FDA label 293699e1-d0c8-4d54-b360-e76b26b7da68

5 WARNINGS AND PRECAUTIONS Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/ritonavir. Monitor liver function before and during therapy, especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases. ( 5.2 , 6 ) Skin reactions ranging from mild to severe, including Stevens-Johnson Syndrome and toxic epidermal necrolysis, have been reported. Discontinue treatment if severe reaction develops. ( 5.3 , 6 ) Use with caution in patients with a known sulfonamide allergy. ( 5.4 ) Patients may develop new onset diabetes mellitus or hyperglycemia. Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required. ( 5.6 ) Patients may develop redistribution/accumulation of body fat ( 5.7 ) or immune reconstitution syndrome. ( 5.8 ) Patients with hemophilia may develop increased bleeding events. ( 5.9 ) PREZISTA/ritonavir should not be used in pediatric patients below 3 years of age. ( 5.11 ) 5.1 General PREZISTA must be co-administered with ritonavir and food to achieve the desired antiviral effect. Failure to administer PREZISTA with ritonavir and food may result in a loss of efficacy of darunavir. Please refer to ritonavir prescribing information for additional information on precautionary measures. 5.2 Hepatotoxicity Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/ritonavir. During the clinical development program (N=3063), hepatitis was reported in 0.5% of patients receiving combination therapy with PREZISTA/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events. Post-marketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with PREZISTA/ritonavir therapy has not been established. Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of PREZISTA/ritonavir treatment. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA/ritonavir should prompt consideration of interruption or discontinuation of treatment. 5.3 Severe Skin Reactions During the clinical development program (n=3063), severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, have been reported in 0.4% of subjects. Stevens-Johnson Syndrome was rarely (<0.1%) reported during the clinical development program. During post-marketing experience toxic epidermal necrolysis has been reported. Discontinue PREZISTA/rtv immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia. Rash (all grades, regardless of causality) occurred in 10.3% of subjects treated with PREZISTA/rtv [ also see Adverse Reactions (6) ]. Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using PREZISTA/rtv was 0.5%. 5.4 Sulfa Allergy Darunavir contains a sulfonamide moiety. PREZISTA should be used with caution in patients with a known sulfonamide allergy. In clinical studies with PREZISTA/ritonavir, the incidence and severity of rash was similar in subjects with or without a history of sulfonamide allergy. 5.5 Drug Interactions See Table 2 for a listing of drugs that are contraindicated for use with PREZISTA/ritonavir due to potentially life-threatening adverse events, significant drug-drug interactions, or loss of therapeutic effect to PREZISTA [ see Contraindications (4) ]. Please refer to Table 7 for established and other potentially significant drug-drug interactions [ see Drug Interactions (7.3) ]. 5.6 Diabetes Mellitus / Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between PI therapy and these events have not been established. 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. 5.8 Immune Reconstitution Syndrome During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jirovecii pneumonia, and tuberculosis), which may necessitate further evaluation and treatment. 5.9 Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with PIs. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship between PI therapy and these episodes has not been established. 5.10 Resistance/Cross-Resistance Because the potential for HIV cross-resistance among PIs has not been fully explored in PREZISTA/ritonavir treated patients, the effect therapy with PREZISTA will have on the activity of subsequently administered PIs is unknown [ see Microbiology (12.4) ]. 5.11 Pediatric Patients Do not administer PREZISTA/ritonavir in pediatric patients below 3 years of age in view of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age [ see Use in Specific Populations (8.1 and 8.4) , Clinical Pharmacology (12.3) , and Nonclinical Toxicology (13.2) ]. The safety and efficacy of PREZISTA/ritonavir in pediatric patients 3 to < 6 years of age have not been established.

