FDA label 0fd0b2eb-cbaa-89a6-e063-6294a90afaa6

WARNING: POSTTREATMENT ACUTE EXACERBATIONS OF HEPATITIS B Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine or tenofovir disoproxil fumarate. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue TEMIXYS and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti- hepatitis B therapy may be warranted [see Warnings and Precautions (5.1) ] . WARNING: POSTTREATMENT ACUTE EXACERBATIONS OF HEPATITIS B See full prescribing information for complete boxed warning. Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine or tenofovir disoproxil fumarate. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Co-infected HIV-1/HBV Patients: Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. ( 5.1 ) New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering TEMIXYS with concurrent or recent use of nephrotoxic drugs. ( 5.2 ) Immune reconstitution syndrome: Observed in HIV-infected patients. May necessitate further evaluation and treatment ( 5.3 ) 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. ( 5.4 ) Lactic acidosis and severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.5 ) Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving interferon and ribavirin-based regimens. Monitor for treatment-associated toxicities. Discontinue TEMIXYS as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. ( 5.7 ) Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. ( 5.8 ) 5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV All patients with HIV-1 should be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. Posttreatment Exacerbations of Hepatitis : Discontinuation of anti-HBV therapy, including 3TC and TDF may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue TEMIXYS 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. If treatment with EPIVIR-HBV, TDF or a tenofovir alafenamide (TAF)-containing product is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV-1 treatment. 5.2 New Onset or Worsening Renal Impairment TDF, a component of TEMIXYS, 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 TDF [see Adverse Reactions (6.2) ] . Prior to initiation and during use of TEMIXYS, 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. Avoid TEMIXYS 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 tenofovir disoproxil fumarate. 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. 5.3 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including 3TC and TDF. 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 jiroveci 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. 5.4 Bone Loss and Mineralization Defects Bone Mineral Density (BMD): In clinical trials in HIV-1 infected adults, TDF was associated with greater decreases in 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 TDF [see Adverse Reactions (6.1) ] . Clinical trials evaluating TDF-containing regimens in pediatric subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected pediatric subjects 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 TDF-treated HIV-1 infected pediatric subjects as compared to the control groups. In all pediatric trials, normal skeletal growth (height) was not affected for the duration of the clinical trials. The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk 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 adults 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 the use of TDF [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) ] . 5.5 Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals. Treatment with TEMIXYS 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). 5.6 Risk of Adverse Reactions Due to Drug Interactions The concomitant use of TEMIXYS 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 3 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 TEMIXYS; review concomitant medications during therapy with TEMIXYS; and monitor for adverse reactions associated with the concomitant drugs. 5.7 Risk of Hepatic Decompensation When Used with Interferon- and Ribavirin-Based Regimens In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as 3TC, a component of TEMIXYS. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with 3TC in HIV-1/HCV co-infected patients [see Clinical Pharmacology (12.3) ] , hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and 3TC should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of 3TC should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). See the full prescribing information for interferon and ribavirin. 5.8 Pancreatitis In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, 3TC, a component of TEMIXYS, should be used with caution. Treatment with TEMIXYS should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1) ] .

