FDA label 7d3c0c46-e0e3-1897-e053-2a91aa0a164e

WARNING: RISK OF LACTIC ACIDOSIS, EXACERBATIONS OF HEPATITIS B IN CO-INFECTED PATIENTS UPON DISCONTINUATION OF EPIVIR , DIFFERENT FORMULATIONS OF EPIVIR. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.1)] . 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 EPIVIR. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue EPIVIR and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.2)]. EPIVIR Tablets and Oral Solution (used to treat HIV-1 infection) contain a higher dose of the active ingredient (lamivudine) than EPIVIR-HBV ® Tablets and Oral Solution (used to treat chronic HBV infection). Patients with HIV-1 infection should receive only dosage forms appropriate for treatment of HIV-1 [see Warnings and Precautions (5.2)] . WARNING: LACTIC ACIDOSIS, POSTTREATMENT EXACERBATIONS OF HEPATITIS B IN CO-INFECTED PATIENTS, DIFFERENT FORMULATIONS OF EPIVIR See full prescribing information for complete boxed warning Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. (5.1) 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 EPIVIR. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. (5.2) Patients with HIV-1 infection should receive only dosage forms of EPIVIR appropriate for treatment of HIV-1. (5.2)

5 WARNINGS AND PRECAUTIONS Lactic acidosis and severe hepatomegaly with steatosis: Reported with the use of nucleoside analogues. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatoxicity occur. (5.1) Severe acute exacerbations of hepatitis: Reported in patients who are co-infected with hepatitis B virus and HIV-1 and discontinued EPIVIR. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. (5.2) Patients with HIV-1 infection should receive only dosage forms of EPIVIR appropriate for treatment of HIV-1. (5.2) Co-infected HIV-1/HBV Patients: Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. (5.2) Emtricitabine should not be administered concomitantly with lamivudine-containing products. (5.3) 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 EPIVIR as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.4) Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. (5.5) Immune reconstitution syndrome (5.6) and redistribution/accumulation of body fat (5.7) have been reported in patients treated with combination antiretroviral therapy. 5.1 Lactic Acidosis/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, including lamivudine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering EPIVIR to any patient with known risk factors for liver disease; however, cases also have been reported in patients with no known risk factors. Treatment with EPIVIR 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). 5.2 Patients With HIV-1 and Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis: In clinical trials in non-HIV-1-infected patients treated with lamivudine for chronic hepatitis B, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis. Important Differences Among Lamivudine-Containing Products: EPIVIR Tablets and Oral Solution contain a higher dose of the same active ingredient (lamivudine) than EPIVIR-HBV Tablets and EPIVIR-HBV Oral Solution. EPIVIR-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of lamivudine in EPIVIR-HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV. If treatment with EPIVIR-HBV 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. If a decision is made to administer lamivudine to patients co-infected with HIV-1 and HBV, EPIVIR Tablets, EPIVIR Oral Solution, COMBIVIR ® (lamivudine/zidovudine) Tablets, EPZICOM ® (abacavir sulfate and lamivudine) Tablets, or TRIZIVIR ® (abacavir sulfate, lamivudine, and zidovudine) Tablets should be used as part of an appropriate combination regimen. Emergence of Lamivudine-Resistant HBV: In non–HIV-1-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see full prescribing information for EPIVIR-HBV for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. 5.3 Use With Other Lamivudine- and Emtricitabine-Containing Products EPIVIR should not be administered concomitantly with other lamivudine-containing products including EPIVIR-HBV Tablets, EPIVIR Oral Solution, COMBIVIR (lamivudine/zidovudine) Tablets, EPZICOM (abacavir sulfate and lamivudine) Tablets, or TRIZIVIR (abacavir sulfate, lamivudine, and zidovudine) or emtricitabine-containing products, including ATRIPLA ® (efavirenz, emtricitabine, and tenofovir), EMTRIVA ® (emtricitabine), or TRUVADA ® (emtricitabine and tenofovir). 