FDA label dd74d4f9-ed20-47b0-bb3d-4a8ad228a21e

WARNING: RISK OF HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS, AND SEVERE HEPATOMEGALY Serious and sometimes fatal hypersensitivity reactions have been associated with ZIAGEN (abacavir sulfate). Hypersensitivity to abacavir is a multi-organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups: (1) fever, (2) rash, (3) gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain), (4) constitutional (including generalized malaise, fatigue, or achiness), and (5) respiratory (including dyspnea, cough, or pharyngitis). Discontinue ZIAGEN as soon as a hypersensitivity reaction is suspected. Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. HLA-B*5701-negative patients may develop a suspected hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B*5701-positive patients. Regardless of HLA-B*5701 status, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible. Following a hypersensitivity reaction to abacavir, NEVER restart ZIAGEN or any other abacavir-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death. Reintroduction of ZIAGEN or any other abacavir-containing product, even in patients who have no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy, can result in serious or fatal hypersensitivity reactions. Such reactions can occur within hours [see Warnings and Precautions (5.1)] . Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including ZIAGEN and other antiretrovirals [see Warnings and Precautions (5.2)] . WARNING: HYPERSENSITIVITY REACTIONS/LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY See full prescribing information for complete boxed warning. Serious and sometimes fatal hypersensitivity reactions have been associated with ZIAGEN (abacavir sulfate). (5.1) Hypersensitivity to abacavir is a multi-organ clinical syndrome. (5.1) Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. (5.1) Discontinue ZIAGEN as soon as a hypersensitivity reaction is suspected. Regardless of HLA-B*5701 status, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible. (5.1) Following a hypersensitivity reaction to abacavir, NEVER restart ZIAGEN or any other abacavir-containing product. (5.1) Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. (5.2)

5 WARNINGS AND PRECAUTIONS Hypersensitivity: Serious and sometimes fatal hypersensitivity reactions have been associated with ZIAGEN and other abacavir-containing products. Read full prescribing information section 5.1 before prescribing ZIAGEN. (5.1) Lactic acidosis and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues. (5.2) Immune reconstitution syndrome (5.3) and redistribution/accumulation of body fat have been reported in patients treated with combination antiretroviral therapy. (5.4) 5.1 Hypersensitivity Reaction Serious and sometimes fatal hypersensitivity reactions have been associated with ZIAGEN and other abacavir-containing products. Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of a hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances when the potential benefit outweighs the risk. HLA-B*5701-negative patients may develop a hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B*5701-positive patients. Regardless of HLA-B*5701 status, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible. Important information on signs and symptoms of hypersensitivity, as well as clinical management, is presented below. Signs and Symptoms of Hypersensitivity: Hypersensitivity to abacavir is a multi-organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups. Group 1: Fever Group 2: Rash Group 3: Gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain) Group 4: Constitutional (including generalized malaise, fatigue, or achiness) Group 5: Respiratory (including dyspnea, cough, or pharyngitis). Hypersensitivity to abacavir following the presentation of a single sign or symptom has been reported infrequently. Hypersensitivity to abacavir was reported in approximately 8% of 2,670 patients (n = 206) in 9 clinical trials (range: 2% to 9%) with enrollment from November 1999 to February 2002. Data on time to onset and symptoms of suspected hypersensitivity were collected on a detailed data collection module. The frequencies of symptoms are shown in Figure 1. Symptoms usually appeared within the first 6 weeks of treatment with abacavir, although the reaction may occur at any time during therapy. Median time to onset was 9 days; 89% appeared within the first 6 weeks; 95% of patients reported symptoms from 2 or more of the 5 groups listed above. Figure 1. Hypersensitivity-Related Symptoms Reported With ≥10% Frequency in Clinical Trials (n = 206 Patients) Other less common signs and symptoms of hypersensitivity include lethargy, myolysis, edema, abnormal chest x-ray findings (predominantly infiltrates, which can be localized), and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, and death have occurred in association with hypersensitivity reactions. In one study, 4 patients (11%) receiving ZIAGEN 