6 ADVERSE REACTIONS Most common adverse reactions (incidence greater than 10%, with lamivudine and tenofovir disoproxil fumarate) were headache, pain, depression, diarrhea, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Celltrion, Inc. at 1-844-837-6511 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . The following adverse reactions are discussed in other sections of the labeling: Exacerbations of hepatitis B [see Boxed Warning , Warnings and Precautions (5.1) ] New onset or worsening renal impairment [see Warnings and Precautions (5.2) ] Immune reconstitution syndrome [see Warnings and Precautions (5.3) ] Bone Loss and Mineralization Defects [see Warnings and Precautions (5.4) ] Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.5) ] Hepatic decompensation in patient co-infected with HIV-1 and hepatitis C [see Warnings and Precautions (5.7) ] Pancreatitis [see Warnings and Precautions (5.8) ] 6.1 Clinical Trials Experience 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. Lamivudine and Tenofovir Disoproxil Fumarate Clinical Trials in Treatment-Naïve HIV-1 Infected Adult Subjects In Trial 903, 600 antiretroviral-naïve subjects received TDF (N=299) or stavudine (d4T) (N=301) administered in combination with lamivudine (3TC) and efavirenz (EFV) for 144 weeks. The most common adverse reactions were mild to moderate gastrointestinal events and dizziness. Mild adverse reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Table 1 provides the treatment-emergent adverse reactions (Grade 2-4) occurring in greater than or equal to 5% of subjects treated in any treatment group. Table 1: Selected Adverse Reactions a (Grades 2-4) Reported in ≥5% in Any Treatment Group in Trial 903 (0-144 Weeks) TDF + 3TC + EFV d4T + 3TC + EFV N=299 N=301 Rash event b 18% 12% Headache 14% 17% Pain 13% 12% Diarrhea 11% 13% Depression 11% 10% Back pain 9% 8% Nausea 8% 9% Fever 8% 7% Abdominal pain 7% 12% Asthenia 6% 7% Anxiety 6% 6% Vomiting 5% 9% Insomnia 5% 8% Arthralgia 5% 7% Pneumonia 5% 5% Dyspepsia 4% 5% Dizziness 3% 6% Myalgia 3% 5% Lipodystrophy c 1% 8% Peripheral neuropathy d 1% 5% a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. c Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. d Peripheral neuropathy includes peripheral neuritis and neuropathy. Laboratory Abnormalities : Table 2 provides a list of laboratory abnormalities (Grades 3-4) observed in Trial 903. With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the d4T group (40% and 9%) compared with tenofovir disoproxil fumarate group (19% and 1%), respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir disoproxil fumarate and d4T treatment arms. Table 2: Grades 3-4 Laboratory Abnormalities Reported in ≥1% of tenofovir disoproxil fumarate-treated subjects in Trial 903 (0-144 Weeks) TDF + 3TC + EFV d4T + 3TC + EFV N=299 N=301 Any ≥ Grade 3 Laboratory Abnormality 36% 42% Fasting Cholesterol (>240 mg/dL) 19% 40% Creatine Kinase (M: >990 U/L; F: >845 U/L) 12% 12% Serum Amylase (>175 U/L) 9% 8% AST (M: >180 U/L; F: >170 U/L) 5% 7% ALT (M: >215 U/L; F: >170 U/L) 4% 5% Hematuria (>100 RBC/HPF) 7% 7% Neutrophils (<750/mm 3 ) 3% 1% Fasting Triglycerides (>750 mg/dL) 1% 9% Pancreatitis: Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experiences pediatric subjects receiving 3TC alone or in combination with other antiretroviral agents [see Warnings and Precautions (5.8) ] . Changes in Bone Mineral Density In HIV-1 infected adult subjects in Trial 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving TDF + 3TC + EFV (−2.2% ± 3.9) compared with subjects receiving d4T + 3TC + EFV (−1.0% ± 4.6) through 144 weeks. Changes in BMD at the hip were similar between the two treatment groups (−2.8% ± 3.5 in the TDF group vs. −2.4% ± 4.5 in the d4T group). In both groups, the majority of the reduction in BMD occurred in the first 24-48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of TDF-treated subjects vs. 21% of the d4T-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the TDF group and 6 subjects in the d4T group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone- specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the TDF group relative to the d4T group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range [see Warnings and Precautions (5.4) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use for each of the individual components of TEMIXYS. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to 3TC and TDF. Lamivudine Body as a Whole : Redistribution/accumulation of body fat. Endocrine and Metabolic : Hyperglycemia. General : Weakness. Hemic and Lymphatic : Anemia (including pure red cell aplasia and severe anemias progressing on therapy). Hepatic and Pancreatic : Lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.5) ] , posttreatment exacerbations of hepatitis B [see Warnings and Precautions (5.1) ] . Hypersensitivity : Anaphylaxis, urticaria. Musculoskeletal : Muscle weakness, CPK elevation, rhabdomyolysis. Skin : Alopecia, pruritus. Tenofovir disoproxil fumarate 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.