5.4 Use With Interferon- and Ribavirin-Based Regimens In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine. 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 lamivudine 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 EPIVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of EPIVIR 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 >6). See the complete prescribing information for interferon and ribavirin. 5.5 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, EPIVIR should be used with caution. Treatment with EPIVIR should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1)]. 5.6 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EPIVIR. During the initial phase of combination antiretroviral treatment, 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. 5.7 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

6 ADVERSE REACTIONS The most common reported adverse reactions (incidence ≥15%) in adults were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough. (6.1) The most common reported adverse reactions (incidence ≥15%) in pediatric patients were fever and cough. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience The following adverse reactions are discussed in greater detail in other sections of the labeling: Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.1)]. Severe acute exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.2)]. Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis C [see Warnings and Precautions (5.4)]. Pancreatitis [see Warnings and Precautions (5.5)]. 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. Adults - Clinical Trials in HIV-1: The safety profile of EPIVIR in adults is primarily based on 3,568 HIV-1-infected patients in 7 clinical trials. The most common adverse reactions are headache, nausea, malaise, fatigue, nasal signs and symptoms, diarrhea and cough. Selected clinical adverse reactions in ≥5% of patients during therapy with EPIVIR 150 mg twice daily plus RETROVIR ® 200 mg 3 times daily for up to 24 weeks are listed in Table 3. Table 3. Selected Clinical Adverse Reactions (≥5% Frequency) in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) Adverse Reaction EPIVIR 150 mg Twice Daily plus RETROVIR (n = 251) RETROVIR a (n = 230) Body as a Whole Headache 35% 27% Malaise & fatigue 27% 23% Fever or chills 10% 12% Digestive Nausea 33% 29% Diarrhea 18% 22% Nausea & vomiting 13% 12% Anorexia and/or decreased appetite 10% 7% Abdominal pain 9% 11% Abdominal cramps 6% 3% Dyspepsia 5% 5% Nervous System Neuropathy 12% 10% Insomnia & other sleep disorders 11% 7% Dizziness 10% 4% Depressive disorders 9% 4% Respiratory Nasal signs & symptoms 20% 11% Cough 18% 13% Skin Skin rashes 9% 6% Musculoskeletal Musculoskeletal pain 12% 10% Myalgia 8% 6% Arthralgia 5% 5% a Either zidovudine monotherapy or zidovudine in combination with zalcitabine. Pancreatitis: Pancreatitis was observed in 9 out of 2,613 adult patients (0.3%) who received EPIVIR in controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and NUCB3007 [see Warnings and Precautions (5.5)]. EPIVIR 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in patients receiving EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) for 48 weeks were similar. Selected laboratory abnormalities observed during therapy are summarized in Table 4. Table 4. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Studies (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and a Clinical Endpoint Study (NUCB3007) Test (Threshold Level) 24-Week Surrogate Endpoint Studies a Clinical Endpoint Study a EPIVIR plus RETROVIR RETROVIR b EPIVIR plus Current Therapy Placebo plus Current Therapy c Absolute neutrophil count (<750/mm 3 ) 7.2% 5.4% 15% 13% Hemoglobin (<8.0 g/dL) 2.9% 1.8% 2.2% 3.4% Platelets (<50,000/mm 3 ) 0.4% 1.3% 2.8% 3.8% ALT (>5.0 x ULN) 3.7% 3.6% 3.8% 1.9% AST (>5.0 x ULN) 1.7% 1.8% 4.0% 2.1% Bilirubin (>2.5 x ULN) 0.8% 0.4% ND ND Amylase (>2.0 x ULN) 4.2% 1.5% 2.2% 1.1% a The median duration on study was 12 months. b Either zidovudine monotherapy or zidovudine in combination with zalcitabine. c Current therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine. ULN = Upper limit of normal. ND = Not done. The frequencies of selected laboratory