600 mg once daily experienced hypotension with a hypersensitivity reaction compared with 0 patients receiving ZIAGEN 300 mg twice daily. Physical findings associated with hypersensitivity to abacavir in some patients include lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and rash. The rash usually appears maculopapular or urticarial, but may be variable in appearance. There have been reports of erythema multiforme. Hypersensitivity reactions have occurred without rash. Laboratory abnormalities associated with hypersensitivity to abacavir in some patients include elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, and lymphopenia. Clinical Management of Hypersensitivity: Discontinue ZIAGEN as soon as a hypersensitivity reaction is suspected. To minimize the risk of a life-threatening hypersensitivity reaction, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications). Following a hypersensitivity reaction to abacavir, NEVER restart ZIAGEN or any other abacavir-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death. When therapy with ZIAGEN has been discontinued for reasons other than symptoms of a hypersensitivity reaction, and if reinitiation of ZIAGEN or any other abacavir-containing product is under consideration, carefully evaluate the reason for discontinuation of ZIAGEN to ensure that the patient did not have symptoms of a hypersensitivity reaction. If the patient is of unknown HLA-B*5701 status, screening for the allele is recommended prior to reinitiation of ZIAGEN. If hypersensitivity cannot be ruled out, DO NOT reintroduce ZIAGEN or any other abacavir-containing product. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction. If symptoms consistent with hypersensitivity are not identified, reintroduction can be undertaken with continued monitoring for symptoms of a hypersensitivity reaction. Make patients aware that a hypersensitivity reaction can occur with reintroduction of ZIAGEN or any other abacavir-containing product and that reintroduction of ZIAGEN or any other abacavir-containing product needs to be undertaken only if medical care can be readily accessed by the patient or others. Risk Factor: HLA-B*5701 Allele: Studies have shown that carriage of the HLA-B*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir. CNA106030 (PREDICT-1), a randomized, double-blind study, evaluated the clinical utility of prospective HLA-B*5701 screening on the incidence of abacavir hypersensitivity reaction in abacavir-naive HIV-1-infected adults (n = 1,650). In this study, use of pre-therapy screening for the HLA-B*5701 allele and exclusion of subjects with this allele reduced the incidence of clinically suspected abacavir hypersensitivity reactions from 7.8% (66/847) to 3.4% (27/803). Based on this study, it is estimated that 61% of patients with the HLA-B*5701 allele will develop a clinically suspected hypersensitivity reaction during the course of abacavir treatment compared with 4% of patients who do not have the HLA-B*5701 allele. Screening for carriage of the HLA -B*5701 allele is recommended prior to initiating treatment with abacavir. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, initiating or reinitiating treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances where potential benefit outweighs the risk. Skin patch testing is used as a research tool and should not be used to aid in the clinical diagnosis of abacavir hypersensitivity. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision-making. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction. Abacavir Hypersensitivity Reaction Registry: An Abacavir Hypersensitivity Registry has been established to facilitate reporting of hypersensitivity reactions and collection of information on each case. Physicians should register patients by calling 1-800-270-0425. 5.2 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 abacavir 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 ZIAGEN to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with ZIAGEN 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). 5.3 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including ZIAGEN. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond 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. 5.4 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. 5.5 Myocardial Infarction In a published prospective, observational, epidemiological study designed to investigate the rate of myocardial infarction in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of myocardial infarction (MI). 1 In a sponsor-conducted pooled analysis of clinical trials, no excess risk of myocardial infarction was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive. As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking). Figure 1. Hypersensitivity-Related Symptoms Reported With Greater Than or Equal to 10% Frequency in Clinical Trials (n = 206 Patients)

