based on studies conducted with either emtricitabine and tenofovir disoproxil fumarate, the components of emtricitabine and tenofovir disoproxil fumarate tablets (ftc and tdf) as individual agents and/or in combination, or are predicted drug interactions that may occur with emtricitabine and tenofovir disoproxil fumarate tablets [see clinical pharmacology (12.3)]. table 7 established and significanta drug interactions: alteration in dose or regimen may be recommended based on drug interaction trials a.this table is not all inclusive. b.↑=increase, ↓=decrease c.indicates that a drug-drug interaction trial was conducted.

vaccination. 5.2 comprehensive management to reduce the risk of sexually transmitted infections, including hiv-1 and development of hiv-1 resistance when emtricitabine and tenofovir disoproxil fumarate tablets are used for hiv-1 prep use emtricitabine and tenofovir disoproxil fumarate tablets 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 emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep to maximal protection against hiv-1 infection is unknown. risk of 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 emtricitabine and tenofovir disoproxil fumarate tablets 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 emtricitabine and tenofovir disoproxil fumarate tablets, because emtricitabine and tenofovir disoproxil fumarate tablets 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 emtricitabine and tenofovir disoproxil fumarate tablets 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 emtricitabine and tenofovir disoproxil fumarate tablets 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 emtricitabine and tenofovir disoproxil fumarate tablets 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 emtricitabine and tenofovir disoproxil fumarate tablets dosing schedule. the effectiveness of emtricitabine and tenofovir disoproxil fumarate tablets in reducing the risk of acquiring hiv-1 is strongly correlated with adherence, as demonstrated by measurable drug levels in clinical trials of emtricitabine and tenofovir disoproxil fumarate tablets 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)]. 5.3 new onset or worsening renal impairment 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 emtricitabine and tenofovir disoproxil fumarate tablets [see adverse reactions (6.2)]. prior to initiation and during use of emtricitabine and tenofovir disoproxil fumarate tablets, 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. emtricitabine and tenofovir disoproxil fumarate tablets 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 individuals 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. treatment of hiv-1 infection dosing interval adjustment of emtricitabine and tenofovir disoproxil fumarate tablets and close monitoring of renal function are recommended in all patients with estimated creatinine clearance 30 to 49 ml/min [see dosage and administration (2.6)]. no safety or efficacy data are available in patients with renal impairment who received emtricitabine and tenofovir disoproxil fumarate using these dosing guidelines, so the potential benefit of emtricitabine and tenofovir disoproxil fumarate tablets therapy should be assessed against the potential risk of renal toxicity. emtricitabine and tenofovir disoproxil fumarate tablets are not recommended in patients with estimated creatinine clearance below 30 ml/min or patients requiring hemodialysis. hiv-1 prep emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep are not recommended in uninfected individuals with estimated creatinine clearance less than 60 ml/min. if a decrease in estimated creatinine clearance is observed while using emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep, evaluate potential causes and re-assess potential risks and benefits of continued use [see dosage and administration (2.6)]. 5.4 immune reconstitution syndrome immune reconstitution syndrome has been reported in hiv-1 infected patients treated with combination antiretroviral therapy, including emtricitabine and tenofovir disoproxil fumarate tablets. 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-barr¡sr 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. 5.5 bone loss and mineralization defects bone mineral density in clinical trials in hiv-1 infected adults and in a clinical trial of hiv-1 uninfected individuals, tdf (a component of emtricitabine and tenofovir disoproxil fumarate tablets) was associated with slightly greater decreases in bone mineral density (bmd) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators [see adverse reactions (6.1)]. serum parathyroid hormone levels and 1,25 vitamin d levels were also higher in subjects receiving tdf. clinical trials evaluating tdf in pediatric and adolescent subjects were conducted. under normal circumstances, bmd increases rapidly in pediatric patients. in hiv-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. total body bmd gain was less in the tdf-treated hiv-1 infected pediatric subjects as compared to the control groups. similar trends were observed in adolescent subjects aged 12 years to less than 18 years treated for chronic hepatitis b. in all pediatric trials, skeletal growth (height) appeared to be unaffected. the effects of tdf-associated changes in bmd and biochemical markers on long-term bone health and future fracture risk are unknown. assessment of bmd should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. although the effect of supplementation with calcium and vitamin d was not studied, such supplementation may be beneficial. if bone abnormalities are suspected, appropriate consultation should be obtained. mineralization defects cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with tdf use [see adverse reactions (6.1)]. arthralgia and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving tdf-containing products [see warnings and precautions (5.3)]. 5.6 lactic acidosis/severe hepatomegaly with steatosis 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 emtricitabine and tenofovir disoproxil fumarate tablets, alone or in combination with other antiretrovirals. treatment with emtricitabine and tenofovir disoproxil fumarate tablets 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). 5.7 risk of adverse reactions due to drug interactions the concomitant use of emtricitabine and tenofovir disoproxil fumarate tablets 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 emtricitabine and tenofovir disoproxil fumarate tablets; review concomitant medications during therapy with emtricitabine and tenofovir disoproxil fumarate tablets; and monitor for adverse reactions associated with the concomitant drugs.