abnormalities reported in patients receiving EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar. Pediatric Patients – Clinical Trials in HIV-1: EPIVIR Oral Solution has been studied in 638 pediatric patients 3 months to 18 years of age in 3 clinical trials. Selected clinical adverse reactions and physical findings with a ≥5% frequency during therapy with EPIVIR 4 mg/kg twice daily plus RETROVIR 160 mg/m 2 3 times daily in therapy-naive (≤56 days of antiretroviral therapy) pediatric patients are listed in Table 5. Table 5. Selected Clinical Adverse Reactions and Physical Findings (≥5% Frequency) in Pediatric Patients in Study ACTG300 Adverse Reaction EPIVIR plus RETROVIR (n = 236) Didanosine (n = 235) Body as a Whole Fever 25% 32% Digestive Hepatomegaly 11% 11% Nausea & vomiting 8% 7% Diarrhea 8% 6% Stomatitis 6% 12% Splenomegaly 5% 8% Respiratory Cough 15% 18% Abnormal breath sounds/wheezing 7% 9% Ear, Nose, and Throat Signs or symptoms of ears a 7% 6% Nasal discharge or congestion 8% 11% Other Skin rashes 12% 14% Lymphadenopathy 9% 11% a Includes pain, discharge, erythema, or swelling of an ear. Pancreatitis: Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric patients receiving EPIVIR alone or in combination with other antiretroviral agents. In an open-label dose-escalation study (NUCA2002), 14 patients (14%) developed pancreatitis while receiving monotherapy with EPIVIR. Three of these patients died of complications of pancreatitis. In a second open-label study (NUCA2005), 12 patients (18%) developed pancreatitis. In Study ACTG300, pancreatitis was not observed in 236 patients randomized to EPIVIR plus RETROVIR. Pancreatitis was observed in 1 patient in this study who received open-label EPIVIR in combination with RETROVIR and ritonavir following discontinuation of didanosine monotherapy [see Warnings and Precautions (5.5)]. Paresthesias and Peripheral Neuropathies: Paresthesias and peripheral neuropathies were reported in 15 patients (15%) in Study NUCA2002, 6 patients (9%) in Study NUCA2005, and 2 patients (<1%) in Study ACTG300. Selected laboratory abnormalities experienced by therapy-naive (≤56 days of antiretroviral therapy) pediatric patients are listed in Table 6. Table 6. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Pediatric Patients in Study ACTG300 Test (Threshold Level) EPIVIR plus RETROVIR Didanosine Absolute neutrophil count (<400/mm 3 ) 8% 3% Hemoglobin (<7.0 g/dL) 4% 2% Platelets (<50,000/mm 3 ) 1% 3% ALT (>10 x ULN) 1% 3% AST (>10 x ULN) 2% 4% Lipase (>2.5 x ULN) 3% 3% Total Amylase (>2.5 x ULN) 3% 3% ULN = Upper limit of normal. Neonates - Clinical Trials in HIV-1: Limited short-term safety information is available from 2 small, uncontrolled studies in South Africa in neonates receiving lamivudine with or without zidovudine for the first week of life following maternal treatment starting at Week 38 or 36 of gestation [see Clinical Pharmacology (12.3)] . Selected adverse reactions reported in these neonates included increased liver function tests, anemia, diarrhea, electrolyte disturbances, hypoglycemia, jaundice and hepatomegaly, rash, respiratory infections, and sepsis; 3 neonates died (1 from gastroenteritis with acidosis and convulsions, 1 from traumatic injury, and 1 from unknown causes). Two other nonfatal gastroenteritis or diarrhea cases were reported, including 1 with convulsions; 1 infant had transient renal insufficiency associated with dehydration. The absence of control groups limits assessments of causality, but it should be assumed that perinatally exposed infants may be at risk for adverse reactions comparable to those reported in pediatric and adult HIV-1-infected patients treated with lamivudine-containing combination regimens. Long-term effects of in utero and infant lamivudine exposure are not known. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been reported during postmarketing use of EPIVIR. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to lamivudine. Body as a Whole: Redistribution/accumulation of body fat [see Warnings and Precautions (5.7)]. 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, posttreatment exacerbation of hepatitis B [see Boxed Warning, Warnings and Precautions (5.1, 5.2)]. Hypersensitivity: Anaphylaxis, urticaria. Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis. Skin: Alopecia, pruritus.