6 ADVERSE REACTIONS The safety assessment is based on all safety data from the Phase 2b studies (Studies TMC114-C213, TMC114-C202, TMC114-C215, and TMC114-C208) and Phase 3 studies (TMC114-C211, TMC114-C214, TMC114-C209, DUET-1 (TMC125-C206), and DUET-2 (TMC125-C216)) reported with PREZISTA/ritonavir in a total of 3063 subjects. 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. Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions. The most common clinical adverse drug reactions to PREZISTA/ritonavir (incidence ≥ 5%) of at least moderate intensity (≥ Grade 2) were diarrhea, nausea, rash, headache, abdominal pain and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Tibotec Therapeutics at 1-877-REACH-TT or 1-877-732-2488 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience: Treatment-Naïve Adults Study TMC114-C211 The safety assessment is based on all safety data from the Phase 3 trial TMC114-C211 comparing PREZISTA/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day in 689 antiretroviral treatment-naïve HIV-1-infected adult subjects. The total mean exposure for subjects in the PREZISTA/ritonavir 800/100 mg once daily arm and in the lopinavir/ritonavir 800/200 mg per day arm was 95.0 and 91.4 weeks, respectively. The majority of the adverse drug reactions (ADRs) reported during treatment with PREZISTA/ritonavir 800/100 mg once daily were mild in severity. The most common clinical ADRs to PREZISTA/ritonavir 800/100 mg once daily (≥ 5%) of at least moderate intensity (≥ Grade 2) were diarrhea, headache, abdominal pain and rash. 2.3% of subjects in the PREZISTA/ritonavir arm discontinued treatment due to ADRs. ADRs to PREZISTA/ritonavir 800/100 mg once daily of at least moderate intensity (≥ Grade 2) in antiretroviral treatment naïve HIV-1-infected adult subjects are presented in Table 3 and subsequent text below the table. Table 3: Selected Clinical Adverse Drug Reactions to PREZISTA/ritonavir 800/100 mg Once Daily Excluding laboratory abnormalities reported as ADRs of At Least Moderate Intensity (≥ Grade 2) Occurring in ≥ 2% of Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects Randomized Study TMC114-C211 System Organ Class, Preferred Term, % PREZISTA/ritonavir 800/100 mg once daily + TDF/FTC N = 343 lopinavir/ritonavir 800/200 mg per day + TDF/FTC N = 346 N=total number of subjects per treatment group TDF = tenofovir disoproxil fumarate FTC = emtricitabine Gastrointestinal Disorders Abdominal pain 5% 6% Diarrhea 8% 15% Nausea 3% 4% Vomiting 2% 3% General Disorders and Administration Site Conditions Fatigue < 1% 3% Metabolism and Nutrition Disorders Anorexia 2% < 1% Nervous System Disorders Headache 6% 5% Skin and Subcutaneous Tissue Disorders Rash 5% 6% Less Common Adverse Reactions Treatment-emergent ADRs of at least moderate intensity (≥ Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving PREZISTA/ritonavir 800/100 mg once daily are listed below by body system: Gastrointestinal Disorders: acute pancreatitis, dyspepsia, flatulence General Disorders and Administration Site Conditions: asthenia Hepatobiliary Disorders: acute hepatitis (e.g., acute hepatitis, cytolytic hepatitis, hepatotoxicity) Immune System Disorders: (drug) hypersensitivity Metabolism and Nutrition Disorders: diabetes mellitus Musculoskeletal and Connective Tissue Disorders: myalgia Psychiatric Disorders: abnormal dreams Skin and Subcutaneous Tissue Disorders: angioedema, pruritus, Stevens-Johnson Syndrome, urticaria Laboratory abnormalities: Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-naïve adult subjects treated with PREZISTA/ritonavir 800/100 mg once daily are presented in Table 4. Table 