6 ADVERSE REACTIONS Serious and sometimes fatal hypersensitivity reactions have been associated with ZIAGEN (abacavir sulfate). In one study, once-daily dosing of ZIAGEN was associated with more severe hypersensitivity reactions [see Warnings and Precautions (5.1)]. The most commonly reported adverse reactions of at least moderate intensity (incidence ≥10%) in adult HIV-1 clinical studies were nausea, headache, malaise and fatigue, nausea and vomiting, and dreams/sleep disorders. (6.1) The most commonly reported adverse reactions of at least moderate intensity (incidence ≥5%) in pediatric HIV-1 clinical studies were fever and/or chills, nausea and vomiting, skin rashes, and ear/nose/throat infections. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults: Therapy-Naive Adults: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 2. Table 2. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, ≥5% Frequency) in Therapy-Naive Adults (CNA30024 * ) Through 48 Weeks of Treatment * This study used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the study, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 patients in the abacavir group and 3% of 325 patients in the zidovudine group. † Ten (3%) cases of suspected drug hypersensitivity were reclassified as not being due to abacavir following unblinding. Adverse Reaction ZIAGEN plus Lamivudine plus Efavirenz (n = 324) Zidovudine plus Lamivudine plus Efavirenz (n = 325) Dreams/sleep disorders 10% 10% Drug hypersensitivity 9% <1% † Headaches/migraine 7% 11% Nausea 7% 11% Fatigue/malaise 7% 10% Diarrhea 7% 6% Rashes 6% 12% Abdominal pain/gastritis/ gastrointestinal signs and symptoms 6% 8% Depressive disorders 6% 6% Dizziness 6% 6% Musculoskeletal pain 6% 5% Bronchitis 4% 5% Vomiting 2% 9% Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 3. Table 3. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, ≥5% Frequency) in Therapy-Naive Adults (CNA3005) Through 48 Weeks of Treatment Adverse Reaction ZIAGEN plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 264) Nausea 19% 17% Headache 13% 9% Malaise and fatigue 12% 12% Nausea and vomiting 10% 10% Hypersensitivity reaction 8% 2% Diarrhea 7% 5% Fever and/or chills 6% 3% Depressive disorders 6% 4% Musculoskeletal pain 5% 7% Skin rashes 5% 4% Ear/nose/throat infections 5% 4% Viral respiratory infections 5% 5% Anxiety 5% 3% Renal signs/symptoms <1% 5% Pain (non-site-specific) <1% 5% Five patients receiving ZIAGEN in CNA3005 experienced worsening of pre-existing depression compared with none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms. ZIAGEN Once Daily Versus ZIAGEN Twice Daily (CNA30021): Treatment-emergent clinical adverse reactions (rated by the investigator as at least moderate) with a greater than or equal to 5% frequency during therapy with ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily from CNA30021 were similar. For hypersensitivity reactions, patients receiving ZIAGEN once daily showed a rate of 9% in comparison with a rate of 7% for patients receiving ZIAGEN twice daily. However, patients receiving ZIAGEN 600 mg once daily, experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with patients who received ZIAGEN 300 mg twice daily. Five percent (5%) of patients receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of patients receiving ZIAGEN 300 mg twice daily. Two percent (2%) of patients receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the patients receiving ZIAGEN 300 mg twice daily had this event. Laboratory Abnormalities: Laboratory abnormalities (Grades 3-4) in therapy-naive adults during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 4. Table 4. Laboratory Abnormalities (Grades 3-4) in Therapy-Naive Adults (CNA30024) Through 48 Weeks of Treatment ULN = Upper limit of normal. n = Number of patients assessed. Grade 3/4 Laboratory Abnormalities ZIAGEN plus Lamivudine plus Efavirenz (n = 324) Zidovudine plus Lamivudine plus Efavirenz (n = 325) Elevated CPK (>4 X ULN) 8% 8% Elevated ALT (>5 X ULN) 6% 6% Elevated AST (>5 X ULN) 6% 5% Hypertriglyceridemia (>750 mg/dL) 6% 5% Hyperamylasemia (>2 X ULN) 4% 5% Neutropenia (ANC <750/mm 3 ) 2% 4% Anemia (Hgb ≤6.9 gm/dL) <1% 2% Thrombocytopenia (Platelets <50,000/mm 3 ) 1% <1% Leukopenia (WBC ≤1,500/mm 3 ) <1% 2% Laboratory abnormalities in CNA3005 are listed in Table 5. Table 5. Treatment-Emergent Laboratory Abnormalities (Grades 3-4) in CNA3005 ULN = Upper limit of normal. n = Number of patients assessed. Grade 3/4 Laboratory Abnormalities Number of Subjects by Treatment Group ZIAGEN plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 264) Elevated CPK (>4 x ULN) 18 (7%) 18 (7%) ALT (>5.0 x ULN) 16 (6%) 16 (6%) Neutropenia (<750/mm 3 ) 13 (5%) 13 (5%) Hypertriglyceridemia (>750 mg/dL) 5 (2%) 3 (1%) Hyperamylasemia (>2.0 x ULN) 5 (2%) 1 (<1%) Hyperglycemia (>13.9 mmol/L) 2 (<1%) 2 (<1%) Anemia (Hgb ≤6.9 g/dL) 0 (0%) 3 (1%) The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021. Pediatric Patients: Therapy-Experienced Pediatric Patients: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 8 mg/kg twice daily, lamivudine 4 mg/kg twice daily, and zidovudine 180 mg/m 2 twice daily compared with lamivudine 4 mg/kg twice daily and zidovudine 180 mg/m 2 twice daily from CNA3006 are listed in Table 6. Table 6. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, ≥5% Frequency) in Therapy-Experienced Pediatric Patients (CNA3006) Through 16 Weeks of Treatment Adverse Reaction ZIAGEN plus Lamivudine plus Zidovudine (n = 102) Lamivudine plus Zidovudine (n = 103) Fever and/or chills 9% 7% Nausea and vomiting 9% 2% Skin rashes 7% 1% Ear/nose/throat infections 5% 1% Pneumonia 4% 5% Headache 1% 5% Laboratory Abnormalities: In Study CNA3006, laboratory abnormalities (anemia, neutropenia, liver function test abnormalities, and CPK elevations) were observed with similar frequencies as in a study of therapy-naive adults (CNA30024). Mild elevations of blood glucose were more frequent in pediatric patients receiving ZIAGEN (CNA3006) as compared with adult patients (CNA30024). Other Adverse Events: In addition to adverse reactions and laboratory abnormalities reported in Tables 2, 3, 4, 5, and 6, other adverse reactions observed in the expanded access program were pancreatitis and increased GGT. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following reactions have been identified during postmarketing use of ZIAGEN. Because they 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 ZIAGEN. Body as a Whole: Redistribution/accumulation of body fat. Cardiovascular: Myocardial infarction. Hepatic: Lactic acidosis and hepatic steatosis. Skin: Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. There have also been reports of erythema multiforme with abacavir use.

<table width="0.000" ID="id_822b09df-a7a8-433d-9fc3-3749c2617601"> <caption ID="id_2bdb0041-2eb8-4c69-a79e-4c3684f52f77">Table 2. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, &#x2265;5% Frequency) in Therapy-Naive Adults (CNA30024^*) Through 48 Weeks of Treatment</caption> <col/> <col/> <col/> <tfoot ID="id_9dfbe52f-2ca8-4fb7-b494-f8228984b456"> <tr> <td align="left" valign="top" colspan="3" rowspan="1"> <paragraph> ^* This study used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the study, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 patients in the abacavir group and 3% of 325 patients in the zidovudine group.</paragraph> </td> </tr> <tr> <td align="left" valign="top" colspan="3" rowspan="1" styleCode="Lrule Botrule"> <paragraph> ^&#x2020; Ten (3%) cases of suspected drug hypersensitivity were reclassified as not being due to abacavir following unblinding.</paragraph> </td> </tr> </tfoot> <tbody> <tr ID="id_872b7593-9c0f-4c59-a49c-ddc035372d56"> <td align="center" valign="bottom" rowspan="1" styleCode="Botrule Toprule Rrule"> <paragraph>Adverse Reaction</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Botrule Rrule"> <paragraph>ZIAGEN plus Lamivudine plus Efavirenz</paragraph> <paragraph>(n = 324)</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Botrule"> <paragraph>Zidovudine plus Lamivudine plus Efavirenz</paragraph> <paragraph>(n = 325)</paragraph> </td> </tr> <tr ID="id_17ac2eb3-4f91-4ebf-a478-c5c91c69a20f"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Dreams/sleep disorders</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>10%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>10%</paragraph> </td> </tr> <tr ID="id_9dc41793-e213-4227-ab80-47dfeac1db91"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Drug hypersensitivity</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>9%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>&lt;1%^&#x2020; </paragraph> </td> </tr> <tr ID="id_38f3ade8-df09-421d-8fdd-63227eb6a1a4"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Headaches/migraine</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>7%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>11%</paragraph> </td> </tr> <tr ID="id_fd92dc2e-ab72-4fbb-9cc4-0613f67133cd"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Nausea</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>7%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>11%</paragraph> </td> </tr> <tr ID="id_ce97f5db-7eae-4c07-bb87-53789961f224"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Fatigue/malaise</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>7%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>10%</paragraph> </td> </tr> <tr ID="id_9c4a8d90-728b-4fc9-83b9-02b2193d7e92"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Diarrhea</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>7%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>6%</paragraph> </td> </tr> <tr ID="id_64e2890c-c675-440e-9321-6f1001630604"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Rashes</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>6%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>12%</paragraph> </td> </tr> <tr ID="id_306105aa-1c88-412f-bb3c-b57d74e88acb"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Abdominal