<table width="599.000" ID="id_bdd73752-9398-4f93-a0e2-bcfd730829ff"> <caption ID="id_0c2cf9d8-6de6-4a12-8e1d-575eb00c113f">Table 3. Selected Clinical Adverse Reactions (&#x2265;5% Frequency) in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002)</caption> <col width="45.9%"/> <col width="27.5%"/> <col width="26.5%"/> <tbody> <tr ID="id_0aed840a-3aaa-4c65-aba0-3cb38c18f4b3"> <td align="center" styleCode="Botrule Toprule Rrule Lrule" valign="bottom">Adverse Reaction</td> <td align="center" styleCode="Botrule Rrule" valign="bottom"> <paragraph>EPIVIR 150 mg Twice Daily plus RETROVIR </paragraph>(n = 251) </td> <td align="center" styleCode="Botrule Rrule" valign="bottom"> <paragraph>RETROVIR ^a </paragraph>(n = 230) </td> </tr> <tr ID="id_e62ca5c1-a0a7-4f9a-8805-537e2523ec20"> <td align="left" styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Body as a Whole</content> </td> <td align="center" styleCode="Rrule" valign="bottom"/> <td align="center" styleCode="Rrule" valign="bottom"/> </tr> <tr ID="id_97fce455-5f74-4c3e-bd9a-2109b81e8f31"> <td align="left" styleCode="Lrule Rrule" valign="top"> Headache</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>35%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>27%</paragraph> </td> </tr> <tr ID="id_743b3cbd-ceda-4fd0-90fd-47796b149e5a"> <td align="left" styleCode="Lrule Rrule" valign="top"> Malaise &amp; fatigue</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>27%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>23%</paragraph> </td> </tr> <tr ID="id_35b19ebf-9359-45c9-bd94-f6c378fc6a58"> <td align="left" styleCode="Lrule Rrule" valign="top"> Fever or chills</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>10%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>12%</paragraph> </td> </tr> <tr ID="id_07dd7aa4-742b-45c3-a4e0-72bdf7f78bf3"> <td align="left" styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Digestive</content> </td> <td align="center" styleCode="Rrule" valign="bottom"/> <td align="center" styleCode="Rrule" valign="bottom"/> </tr> <tr ID="id_696fc4f1-f159-4fc8-b359-23606b75ab27"> <td align="left" styleCode="Lrule Rrule" valign="top"> Nausea</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>33%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>29%</paragraph> </td> </tr> <tr ID="id_87d00714-dbb8-4a3c-9250-cf9037a93c1b"> <td align="left" styleCode="Lrule Rrule" valign="top"> Diarrhea</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>18%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>22%</paragraph> </td> </tr> <tr ID="id_01ad8021-ee97-415f-9e3b-fffee614baee"> <td align="left" styleCode="Lrule Rrule" valign="top"> Nausea &amp; vomiting</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>13%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>12%</paragraph> </td> </tr> <tr ID="id_35aee9c1-4ff5-4453-ba8d-29e7c504a5cd"> <td align="left" styleCode="Lrule Rrule" valign="top"> Anorexia and/or decreased appetite</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>10%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>7%</paragraph> </td> </tr> <tr ID="id_8fec630f-ee49-4b03-8e38-151d833a81a1"> <td align="left" styleCode="Lrule Rrule" valign="top"> Abdominal pain</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>9%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>11%</paragraph> </td> </tr> <tr ID="id_08b334c5-6917-4849-a540-5820cdb742cc"> <td align="left" styleCode="Lrule Rrule" valign="top"> Abdominal cramps</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>6%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>3%</paragraph> </td> </tr> <tr ID="id_c386dbc1-5ecd-40ba-a4c4-3a6c94942329"> <td align="left" styleCode="Lrule