4: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects Grade 4 data not applicable in Division of AIDS grading scale. Randomized Study TMC114-C211 Laboratory Parameter Preferred Term, % Limit PREZISTA/ritonavir 800/100 mg once daily + TDF/FTC lopinavir/ritonavir 800/200 mg per day + TDF/FTC N=total number of subjects per treatment group TDF = tenofovir disoproxil fumarate FTC = emtricitabine Biochemistry Alanine Aminotransferase Grade 2 > 2.5 to ≤ 5.0 X ULN 7% 6% Grade 3 > 5.0 to ≤ 10.0 X ULN 3% 3% Grade 4 > 10.0 X ULN < 1% 3% Aspartate Aminotransferase Grade 2 > 2.5 to ≤ 5.0 X ULN 6% 6% Grade 3 > 5.0 to ≤ 10.0 X ULN 4% 2% Grade 4 > 10.0 X ULN 1% 2% Alkaline Phosphatase Grade 2 > 2.5 to ≤ 5.0 X ULN 2% 1% Grade 3 > 5.0 to ≤ 10.0 X ULN 0% < 1% Grade 4 > 10.0 X ULN 0% 0% Hyperbilirubinemia Grade 2 > 1.5 to ≤ 2.5 X ULN < 1% 4% Grade 3 > 2.5 to ≤ 5.0 X ULN < 1% < 1% Grade 4 > 5.0 X ULN 0% 0% Triglycerides Grade 2 5.65-8.48 mmol/L 500-750 mg/dL 3% 8% Grade 3 8.49-13.56 mmol/L 751-1200 mg/dL 1% 5% Grade 4 > 13.56 mmol/L > 1200 mg/dL < 1% < 1% Total Cholesterol Grade 2 6.20-7.77 mmol/L 240-300 mg/dL 16% 23% Grade 3 > 7.77 mmol/L > 300 mg/dL 1% 5% Low-Density Lipoprotein Cholesterol Grade 2 4.13-4.90 mmol/L 160-190 mg/dL 14% 10% Grade 3 ≥ 4.91 mmol/L ≥ 191 mg/dL 5% 5% Elevated Glucose Levels Grade 2 6.95-13.88 mmol/L 126-250 mg/dL 7% 8% Grade 3 13.89-27.75 mmol/L 251-500 mg/dL < 1% 0% Grade 4 > 27.75 mmol/L > 500 mg/dL 0% 0% Pancreatic Lipase Grade 2 > 1.5 to ≤ 3.0 X ULN 2% 1% Grade 3 > 3.0 to ≤ 5.0 X ULN < 1% < 1% Grade 4 > 5.0 X ULN 0% < 1% Pancreatic Amylase Grade 2 > 1.5 to ≤ 2.0 X ULN 5% 2% Grade 3 > 2.0 to ≤ 5.0 X ULN 3% 3% Grade 4 > 5.0 X ULN 0% < 1% 6.2 Clinical Trials Experience: Treatment-Experienced Adults Study TMC114-C214 The safety assessment is based on all safety data from the Phase 3 trial TMC114-C214 comparing PREZISTA/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in 595 antiretroviral treatment-experienced HIV-1-infected adult subjects. The total mean exposure for subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm and in the lopinavir/ritonavir 400/100 mg twice daily arm was 80.7 and 76.4 weeks, respectively. The majority of the ADRs reported during treatment with PREZISTA/ritonavir 600/100 mg twice daily were mild in severity. The most common clinical ADRs to PREZISTA/ritonavir 600/100 mg twice daily (≥ 5%) of at least moderate intensity (≥ Grade 2) were diarrhea, nausea, rash, abdominal pain and vomiting. 4.7% of subjects in the PREZISTA/ritonavir arm discontinued treatment due to ADRs. ADRs to PREZISTA/ritonavir 600/100 mg twice daily of at least moderate intensity (≥ Grade 2) in antiretroviral treatment-experienced HIV-1-infected adult subjects are presented in Table 5 and subsequent text below the table. Table 5: Selected Clinical Adverse Drug Reactions to PREZISTA/ritonavir 600/100 mg Twice Daily Excluding laboratory abnormalities reported as ADRs of At Least Moderate Intensity (≥ Grade 2) Occurring in ≥ 2% of Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjects Randomized Study TMC114-C214 System Organ Class, Preferred Term, % PREZISTA/ritonavir 600/100 mg twice daily + OBR N = 298 lopinavir/ritonavir 400/100 mg twice daily + OBR N = 297 N=total number of subjects per treatment group OBR = optimized background regimen Gastrointestinal Disorders Abdominal distension 2% < 1% Abdominal pain 6% 3% Diarrhea 14% 20% Dyspepsia 2% 1% Nausea 7% 6% Vomiting 5% 3% General Disorders and Administration Site Conditions Asthenia 3% 1% Fatigue 2% 1% Metabolism and Nutrition Disorders Anorexia 2% 2% Diabetes mellitus 2% < 1% Nervous System Disorders Headache 3% 3% Skin and Subcutaneous Tissue Disorders Rash 7% 3% Less