<table border="1" cellspacing="0" cellpadding="0"><tbody><tr><td rowspan="2" valign="top"/><td valign="top"><paragraph><content styleCode="bold">TDF + 3TC + EFV</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">d4T + 3TC + EFV</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">N=299</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">N=301</content></paragraph></td></tr><tr><td valign="top"><paragraph>Rash event ^b</paragraph></td><td valign="top"><paragraph>18%</paragraph></td><td valign="top"><paragraph>12%</paragraph></td></tr><tr><td valign="top"><paragraph>Headache</paragraph></td><td valign="top"><paragraph>14%</paragraph></td><td valign="top"><paragraph>17%</paragraph></td></tr><tr><td valign="top"><paragraph>Pain</paragraph></td><td valign="top"><paragraph>13%</paragraph></td><td valign="top"><paragraph>12%</paragraph></td></tr><tr><td valign="top"><paragraph>Diarrhea</paragraph></td><td valign="top"><paragraph>11%</paragraph></td><td valign="top"><paragraph>13%</paragraph></td></tr><tr><td valign="top"><paragraph>Depression</paragraph></td><td valign="top"><paragraph>11%</paragraph></td><td valign="top"><paragraph>10%</paragraph></td></tr><tr><td valign="top"><paragraph>Back pain</paragraph></td><td valign="top"><paragraph>9%</paragraph></td><td valign="top"><paragraph>8%</paragraph></td></tr><tr><td valign="top"><paragraph>Nausea</paragraph></td><td valign="top"><paragraph>8%</paragraph></td><td valign="top"><paragraph>9%</paragraph></td></tr><tr><td valign="top"><paragraph>Fever</paragraph></td><td valign="top"><paragraph>8%</paragraph></td><td valign="top"><paragraph>7%</paragraph></td></tr><tr><td valign="top"><paragraph>Abdominal pain</paragraph></td><td valign="top"><paragraph>7%</paragraph></td><td valign="top"><paragraph>12%</paragraph></td></tr><tr><td valign="top"><paragraph>Asthenia</paragraph></td><td valign="top"><paragraph>6%</paragraph></td><td valign="top"><paragraph>7%</paragraph></td></tr><tr><td valign="top"><paragraph>Anxiety</paragraph></td><td valign="top"><paragraph>6%</paragraph></td><td valign="top"><paragraph>6%</paragraph></td></tr><tr><td valign="top"><paragraph>Vomiting</paragraph></td><td valign="top"><paragraph>5%</paragraph></td><td valign="top"><paragraph>9%</paragraph></td></tr><tr><td valign="top"><paragraph>Insomnia</paragraph></td><td valign="top"><paragraph>5%</paragraph></td><td valign="top"><paragraph>8%</paragraph></td></tr><tr><td valign="top"><paragraph>Arthralgia</paragraph></td><td valign="top"><paragraph>5%</paragraph></td><td valign="top"><paragraph>7%</paragraph></td></tr><tr><td valign="top"><paragraph>Pneumonia</paragraph></td><td valign="top"><paragraph>5%</paragraph></td><td valign="top"><paragraph>5%</paragraph></td></tr><tr><td valign="top"><paragraph>Dyspepsia</paragraph></td><td valign="top"><paragraph>4%</paragraph></td><td valign="top"><paragraph>5%</paragraph></td></tr><tr><td valign="top"><paragraph>Dizziness</paragraph></td><td valign="top"><paragraph>3%</paragraph></td><td valign="top"><paragraph>6%</paragraph></td></tr><tr><td valign="top"><paragraph>Myalgia</paragraph></td><td valign="top"><paragraph>3%</paragraph></td><td valign="top"><paragraph>5%</paragraph></td></tr><tr><td valign="top"><paragraph>Lipodystrophy ^c</paragraph></td><td valign="top"><paragraph>1%</paragraph></td><td valign="top"><paragraph>8%</paragraph></td></tr><tr><td valign="top"><paragraph>Peripheral neuropathy ^d</paragraph></td><td valign="top"><paragraph>1%</paragraph></td><td valign="top"><paragraph>5%</paragraph></td></tr></tbody></table>

<table border="1" cellspacing="0" cellpadding="0"><tbody><tr><td rowspan="2" valign="top"><paragraph/></td><td valign="top"><paragraph><content styleCode="bold">TDF + 3TC + EFV</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">d4T + 3TC + EFV</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">N=299</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">N=301</content></paragraph></td></tr><tr><td valign="top"><paragraph>Any <content styleCode="bold">&#x2265;</content>Grade 3 Laboratory Abnormality </paragraph></td><td><paragraph>36%</paragraph></td><td><paragraph>42%</paragraph></td></tr><tr><td valign="top"><paragraph>Fasting Cholesterol (&gt;240 mg/dL)</paragraph></td><td><paragraph>19%</paragraph></td><td><paragraph>40%</paragraph></td></tr><tr><td valign="top"><paragraph>Creatine Kinase (M: &gt;990 U/L; F: &gt;845 U/L)</paragraph></td><td><paragraph>12%</paragraph></td><td><paragraph>12%</paragraph></td></tr><tr><td valign="top"><paragraph>Serum Amylase (&gt;175 U/L)</paragraph></td><td><paragraph>9%</paragraph></td><td><paragraph>8%</paragraph></td></tr><tr><td valign="top"><paragraph>AST (M: &gt;180 U/L; F: &gt;170 U/L)</paragraph></td><td><paragraph>5%</paragraph></td><td><paragraph>7%</paragraph></td></tr><tr><td valign="top"><paragraph>ALT (M: &gt;215 U/L; F: &gt;170 U/L)</paragraph></td><td><paragraph>4%</paragraph></td><td><paragraph>5%</paragraph></td></tr><tr><td valign="top"><paragraph>Hematuria (&gt;100 RBC/HPF)</paragraph></td><td><paragraph>7%</paragraph></td><td><paragraph>7%</paragraph></td></tr><tr><td valign="top"><paragraph>Neutrophils (&lt;750/mm ³) </paragraph></td><td><paragraph>3%</paragraph></td><td><paragraph>1%</paragraph></td></tr><tr><td valign="top"><paragraph>Fasting Triglycerides (&gt;750 mg/dL)</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>9%</paragraph></td></tr></tbody></table>