIV-1 infection are present unless negative infection status is confirmed [see Warnings and Precautions (5.2)].