Rrule" valign="top"> Dyspepsia</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>5%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>5%</paragraph> </td> </tr> <tr ID="id_37eef091-b92a-4994-b7d0-779303bcc1bc"> <td align="left" styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Nervous System</content> </td> <td align="center" styleCode="Rrule" valign="bottom"/> <td align="center" styleCode="Rrule" valign="bottom"/> </tr> <tr ID="id_bb830720-29d7-4bcf-a40e-116c10370718"> <td align="left" styleCode="Lrule Rrule" valign="top"> Neuropathy</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>12%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>10%</paragraph> </td> </tr> <tr ID="id_17b0b6ce-05cd-4395-8134-71ebadf2f5af"> <td align="left" styleCode="Lrule Rrule" valign="top"> Insomnia &amp; other sleep disorders</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>11%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>7%</paragraph> </td> </tr> <tr ID="id_e30fb79c-ac38-4d1e-960e-3eb44260a25b"> <td align="left" styleCode="Lrule Rrule" valign="top"> Dizziness</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>10%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>4%</paragraph> </td> </tr> <tr ID="id_579bd65c-f96e-450e-a81b-af2d6daf0c03"> <td align="left" styleCode="Lrule Rrule" valign="top"> Depressive disorders</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>9%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>4%</paragraph> </td> </tr> <tr ID="id_7366b172-1deb-4b70-bbe4-d465b73e336b"> <td align="left" styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Respiratory</content> </td> <td align="center" styleCode="Rrule" valign="bottom"/> <td align="center" styleCode="Rrule" valign="bottom"/> </tr> <tr ID="id_7cb2e7ea-dcd0-45a3-941c-018b463556f2"> <td align="left" styleCode="Lrule Rrule" valign="top"> Nasal signs &amp; symptoms</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>20%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>11%</paragraph> </td> </tr> <tr ID="id_404a9087-8a3b-47b7-8f26-7f094abf2e84"> <td align="left" styleCode="Lrule Rrule" valign="top"> Cough</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>18%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>13%</paragraph> </td> </tr> <tr ID="id_60ec4b6a-a162-4b79-953b-a31624fd8a04"> <td align="left" styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Skin</content> </td> <td align="center" styleCode="Rrule" valign="bottom"/> <td align="center" styleCode="Rrule" valign="bottom"/> </tr> <tr ID="id_837dca3d-55d6-4635-90db-b2d77287b924"> <td align="left" styleCode="Lrule Rrule" valign="top"> Skin rashes</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>9%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>6%</paragraph> </td> </tr> <tr ID="id_e097e25d-5878-4cdf-a28b-feef3b3b5079"> <td align="left" styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Musculoskeletal</content> </td> <td align="center" styleCode="Rrule" valign="bottom"/> <td align="center" styleCode="Rrule" valign="bottom"/> </tr> <tr ID="id_cc129877-1263-4280-81d6-094bee62e921"> <td align="left" styleCode="Lrule Rrule" valign="top"> Musculoskeletal pain</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>12%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>10%</paragraph> </td> </tr> <tr ID="id_468e6940-4c52-4950-a369-865299eb8e80"> <td align="left" styleCode="Lrule Rrule" valign="top"> Myalgia</td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>8%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>6%</paragraph> </td> </tr> <tr ID="id_0f609ce4-d507-4783-b882-a77c362c9c86"> <td align="left" styleCode="Lrule Botrule Rrule" valign="top"> Arthralgia</td> <td align="center" styleCode="Botrule Rrule" valign="bottom"> <paragraph>5%</paragraph> </td> <td align="center" styleCode="Botrule Rrule" valign="bottom"> <paragraph>5%</paragraph> </td> </tr> <tr ID="id_d0e85586-a028-4376-ac14-9574ec221c76"> <td align="left" colspan="3" styleCode="Lrule Botrule Rrule" valign="top"> ^a Either zidovudine monotherapy or zidovudine in combination with zalcitabine. </td> </tr> </tbody> </table>

