WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Comprehensive management to reduce the risk of acquiring HIV-1: 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: 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: May necessitate further evaluation and treatment.

( 5.4 ) Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss.

( 5.5 ) Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

( 5.6 ) 5.1 Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection All patients 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 patients who have discontinued TRUVADA.

Patients 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, initiation of anti-hepatitis B therapy may be warranted, especially in patients 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.

5.2 Comprehensive Management to Reduce the Risk of Acquiring HIV-1 and Development of HIV-1 Resistance When TRUVADA Is Used for HIV-1 PrEP Use TRUVADA for HIV-1 PrEP only as part of a comprehensive prevention strategy that includes other prevention measures, such as safer sex practices, because TRUVADA is not always effective in preventing acquisition of HIV-1 [see Clinical Studies (14.3 and 14.4) ] .

Counsel uninfected individuals about safer sex practices that include consistent and correct use of condoms, knowledge of their HIV-1 status and that of their partner(s), the importance of virologic suppression in their partner(s) with HIV-1, and regular testing for other sexually transmitted infections that can facilitate HIV-1 transmission (such as syphilis, chlamydia, and gonorrhea).

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 drug exposure in HIV-infected individuals.

Many HIV-1 tests, such as rapid tests, detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection.

Prior to initiating TRUVADA for HIV-1 PrEP, evaluate seronegative individuals for current or recent signs or symptoms consistent with acute viral infections (e.g., fever, fatigue, myalgia, skin rash) and ask about potential exposure events (e.g., unprotected, or condom broke during, sex with an HIV-1 infected partner) that may have occurred within the last month.

If clinical symptoms consistent with acute viral infection are present and recent (<1 month) exposures are suspected, delay starting HIV-1 PrEP for at least one month and reconfirm HIV-1 status or use a test approved or cleared by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection.

While using TRUVADA for HIV-1 PrEP, HIV-1 screening tests should be repeated at least every 3 months, and upon diagnosis of any sexually transmitted infections.

Some individuals, such as adolescents, may benefit from more frequent visits and counseling [see Use in Specific Populations (8.4) ] .

If a screening 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 HIV-1, including acute or primary HIV-1 infection.

Counsel uninfected individuals to strictly adhere to the recommended 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 [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 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 patients.

In patients 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 patients at risk of renal dysfunction.

Treatment of HIV-1 Infection Dosing interval adjustment of TRUVADA and close monitoring of renal function are recommended in all patients with estimated creatinine clearance 30–49 mL/min [see Dosage and Administration (2.6) ] .

No safety or efficacy data are available in patients with renal impairment who received TRUVADA using these dosing guidelines, so the potential benefit of TRUVADA therapy should be assessed against the potential risk of renal toxicity.

TRUVADA is not recommended in patients with estimated creatinine clearance below 30 mL/min or patients requiring hemodialysis.

HIV-1 PrEP TRUVADA for HIV-1 PrEP is 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 TRUVADA 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 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, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of 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 TRUVADA) 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 TRUVADA, alone or in combination with other antiretrovirals.

Treatment with TRUVADA should be suspended in any patient or uninfected 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 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.