ir disoproxil fumarate tablets, 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)]. 2.3 recommended dosage for treatment of hiv-1 infection in adults and pediatric patients weighing at least 35 kg emtricitabine and tenofovir disoproxil fumarate tablet is a two-drug fixed dose combination product containing emtricitabine (ftc) and tenofovir disoproxil fumarate (tdf). the recommended dosage of emtricitabine and tenofovir disoproxil fumarate tablets 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)]. 2.5 recommended dosage for hiv-1 prep in adults and adolescents weighing at least 35 kg the dosage of emtricitabine and tenofovir disoproxil fumarate tablets 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)]. 2.6 dosage adjustment in individuals with renal impairment 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 to 80 ml/min). the safety and effectiveness of the dosing interval adjustment recommendations in patients with moderate renal impairment (creatinine clearance 30 to 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. table 2 dosage interval adjustment for hiv-1 infected adult patients with altered creatinine clearance a.calculated using ideal (lean) body weight creatinine clearance (ml/min)a 50 30 to 49 <30 (including patients requiring hemodialysis) recommended dosing interval every 24 hours every 48 hours emtricitabine and tenofovir disoproxil fumarate tablets are not recommended. hiv-1 prep emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep are not recommended in hiv-1 uninfected individuals with estimated creatinine clearance below 60 ml/min [see warnings and precautions (5.3)]. if a decrease in estimated creatinine clearance is observed in uninfected individuals while using emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep, evaluate potential causes and re-assess potential risks and benefits of continued use [see warnings and precautions (5.3)]

red in combination with either ftc+tdf (n=257) or zidovudine (azt)/lamivudine (3tc) (n=254) for 144 weeks. the most common adverse reactions (incidence greater than or equal to 10%, all grades) included diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. table 3 provides the treatment-emergent adverse reactions (grades 2 to 4) occurring in greater than or equal to 5% of subjects treated in any treatment group. skin discoloration, manifested by hyperpigmentation, occurred in 3% of subjects taking ftc+tdf, and was generally mild and asymptomatic. the mechanism and clinical significance are unknown. table 3 selected adverse reactionsa (grades 2 to 4) reported in 5% in any treatment group in study 934 (0 to 144 weeks) a.frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b.from weeks 96 to 144 of the trial, subjects received emtricitabine and tenofovir disoproxil fumarate tablets with efavirenz in place of ftc+tdf with efavirenz. c.rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. ftc+tdf+efvb azt/3tc+efv n=257 n=254 fatigue 9% 8% depression 9% 7% nausea 9% 7% diarrhea 9% 5% dizziness 8% 7% upper respiratory tract infections 8% 5% sinusitis 8% 4% rash eventc 7% 9% headache 6% 5% insomnia 5% 7% nasopharyngitis 5% 3% vomiting 2% 5% laboratory abnormalities: laboratory abnormalities observed in this trial were generally consistent with those seen in other trials of tdf and/or ftc (table 4). table 4 significant laboratory abnormalities reported in 1% of subjects in any treatment group in study 934 (0 to 144 weeks) a.from weeks 96 to 144 of the trial, subjects received emtricitabine and tenofovir disoproxil fumarate tablets with efavirenz in place of ftc+tdf with efavirenz. ftc+tdf+efva azt/3tc+efv n=257 n=254 any grade 3 laboratory abnormality 30% 26% fasting cholesterol (>240 mg/dl) 22% 24% creatine kinase (m: >990 u/l) (f: >845 u/l) 9% 7% serum amylase (>175 u/l) 8% 4% alkaline phosphatase (>550 u/l) 1% 0% ast (m: >180 u/l) (f: >170 u/l) 3% 3% alt (m: >215 u/l) (f: >170 u/l) 2% 3% hemoglobin (<8.0 mg/dl) 0% 4% hyperglycemia (>250 mg/dl) 2% 1% hematuria (>75 rbc/hpf) 3% 2% glycosuria ( 3+) <1% 1% neutrophils (<750/mm3) 3% 5% fasting triglycerides (>750 mg/dl) 4% 2% clinical trials in pediatric subjects: emtricitabine in addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects (3 months to less than 18 years of age) who received treatment with ftc in the larger of two open-label, uncontrolled pediatric trials (n=116). tenofovir disoproxil fumarate in pediatric clinical trials (studies 352 and 321) conducted in 184 hiv 1 infected subjects 2 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with tdf were consistent with those observed in clinical trials of tdf in adults. in study 352 (2 to less than 12 years of age), 89 pediatric subjects received tdf for a median exposure of 104 weeks. of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy. three of these 4 subjects presented with hypophosphatemia and had decreases in total body or spine bmd z-score [see warnings and precautions (5.5)]. total body bmd gain at week 48 was less in the tdf group compared to the stavudine (d4t) or zidovudine (azt) treatment groups. the mean rate of bmd gain in lumbar spine was similar between treatment groups. one tdf-treated subject and none of the d4t- or azt-treated subjects experienced significant (greater than 4%) lumbar spine bmd loss at week 48. changes from baseline in bmd z-scores were −0.012 for lumbar spine and −0.338 for total body in the 64 subjects who were treated with tdf for 96 weeks. in study 321 (12 to less than 18 years of age), the mean rate of bmd gain at week 48 was less in the tdf compared to the placebo treatment group. six tdf-treated subjects and one placebo-treated subject had significant (greater than 4%) lumbar spine bmd loss at week 48. changes from baseline bmd z-scores were −0.341 for lumbar spine and −0.458 for total body in the 28 subjects who were treated with tdf for 96 weeks. in both trials, skeletal growth (height) appeared to be unaffected. adverse reactions from clinical trial experience in uninfected subjects taking emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep clinical trials in adult subjects: the safety profile of emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep was comparable to that observed in clinical trials of hiv-infected subjects based on two randomized placebo-controlled clinical trials (iprex, partners prep) in which 2,830 hiv-1 uninfected adults received emtricitabine and tenofovir disoproxil fumarate tablets once daily for hiv-1 prep. subjects were followed for a median of 71 weeks and 87 weeks, respectively. table 5 provides a list of selected adverse events that occurred in 2% or more of subjects in any treatment group in the iprex trial, with an incidence greater than placebo. table 5 selected adverse events (all grades) reported in 2 % in any treatment group in the iprex trial and greater than placebo ftc/tdf placebo (n=1251) (n=1248) headache 7% 6% abdominal pain 4% 2% weight decreased 3% 2% in the partners prep trial, the frequency of adverse events in the emtricitabine and tenofovir disoproxil fumarate tablets treatment group was generally either less than or the same as in the placebo group. laboratory abnormalities: table 6 provides a list of grade 2 to 4 laboratory abnormalities observed in the iprex and partners prep trials. six subjects in the tdf-containing arms of the partners prep trial discontinued from the trial due to an increase in serum creatinine compared with no discontinuations in the placebo group. one subject in the emtricitabine and tenofovir disoproxil