Common Adverse Reactions Treatment-emergent ADRs of at least moderate intensity (≥ Grade 2) occurring in less than 2% of antiretroviral treatment-experienced subjects receiving PREZISTA/ritonavir 600/100 mg twice daily are listed below by body system: Gastrointestinal Disorders: a cute pancreatitis, flatulence Musculoskeletal and Connective Tissue Disorders: myalgia Psychiatric Disorders: abnormal dreams Skin and Subcutaneous Tissue Disorders: pruritus, urticaria Laboratory abnormalities: Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-experienced adult subjects treated with PREZISTA/ritonavir 600/100 mg twice daily are presented in Table 6. Table 6: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjects Grade 4 data not applicable in Division of AIDS grading scale. Randomized Study TMC114-C214 Laboratory Parameter Preferred Term, % Limit PREZISTA/ritonavir 600/100 mg twice daily + OBR lopinavir/ritonavir 400/100 mg twice daily + OBR N=total number of subjects per treatment group OBR = optimized background regimen Biochemistry Alanine Aminotransferase Grade 2 > 2.5 to ≤ 5.0 X ULN 7% 5% Grade 3 > 5.0 to ≤ 10.0 X ULN 2% 2% Grade 4 > 10.0 X ULN 1% 2% Aspartate Aminotransferase Grade 2 > 2.5 to ≤ 5.0 X ULN 6% 6% Grade 3 > 5.0 to ≤ 10.0 X ULN 2% 2% Grade 4 > 10.0 X ULN < 1% 2% Alkaline Phosphatase Grade 2 > 2.5 to ≤ 5.0 X ULN < 1% 0% Grade 3 > 5.0 to ≤ 10.0 X ULN < 1% < 1% Grade 4 > 10.0 X ULN 0% 0% Hyperbilirubinemia Grade 2 > 1.5 to ≤ 2.5 X ULN < 1% 2% Grade 3 > 2.5 to ≤ 5.0 X ULN < 1% < 1% Grade 4 > 5.0 X ULN < 1% 0% Triglycerides Grade 2 5.65-8.48 mmol/L 500-750 mg/dL 10% 11% Grade 3 8.49-13.56 mmol/L 751-1200 mg/dL 7% 10% Grade 4 > 13.56 mmol/L > 1200 mg/dL 3% 6% Total Cholesterol Grade 2 6.20-7.77 mmol/L 240-300 mg/dL 25% 23% Grade 3 > 7.77 mmol/L > 300 mg/dL 10% 14% Low-Density Lipoprotein Cholesterol Grade 2 4.13-4.90 mmol/L 160-190 mg/dL 14% 14% Grade 3 ≥ 4.91 mmol/L ≥ 191 mg/dL 8% 9% Elevated Glucose Levels Grade 2 6.95-13.88 mmol/L 126-250 mg/dL 10% 11% Grade 3 13.89-27.75 mmol/L 251-500 mg/dL 1% < 1% Grade 4 > 27.75 mmol/L > 500 mg/dL < 1% 0% Pancreatic Lipase Grade 2 > 1.5 to ≤ 3.0 X ULN 3% 4% Grade 3 > 3.0 to ≤ 5.0 X ULN 2% < 1% Grade 4 > 5.0 X ULN < 1% 0% Pancreatic Amylase Grade 2 > 1.5 to ≤ 2.0 X ULN 6% 7% Grade 3 > 2.0 to ≤ 5.0 X ULN 7% 3% Grade 4 > 5.0 X ULN 0% 0% 6.3 Serious ADRs The following serious ADRs of at least moderate intensity (≥ Grade 2) occurred in the Phase 2b studies (Studies TMC114-C213, TMC114-C202, TMC114-C215, and TMC114-C208) and Phase 3 studies (TMC114-C211, TMC114-C214, TMC114-C209, DUET-1 (TMC125-C206), and DUET-2 (TMC125-C216)) with PREZISTA/ritonavir: abdominal pain, acute hepatitis, acute pancreatitis, anorexia, asthenia, diabetes mellitus, diarrhea, fatigue, headache, hepatic enzyme increased, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, immune reconstitution syndrome, low density lipoprotein increased, nausea, pancreatic enzyme increased, rash, Stevens-Johnson Syndrome, and vomiting. 6.4 Additional ADRs to PREZISTA/ritonavir identified in adult subjects in other clinical trials The additional ADR of interest identified from other clinical trials was osteonecrosis. 6.5 Patients co-infected with hepatitis B and/or hepatitis C virus In subjects co-infected with hepatitis B or C virus receiving PREZISTA/ritonavir, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving PREZISTA/ritonavir who were not co-infected, except for increased hepatic enzymes [ see Warnings and Precautions (5.2) ]. The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection. 