<table width="0.000" ID="id_7924a97b-8f7c-4c26-acae-45fb2b449c2c"> <caption ID="id_98bcb4a6-cd9c-4f88-af34-8f169967831c">Table 4. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Studies (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and a Clinical Endpoint Study (NUCB3007)</caption> <col/> <col/> <col/> <col/> <col/> <tbody> <tr ID="id_3801c373-0030-42c1-be92-e8c3afe05ba7"> <td align="center" rowspan="2" styleCode="Botrule Toprule Rrule" valign="bottom"> <paragraph>Test </paragraph> <paragraph>(Threshold Level)</paragraph> </td> <td align="center" colspan="2" styleCode="Botrule Rrule" valign="bottom"> <paragraph>24-Week Surrogate Endpoint</paragraph> <paragraph>Studies ^a </paragraph> </td> <td align="center" colspan="2" styleCode="Botrule" valign="bottom"> <paragraph>Clinical Endpoint</paragraph> <paragraph>Study ^a </paragraph> </td> </tr> <tr ID="id_f43b4acc-ec3b-43b2-b9a9-5da6e8db1eeb"> <td align="center" styleCode="Botrule Rrule" valign="bottom"> <paragraph>EPIVIR plus</paragraph> <paragraph>RETROVIR</paragraph> </td> <td align="center" styleCode="Botrule Rrule" valign="bottom"> <paragraph>RETROVIR ^b </paragraph> </td> <td align="center" styleCode="Botrule Rrule" valign="bottom"> <paragraph>EPIVIR plus</paragraph> <paragraph>Current Therapy</paragraph> </td> <td align="center" styleCode="Botrule" valign="bottom"> <paragraph>Placebo plus</paragraph> <paragraph>Current Therapy ^c </paragraph> </td> </tr> <tr ID="id_29ad523d-4178-4481-9f8a-b0daf29ad9ec"> <td align="left" styleCode="Rrule" valign="top"> <paragraph>Absolute neutrophil count (&lt;750/mm ³) </paragraph> </td> <td align="center" styleCode="Rrule" valign="top"> <paragraph>7.2%</paragraph> </td> <td align="center" styleCode="Rrule" valign="top"> <paragraph>5.4%</paragraph> </td> <td align="center" styleCode="Rrule" valign="top"> <paragraph>15%</paragraph> </td> <td align="center" valign="top"> <paragraph>13%</paragraph> </td> </tr> <tr ID="id_eaac97f1-105c-4124-8e36-8f2683c0604d"> <td align="left" styleCode="Rrule" valign="top"> <paragraph>Hemoglobin (&lt;8.0 g/dL)</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>2.9%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>1.8%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>2.2%</paragraph> </td> <td align="center" valign="bottom"> <paragraph>3.4%</paragraph> </td> </tr> <tr ID="id_3122fe89-e711-40cd-a1b2-8d10cd7dedb3"> <td align="left" styleCode="Rrule" valign="top"> <paragraph>Platelets (&lt;50,000/mm ³) </paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>0.4%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>1.3%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>2.8%</paragraph> </td> <td align="center" valign="bottom"> <paragraph>3.8%</paragraph> </td> </tr> <tr ID="id_ffdfc525-1ef1-427b-9a84-d6caa1e55ec9"> <td align="left" styleCode="Rrule" valign="top"> <paragraph>ALT (&gt;5.0 x ULN)</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>3.7%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>3.6%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>3.8%</paragraph> </td> <td align="center" valign="bottom"> <paragraph>1.9%</paragraph> </td> </tr> <tr ID="id_6e1a6a40-c0f8-4916-838f-100751e93e91"> <td align="left" styleCode="Rrule" valign="top"> <paragraph>AST (&gt;5.0 x ULN)</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>1.7%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>1.8%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>4.0%</paragraph> </td> <td