fumarate tablets arm of the iprex trial discontinued from the trial due to an increase in serum creatinine and another subject discontinued due to low serum phosphorus. grades 2 to 3 proteinuria (2 to 4+) and/or glycosuria (3+) occurred in less than 1% of subjects treated with emtricitabine and tenofovir disoproxil fumarate tablets in the iprex trial and partners prep trial. table 6 laboratory abnormalities (highest toxicity grade reported for each subject) in the iprex trial and partners prep trial a.grading is per daids criteria. iprex trial partners prep trial grade 2 to 4a ftc/tdf (n=1251) placebo (n=1248) ftc/tdf (n=1579) placebo (n=1584) creatinine (>1.4 uln) <1% <1% <1% <1% phosphorus (<2.0 mg/dl) 10% 8% 9% 9% ast (>2.6 uln) 5% 5% <1% <1% alt (>2.6 uln) 7% 7% <1% <1% hemoglobin (<9.4 mg/dl) 1% 2% 2% 2% neutrophils (<750/mm3) <1% <1% 5% 3% changes in bone mineral density: in clinical trials of hiv-1 uninfected individuals, decreases in bmd were observed. in the iprex trial, a substudy of 503 subjects found mean changes from baseline in bmd ranging from –0.4% to –1.0% across total hip, spine, femoral neck, and trochanter in the emtricitabine and tenofovir disoproxil fumarate tablets group compared with the placebo group, which returned toward baseline after discontinuation of treatment. thirteen percent of emtricitabine and tenofovir disoproxil fumarate tablets-treated subjects versus 6% of placebo- treated subjects lost at least 5% of bmd at the spine during treatment. bone fractures were reported in 1.7% of the emtricitabine and tenofovir disoproxil fumarate tablets group compared with 1.4% in the placebo group. no correlation between bmd and fractures was noted [see clinical studies (14.3)]. the partners prep trial found similar fracture rates between the treatment and placebo groups (0.8% and 0.6%, respectively); no bmd evaluations were performed in this trial [see clinical studies (14.4)]. clinical trials in adolescent subjects in a single-arm, open-label clinical trial (atn113), in which 67 hiv-1 uninfected adolescent (15 to 18 years of age) men who have sex with men received emtricitabine and tenofovir disoproxil fumarate tablets once daily for hiv-1 prep, the safety profile of emtricitabine and tenofovir disoproxil fumarate tablets was similar to that observed in adults. median duration to exposure of emtricitabine and tenofovir disoproxil fumarate tablets was 47 weeks [see use in specific populations (8.4)]. in the atn113 trial, median bmd increased from baseline to week 48, +2.58% for lumbar spine and +0.72% for total body. one subject had significant (greater than or equal to 4%) total body bmd loss at week 24. median changes from baseline bmd z-scores were 0.0 for lumbar spine and −0.2 for total body at week 48. three subjects showed a worsening (change from > −2 to ≤ −2) from baseline in their lumbar spine or total body bmd z-scores at week 24 or 48. interpretation of these data, however, may be limited by the low rate of adherence to emtricitabine and tenofovir disoproxil fumarate tablets by week 48. 6.2 postmarketing experience 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.

based on studies conducted with either emtricitabine and tenofovir disoproxil fumarate, the components of emtricitabine and tenofovir disoproxil fumarate tablets (ftc and tdf) as individual agents and/or in combination, or are predicted drug interactions that may occur with emtricitabine and tenofovir disoproxil fumarate tablets [see clinical pharmacology (12.3)]. table 7 established and significanta drug interactions: alteration in dose or regimen may be recommended based on drug interaction trials a.this table is not all inclusive. b.↑=increase, ↓=decrease c.indicates that a drug-drug interaction trial was conducted.