pain/gastritis/ gastrointestinal signs and symptoms</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>6%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>8%</paragraph> </td> </tr> <tr ID="id_22a50b80-2ed2-422d-acbe-561982e60724"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Depressive disorders</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>6%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>6%</paragraph> </td> </tr> <tr ID="id_e704f36e-197d-4190-8c81-6708ff1c7ce8"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Dizziness</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>6%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>6%</paragraph> </td> </tr> <tr ID="id_b0f56267-10b7-4094-97e7-d5d55d5e6579"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Musculoskeletal pain</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>6%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>5%</paragraph> </td> </tr> <tr ID="id_56d12143-86ec-4f3f-b68e-0f47c61db5c3"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Bronchitis</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>4%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>5%</paragraph> </td> </tr> <tr ID="id_255dfc46-ee3c-44b9-b6c6-e5cd570564ce"> <td align="left" valign="top" rowspan="1" styleCode="Botrule Rrule"> <paragraph>Vomiting</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Botrule Rrule"> <paragraph>2%</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Botrule"> <paragraph>9%</paragraph> </td> </tr> </tbody> </table>

<table width="0.000" ID="id_79f2eff8-e69c-4cc0-a9e2-9c725e3dc108"> <caption ID="id_f5c8ec7c-a1ed-4a19-8663-08d953467c35">Table 3. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, &#x2265;5% Frequency) in Therapy-Naive Adults (CNA3005) Through 48 Weeks of Treatment</caption> <col/> <col/> <col/> <tbody> <tr ID="id_6d6e4b49-3360-47e2-bea3-8933b516e4e8"> <td align="center" valign="bottom" rowspan="1" styleCode="Botrule Toprule Rrule"> <paragraph>Adverse Reaction</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Botrule Rrule"> <paragraph>ZIAGEN plus Lamivudine/Zidovudine</paragraph> <paragraph>(n = 262)</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Botrule"> <paragraph>Indinavir plus Lamivudine/Zidovudine</paragraph> <paragraph>(n = 264)</paragraph> </td> </tr> <tr ID="id_260b1854-d555-4afd-b0f9-23a60a00ef4a"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Nausea</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>19%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>17%</paragraph> </td> </tr> <tr ID="id_0874e540-69b7-4276-9198-94d607ab2d86"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Headache</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>13%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>9%</paragraph> </td> </tr> <tr ID="id_f0acfd28-9e47-48f0-9b44-9e413191081f"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Malaise and fatigue</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>12%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>12%</paragraph> </td> </tr> <tr ID="id_0d7f6756-1d3b-4f63-9795-2225a51238ca"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Nausea and vomiting</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>10%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>10%</paragraph> </td> </tr> <tr ID="id_40813ed2-6362-4b85-b033-0f1ccd582d67"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Hypersensitivity reaction</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>8%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>2%</paragraph> </td> </tr> <tr ID="id_0854a2ea-a2bf-402e-b94e-40391a1898d4"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Diarrhea</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>7%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>5%</paragraph> </td> </tr> <tr ID="id_6528d4d0-fbf5-420a-8d5b-3cf1156d8914"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Fever and/or chills</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>6%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>3%</paragraph> </td> </tr> <tr ID="id_d9e64f6e-f3b0-4267-8771-dd2315ff234f"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Depressive disorders</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>6%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>4%</paragraph> </td> </tr> <tr ID="id_f2e05970-b40d-478c-8ce3-73f5b42c3686"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Musculoskeletal pain</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>5%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>7%</paragraph> </td> </tr> <tr ID="id_52f5fe91-e2cf-41b3-a59e-43a75a84e2bd"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Skin rashes</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>5%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>4%</paragraph> </td> </tr> <tr ID="id_f16f32f3-e216-4ed5-9553-083db41ca3b3"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Ear/nose/throat