6.6 Clinical Trials Experience: Pediatric Patients PREZISTA/ritonavir has been studied in 80 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 6 to < 18 years of age and weighing at least 44 lbs (20 kg) in combination with other antiretroviral agents [ see Use in Specific Populations (8.4) and Clinical Studies (14.4) ]. Frequency, type, and severity of ADRs in pediatric subjects were comparable to those observed in adults. ADRs to PREZISTA/ritonavir (all grades, ≥ 3%), excluding laboratory abnormalities reported as ADRs, were vomiting (13%), diarrhea (11%), abdominal pain (10%), headache (9%), rash (5%), nausea (4%) and fatigue (3%). Grade 3 or 4 laboratory abnormalities were ALT increased (Grade 3: 3%; Grade 4: 1%), AST increased (Grade 3: 1%), pancreatic amylase increased (Grade 3: 4%, Grade 4: 1%), pancreatic lipase increased (Grade 3: 1%), total cholesterol increased (Grade 3: 1%), and LDL increased (Grade 3: 3%). 6.7 Postmarketing Experience The following events have been identified during postmarketing use of PREZISTA. Because these events 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. Redistribution of body fat has been reported. Rarely, rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors and PREZISTA/ritonavir) and toxic epidermal necrolysis have been reported [ see Warnings and Precautions (5.3) ].

<table width="90%" ID="table3"> <caption>Table 3: Selected Clinical Adverse Drug Reactions to PREZISTA/ritonavir 800/100 mg Once Daily<footnote>Excluding laboratory abnormalities reported as ADRs</footnote> of At Least Moderate Intensity (&#x2265; Grade 2) Occurring in &#x2265; 2% of Antiretroviral Treatment-Na&#xEF;ve HIV-1-Infected Adult Subjects</caption> <col width="55%" align="left" valign="top"/> <col width="25%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <thead> <tr styleCode="Botrule"> <th styleCode="Lrule"/> <th styleCode="Lrule Rrule" colspan="2">Randomized Study TMC114-C211</th> </tr> <tr> <th styleCode="Lrule">System Organ Class, Preferred Term, %</th> <th styleCode="Lrule">PREZISTA/ritonavir 800/100 mg once daily + TDF/FTC N = 343</th> <th styleCode="Lrule Rrule">lopinavir/ritonavir 800/200 mg per day + TDF/FTC N = 346</th> </tr> </thead> <tfoot> <tr> <td colspan="3" align="left">N=total number of subjects per treatment group TDF = tenofovir disoproxil fumarate FTC = emtricitabine</td> </tr> </tfoot> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Gastrointestinal Disorders</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Abdominal pain</td> <td styleCode="Rrule">5%</td> <td styleCode="Rrule">6%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Diarrhea</td> <td styleCode="Rrule">8%</td> <td styleCode="Rrule">15%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Nausea</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">4%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Vomiting</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">General Disorders and Administration Site Conditions</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Fatigue</td> <td styleCode="Rrule">&lt; 1%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Metabolism and Nutrition Disorders</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Anorexia</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">&lt; 1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Nervous System Disorders</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Headache</td> <td styleCode="Rrule">6%</td> <td styleCode="Rrule">5%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Rash</td> <td styleCode="Rrule">5%</td> <td styleCode="Rrule">6%</td> </tr> </tbody> </table>