n the u.s. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15 to 20%. in animal reproduction studies, no adverse developmental effects were observed when the components of emtricitabine and tenofovir disoproxil fumarate tablets were administered separately at doses/exposures ≥60 (ftc), ≥14 (tdf) and 2.7 (tenofovir) times those of the recommended daily dose of emtricitabine and tenofovir disoproxil fumarate tablets (see data). clinical considerations disease-associated maternal and/or embryo/fetal risk: hiv-1 prep published studies indicate an increased risk of hiv-1 infection during pregnancy and an increased risk of mother to child transmission during acute hiv-1 infection. in women at risk of acquiring hiv-1, consideration should be given to methods to prevent acquisition of hiv, including continuing or initiating emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep, during pregnancy. data human data: emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep in an observational study based on prospective reports to the apr, 78 hiv-seronegative women exposed to emtricitabine and tenofovir disoproxil fumarate tablets during pregnancy delivered live-born infants with no major malformations. all but one were first trimester exposures, and the median duration of exposure was 10.5 weeks. there were no new safety findings in the women receiving emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep compared with hiv-1 infected women treated with other antiretroviral medications. emtricitabine based on prospective reports to the apr of exposures to ftc-containing regimens during pregnancy resulting in live births (including over 3,300 exposed in the first trimester and over 1,300 exposed in the second/third trimester), the prevalence of major birth defects in live births was 2.6% (95% ci: 2.1% to 3.2%) and 2.3% (95% ci: 1.6% to 3.3%) following first and second/third trimester exposure, respectively to ftc-containing regimens. tenofovir disoproxil fumarate based on prospective reports to the apr of exposures to tdf-containing regimens during pregnancy resulting in live births (including over 4,000 exposed in the first trimester and over 1,700 exposed in the second/third trimester), the prevalence of major birth defects in live births was 2.4% (95% ci: 2.0% to 2.9%) and 2.4% (95% ci: 1.7% to 3.2%) following first and second/third trimester exposure, respectively to tdf-containing regimens. methodologic limitations of the apr include the use of macdp as the external comparator group. the macdp population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation. additionally, published observational studies on emtricitabine and tenofovir exposure in pregnancy have not shown an increased risk for major malformations. animal data: emtricitabine ftc was administered orally to pregnant mice (at 0, 250, 500, or 1,000 mg/kg/day), and rabbits (at 0, 100, 300, or 1,000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). no significant toxicological effects were observed in embryo-fetal toxicity studies performed with ftc in mice at exposures (auc) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose. in a pre/postnatal development study in mice, ftc was administered orally at doses up to 1,000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (auc) of approximately 60 times higher than human exposures at the recommended daily dose. tenofovir disoproxil fumarate tdf was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days 7 through 17, and 6 through 18, respectively). no significant toxicological effects were observed in embryo-fetal toxicity studies performed with tdf in rats at doses up to 14 times the human dose based on body surface area comparisons and in rabbits at doses up to 19 times the human dose based on body surface area comparisons. in a pre/postnatal development study in rats, tdf was administered orally through lactation at doses up to 600 mg/kg/day; no adverse effects were observed in the offspring at tenofovir exposures of approximately 2.7 times higher than human exposures at the recommended daily dose of emtricitabine and tenofovir disoproxil fumarate tablets. 8.2 lactation risk summary based on published data, ftc and tenofovir have been shown to be present in human breast milk (see data). it is not known if the components of emtricitabine and tenofovir disoproxil fumarate tablets affect milk production or have effects on the breastfed child. treatment of hiv-1 infection: the centers for disease control and prevention recommend that hiv-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of hiv-1. because of the potential for: (1) hiv transmission (in hiv-negative infants); (2) developing viral resistance (in hiv-positive infants); and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are taking emtricitabine and tenofovir disoproxil fumarate tablets for the treatment of hiv-1. hiv-1 prep: in hiv-uninfected women, the developmental and health benefits of breastfeeding and the mother's clinical need for emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep should be