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warnings and cautions
5 WARNINGS AND PRECAUTIONS New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering VIREAD with concurrent or recent use of nephrotoxic drugs. ( 5.2 ) HIV testing: HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. VIREAD should only be used as part of an appropriate antiretroviral combination regimen in HIV-infected patients with or without HBV coinfection. ( 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 VIREAD [see Dosage and Administration (2.1) ] . Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis B. Patients infected with HBV who discontinue VIREAD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption 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. 5.2 New Onset or Worsening Renal Impairment Tenofovir is 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 VIREAD . Tenofovir is 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 VIREAD [see Adverse Reactions (6.2) ] . Prior to initiation and during use of VIREAD, 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. Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 mL/min . No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity. Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 mL/min [see Dosage and Administration (2.4) ] . No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity. VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) . 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. VIREAD 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.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. 5.3 Patients Coinfected with HIV-1 and HBV Due to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen. HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with VIREAD. 5.4 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including VIREAD. 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, VIREAD 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 . Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving VIREAD. In clinical trials in HIV-1 infected adults, VIREAD 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 VIREAD. Clinical trials evaluating VIREAD in pediatric subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects 2 years to less than 18 years of age, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the VIREAD-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic HBV-infected pediatric subjects 2 years to less than 18 years of age. In all pediatric trials, normal skeletal growth (height) was not affected for the duration of the clinical trials [see Adverse Reactions (6.1) ] . The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in adults and pediatric subjects 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients, and in particular, the effects of long-duration exposure in younger children is unknown.The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in adults and pediatric subjects 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients, and in particular, the effects of long-duration exposure in younger children is unknown. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial. 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. If bone abnormalities are suspected, appropriate consultation should be obtained.Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial. 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. 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 VIREAD use [see Adverse Reactions (6.2) ] . 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 (5.2) ]. 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 TDF, alone or in combination with other antiretrovirals. Treatment with VIREAD should be suspended in any patient 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 VIREAD 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 12 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 VIREAD; review concomitant medications during therapy with VIREAD; and monitor for adverse reactions associated with the concomitant drugs.