infections</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>5%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>4%</paragraph> </td> </tr> <tr ID="id_3968c41d-f10d-4c4d-999b-95188cfb0d1a"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Viral respiratory infections</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>5%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>5%</paragraph> </td> </tr> <tr ID="id_fb69beb3-3177-41ae-8e4a-acc5a057017b"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Anxiety</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>5%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>3%</paragraph> </td> </tr> <tr ID="id_09888c85-6317-46f6-8e13-604747fccd76"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Renal signs/symptoms</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>&lt;1%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>5%</paragraph> </td> </tr> <tr ID="id_ba6c87dd-235e-4f8c-a11c-dc3353f147d0"> <td align="left" valign="top" rowspan="1" styleCode="Botrule Rrule"> <paragraph>Pain (non-site-specific)</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>&lt;1%</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Botrule"> <paragraph>5%</paragraph> </td> </tr> </tbody> </table>

<table width="0.000" ID="id_2a0dc8ab-27f4-4cfe-ab03-c13c47a3773e"> <caption ID="id_88103451-2b4e-449d-8275-329e61f37f84">Table 4. Laboratory Abnormalities (Grades 3-4) in Therapy-Naive Adults (CNA30024) Through 48 Weeks of Treatment</caption> <col/> <col/> <col/> <tfoot ID="id_5012d582-9568-4a01-822a-0894fa8792c9"> <tr> <td align="left" valign="top" colspan="3" rowspan="1"> <paragraph>ULN = Upper limit of normal.</paragraph> </td> </tr> <tr> <td align="left" valign="top" colspan="3" styleCode="Lrule Botrule"> <paragraph>n = Number of patients assessed.</paragraph> </td> </tr> </tfoot> <tbody> <tr ID="id_ddcc4772-f9f1-49c6-9eb5-e38b4d3e27fe"> <td align="center" valign="bottom" rowspan="1" styleCode="Botrule Toprule Rrule"> <paragraph>Grade 3/4 </paragraph> <paragraph>Laboratory Abnormalities</paragraph> </td> <td align="center" valign="bottom" rowspan="1" styleCode="Botrule Rrule"> <paragraph>ZIAGEN plus</paragraph> <paragraph>Lamivudine plus Efavirenz</paragraph> <paragraph>(n = 324)</paragraph> </td> <td align="center" valign="bottom" rowspan="1" styleCode="Botrule"> <paragraph>Zidovudine plus</paragraph> <paragraph>Lamivudine plus Efavirenz (n = 325)</paragraph> </td> </tr> <tr ID="id_c30155de-8217-4d41-88f4-a508a34f1499"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Elevated CPK (&gt;4 X ULN)</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>8%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>8%</paragraph> </td> </tr> <tr ID="id_d3069572-2230-47d8-9bf8-ffe12925b17c"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Elevated ALT (&gt;5 X ULN)</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>6%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>6%</paragraph> </td> </tr> <tr ID="id_49f620ad-bcec-4e88-af43-9aedc07f4cd9"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Elevated AST (&gt;5 X ULN)</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>6%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>5%</paragraph> </td> </tr> <tr ID="id_1faf67a7-dfb0-4439-959f-4d7a510ea8fe"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Hypertriglyceridemia (&gt;750 mg/dL)</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>6%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>5%</paragraph> </td> </tr> <tr ID="id_da6883ec-54fd-4e39-8349-b2eca08bfe71"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Hyperamylasemia (&gt;2 X ULN)</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>4%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>5%</paragraph> </td> </tr> <tr ID="id_6f93bb44-0de7-4ad9-aa9f-4f911de6b7eb"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Neutropenia (ANC &lt;750/mm³)</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>2%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>4%</paragraph> </td> </tr> <tr ID="id_1c3cee21-a5d7-458f-a336-2be4c46bf1ca"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Anemia (Hgb &#x2264;6.9 gm/dL)</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>&lt;1%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>2%</paragraph> </td> </tr> <tr ID="id_58bc22c1-0de9-43be-8b41-b0070022d4a9"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Thrombocytopenia (Platelets &lt;50,000/mm³)</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>1%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>&lt;1%</paragraph> </td> </tr> <tr ID="id_c3f0c48c-48e8-40c7-a030-89635dd03065"> <td align="left" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>Leukopenia (WBC &#x2264;1,500/mm³)</paragraph> </td> <td align="center" valign="top" rowspan="1" styleCode="Rrule"> <paragraph>&lt;1%</paragraph> </td> <td align="center" valign="top" rowspan="1"> <paragraph>2%</paragraph> </td> </tr> </tbody> </table>