considered along with any potential adverse effects on the breastfed child from emtricitabine and tenofovir disoproxil fumarate tablets and the risk of hiv-1 acquisition due to nonadherence and subsequent mother to child transmission. women should not breastfeed if acute hiv-1 infection is suspected because of the risk of hiv-1 transmission to the infant. data hiv-1 prep: in a study of 50 breastfeeding women who received emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep between 1 and 24 weeks postpartum (median 13 weeks), after 7 days of treatment, tenofovir was undetectable but ftc was detectable in the plasma of most infants. in these infants, the average ftc plasma concentration was less than 1% of the ftc cmax observed in hiv-infected infants (up to 3 months of age) receiving the therapeutic dose of ftc (3 mg/kg/day). there were no serious adverse events. two infants (4%) had an adverse event of mild diarrhea which resolved. 8.4 pediatric use treatment of hiv-1 infection no pediatric clinical trial was conducted to evaluate the safety and efficacy of emtricitabine and tenofovir disoproxil fumarate tablets in patients with hiv-1 infection. data from previously conducted trials with the individual drug products, ftc and tdf, were relied upon to support dosage recommendations for emtricitabine and tenofovir disoproxil fumarate tablets. for additional information, consult the prescribing information for emtriva and viread. emtricitabine and tenofovir disoproxil fumarate tablets should only be administered to hiv-1 infected pediatric patients with body weight greater than or equal to 17 kg and who are able to swallow a tablet. because it is a fixed-dose combination tablet, emtricitabine and tenofovir disoproxil fumarate tablets cannot be adjusted for patients of lower weight [see warnings and precautions (5.5), adverse reactions (6.1) and clinical pharmacology (12.3)]. emtricitabine and tenofovir disoproxil fumarate tablets are not approved for use in pediatric patients weighing less than 17 kg. hiv-1 prep the safety and effectiveness of emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep in at-risk adolescents weighing at least 35 kg is supported by data from adequate and well-controlled studies of emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep in adults with additional data from safety and pharmacokinetic studies in previously conducted trials with the individual drug products, ftc and tdf, in hiv-1 infected adults and pediatric subjects [see dosage and administration (2.5), adverse reactions (6.1), clinical pharmacology (12.3 and 12.4),and clinical studies (14.3 and 14.4)]. safety, adherence, and resistance were evaluated in a single-arm, open-label clinical trial (atn113) in which 67 hiv-1 uninfected at-risk adolescent men who have sex with men received emtricitabine and tenofovir disoproxil fumarate tablets once daily for hiv-1 prep. the mean age of subjects was 17 years (range 15 to 18 years); 46% were hispanic, 52% black, and 37% white. the safety profile of emtricitabine and tenofovir disoproxil fumarate tablets in atn113 was similar to that observed in the adult hiv-1 prep trials [see adverse reactions (6.1)]. in the atn113 trial, hiv-1 seroconversion occurred in 3 subjects. tenofovir diphosphate levels in dried blood spot assays indicate that these subjects had poor adherence. no tenofovir- or ftc- associated hiv-1 resistance substitutions were detected in virus isolated from the 3 subjects who seroconverted [see microbiology (12.4)]. adherence to study drug, as demonstrated by tenofovir diphosphate levels in dried blood spot assays, declined markedly after week 12 once subjects switched from monthly to quarterly visits, suggesting that adolescents may benefit from more frequent visits and counseling [see warnings and precautions (5.2)]. safety and effectiveness of emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep in pediatric patients weighing less than 35 kg have not been established. 8.5 geriatric use clinical trials of ftc, tdf, or emtricitabine and tenofovir disoproxil fumarate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 renal impairment treatment of hiv-1 infection the dosing interval for emtricitabine and tenofovir disoproxil fumarate tablets should be modified in hiv-infected adult individuals with estimated creatinine clearance of 30 to 49 ml/min. emtricitabine and tenofovir disoproxil fumarate tablets are not recommended in individuals with estimated creatinine clearance below 30 ml/min and in individuals with end-stage renal disease requiring dialysis [see dosage and administration (2.6)]. hiv-1 prep emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep are not recommended in hiv-1 uninfected individuals with estimated creatinine clearance below 60 ml/min. if a decrease in estimated creatinine clearance is observed in uninfected individuals while using emtricitabine and tenofovir disoproxil fumarate tablets for hiv-1 prep, evaluate potential causes and re-assess potential risks and benefits of continued use [see dosage and administration (2.6)].