align="center" valign="bottom"> <paragraph>2.1%</paragraph> </td> </tr> <tr ID="id_af190770-5f06-47f5-81f2-00a4df8c0a66"> <td align="left" styleCode="Rrule" valign="top"> <paragraph>Bilirubin (&gt;2.5 x ULN)</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>0.8%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>0.4%</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>ND</paragraph> </td> <td align="center" valign="bottom"> <paragraph>ND</paragraph> </td> </tr> <tr ID="id_57ad3246-c585-43be-9561-2e661b5ab2b3"> <td align="left" styleCode="Botrule Rrule" valign="top"> <paragraph>Amylase (&gt;2.0 x ULN)</paragraph> </td> <td align="center" styleCode="Botrule Rrule" valign="bottom"> <paragraph>4.2%</paragraph> </td> <td align="center" styleCode="Botrule Rrule" valign="bottom"> <paragraph>1.5%</paragraph> </td> <td align="center" styleCode="Botrule Rrule" valign="bottom"> <paragraph>2.2%</paragraph> </td> <td align="center" styleCode="Botrule" valign="bottom"> <paragraph>1.1%</paragraph> </td> </tr> <tr ID="id_2eec45c2-00ec-4af5-b29f-a944dbcb59b8"> <td align="left" colspan="5" valign="top"> ^a The median duration on study was 12 months. </td> </tr> <tr ID="id_151da86b-9ca8-438f-8351-c884e196c36d"> <td align="left" colspan="5" valign="top"> ^b Either zidovudine monotherapy or zidovudine in combination with zalcitabine. </td> </tr> <tr ID="id_64f5628a-a285-4629-bb7e-4485e629aaf0"> <td align="left" colspan="5" valign="top"> ^c Current therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine. </td> </tr> <tr ID="id_b7acf34d-ff2f-4c85-8c1d-408abb8ce353"> <td align="left" colspan="5" valign="top">ULN = Upper limit of normal.</td> </tr> <tr ID="id_0e4827ef-25a3-419b-92fc-9661007bd5bf"> <td align="left" colspan="5" styleCode="Lrule Botrule" valign="top">ND = Not done.</td> </tr> </tbody> </table>

<table width="0.000" ID="id_b2933a8f-4aa1-4c9b-ab7b-7fb569e4cb1f"> <caption ID="id_ab094099-64e0-41e9-be7b-39d00d64a7d3">Table 5. Selected Clinical Adverse Reactions and Physical Findings (&#x2265;5% Frequency) in Pediatric Patients in Study ACTG300 </caption> <col/> <col/> <col/> <tbody> <tr ID="id_f28d743f-d9a1-47c6-805c-2caeab33413b"> <td align="center" styleCode="Botrule Toprule Rrule" valign="bottom"> <paragraph>Adverse Reaction</paragraph> </td> <td align="center" styleCode="Botrule Rrule" valign="bottom"> <paragraph>EPIVIR plus</paragraph> <paragraph>RETROVIR</paragraph> <paragraph>(n = 236)</paragraph> </td> <td align="center" styleCode="Botrule" valign="bottom"> <paragraph>Didanosine</paragraph> <paragraph>(n = 235)</paragraph> </td> </tr> <tr ID="id_03e39191-35ad-4ad4-8b57-2b85d9abf0e7"> <td align="left" styleCode="Rrule" valign="top"> <paragraph> <content styleCode="bold">Body as a Whole</content> </paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"/> <td align="center" valign="bottom"/> </tr> <tr ID="id_120a0a83-c2b7-4dc4-a883-f6884d9adcfc"> <td align="left" styleCode="Rrule" valign="top"> <paragraph> Fever</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>25%</paragraph> </td> <td align="center" valign="bottom"> <paragraph>32%</paragraph> </td> </tr> <tr ID="id_c9f2e5b0-555b-415a-ac1e-93fa6b0719e9"> <td align="left" styleCode="Rrule" valign="top"> <paragraph> <content styleCode="bold">Digestive</content> </paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"/> <td align="center" valign="bottom"/> </tr> <tr ID="id_5eb035b8-439c-48cf-9312-56015b8d3c3f"> <td align="left" styleCode="Rrule" valign="top"> <paragraph> Hepatomegaly</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>11%</paragraph> </td> <td align="center" valign="bottom"> <paragraph>11%</paragraph> </td> </tr> <tr ID="id_bf51e884-e492-464e-bd32-c15108b4d3c3"> <td align="left" styleCode="Rrule" valign="top"> <paragraph> Nausea &amp; vomiting</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>8%</paragraph> </td> <td align="center" valign="bottom"> <paragraph>7%</paragraph> </td> </tr> <tr ID="id_e99d9f1b-77f6-4b75-a805-323bc10832f9"> <td align="left" styleCode="Rrule" valign="top"> <paragraph> Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>8%</paragraph> </td> <td align="center" valign="bottom"> <paragraph>6%</paragraph> </td> </tr> <tr ID="id_4a4d2608-6c06-4749-b25e-2c75194ca1b8"> <td align="left" styleCode="Rrule" valign="top"> <paragraph> Stomatitis</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>6%</paragraph> </td> <td align="center" valign="bottom"> <paragraph>12%</paragraph> </td> </tr> <tr ID="id_e01f0389-47ce-4ee1-b88f-867d40830fb3"> <td align="left" styleCode="Rrule" valign="top"> <paragraph> Splenomegaly </paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>5%</paragraph> </td> <td align="center" valign="bottom"> <paragraph>8%</paragraph> </td> </tr> <tr ID="id_9c0446ef-a8cc-493c-bdbc-826a819a8d0c"> <td align="left" styleCode="Rrule" valign="top"> <paragraph> <content styleCode="bold">Respiratory</content> </paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"/> <td align="center" valign="bottom"/> </tr> <tr ID="id_efb9cc0f-90b4-410c-8259-a1d3a0438436"> <td align="left" styleCode="Rrule" valign="top"> <paragraph> Cough</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>15%</paragraph> </td> <td align="center" valign="bottom"> <paragraph>18%</paragraph> </td> </tr> <tr ID="id_4dfd923f-58a8-4360-bc9a-4da3e6bc45b8"> <td align="left" styleCode="Rrule" valign="top"> <paragraph> Abnormal breath sounds/wheezing</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>7%</paragraph> </td> <td align="center" valign="bottom"> <paragraph>9%</paragraph> </td> </tr> <tr ID="id_26547b34-1694-409e-8412-e15edae7e821"> <td align="left" styleCode="Rrule" valign="top"> <paragraph> <content styleCode="bold">Ear, Nose, and Throat </content> </paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"/> <td align="center" valign="bottom"/> </tr> <tr ID="id_db034d0d-4fdd-475e-ba90-8afb712dca4d"> <td align="left" styleCode="Rrule" valign="top"> <paragraph> Signs or symptoms of ears ^a </paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>7%</paragraph> </td> <td align="center" valign="bottom"> <paragraph>6%</paragraph> </td> </tr> <tr ID="id_7d37d441-2647-4bc3-9c1b-988afcaa403d"> <td align="left" styleCode="Rrule" valign="top"> <paragraph> Nasal discharge or congestion</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>8%</paragraph> </td> <td align="center" valign="bottom"> <paragraph>11%</paragraph> </td> </tr> <tr ID="id_e51b5f73-7385-49a7-ba3a-ead1672a7379"> <td align="left" styleCode="Rrule" valign="top"> <paragraph> <content styleCode="bold">Other</content> </paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"/> <td align="center" valign="bottom"/> </tr> <tr ID="id_cb8758e4-e302-4b8d-a106-422f7bc1b778"> <td align="left" styleCode="Rrule" valign="top"> <paragraph> Skin rashes</paragraph> </td> <td align="center" styleCode="Rrule" valign="bottom"> <paragraph>12%</paragraph> </td> <td align="center" valign="bottom"> <paragraph>14%</paragraph> </td> </tr> <tr ID="id_0456a74a-f980-4a39-abd3-2121fee74b3f"> <td align="left" styleCode="Botrule Rrule" valign="top"> <paragraph> Lymphadenopathy</paragraph> </td> <td align="center" styleCode="Botrule Rrule" valign="bottom"> <paragraph>9%</paragraph> </td> <td align="center" styleCode="Botrule" valign="bottom"> <paragraph>11%</paragraph> </td> </tr> <tr ID="id_4627fe97-8b74-42cc-a1b7-d9f0c999dd37"> <td align="left" colspan="3" styleCode="Lrule Botrule" valign="top"> ^a Includes pain, discharge, erythema, or swelling of an ear. </td> </tr> </tbody> </table>