<table width="90%" ID="table4"> <caption>Table 4: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Na&#xEF;ve HIV-1-Infected Adult Subjects<footnote>Grade 4 data not applicable in Division of AIDS grading scale.</footnote> </caption> <col width="35%" align="left" valign="top"/> <col width="25%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <thead> <tr styleCode="Botrule"> <th styleCode="Lrule" colspan="2"/> <th styleCode="Lrule Rrule" colspan="2">Randomized Study TMC114-C211</th> </tr> <tr> <th styleCode="Lrule">Laboratory Parameter Preferred Term, %</th> <th styleCode="Lrule">Limit</th> <th styleCode="Lrule">PREZISTA/ritonavir 800/100 mg once daily + TDF/FTC</th> <th styleCode="Lrule Rrule">lopinavir/ritonavir 800/200 mg per day + TDF/FTC</th> </tr> </thead> <tfoot> <tr> <td colspan="4" align="left">N=total number of subjects per treatment group TDF = tenofovir disoproxil fumarate FTC = emtricitabine</td> </tr> </tfoot> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Biochemistry</content> </td> <td styleCode="Rrule" colspan="3"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Alanine Aminotransferase</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">&gt; 2.5 to &#x2264; 5.0 X ULN</td> <td styleCode="Rrule">7%</td> <td styleCode="Rrule">6%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt; 5.0 to &#x2264; 10.0 X ULN</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 4</td> <td styleCode="Rrule">&gt; 10.0 X ULN</td> <td styleCode="Rrule">&lt; 1%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Aspartate Aminotransferase</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">&gt; 2.5 to &#x2264; 5.0 X ULN</td> <td styleCode="Rrule">6%</td> <td styleCode="Rrule">6%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt; 5.0 to &#x2264; 10.0 X ULN</td> <td styleCode="Rrule">4%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 4</td> <td styleCode="Rrule">&gt; 10.0 X ULN</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Alkaline Phosphatase</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">&gt; 2.5 to &#x2264; 5.0 X ULN</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt; 5.0 to &#x2264; 10.0 X ULN</td> <td styleCode="Rrule">0%</td> <td styleCode="Rrule">&lt; 1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 4</td> <td styleCode="Rrule">&gt; 10.0 X ULN</td> <td styleCode="Rrule">0%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Hyperbilirubinemia</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">&gt; 1.5 to &#x2264; 2.5 X ULN</td> <td styleCode="Rrule">&lt; 1%</td> <td styleCode="Rrule">4%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt; 2.5 to &#x2264; 5.0 X ULN</td> <td styleCode="Rrule">&lt; 1%</td> <td styleCode="Rrule">&lt; 1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 4</td> <td styleCode="Rrule">&gt; 5.0 X ULN</td> <td styleCode="Rrule">0%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Triglycerides</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">5.65-8.48 mmol/L 500-750 mg/dL</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">8%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">8.49-13.56 mmol/L 751-1200 mg/dL</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">5%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 4</td> <td styleCode="Rrule">&gt; 13.56 mmol/L &gt; 1200 mg/dL</td> <td styleCode="Rrule">&lt; 1%</td> <td styleCode="Rrule">&lt; 1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Total Cholesterol</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">6.20-7.77 mmol/L 240-300 mg/dL</td> <td styleCode="Rrule">16%</td> <td styleCode="Rrule">23%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt; 7.77 mmol/L &gt; 300 mg/dL</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">5%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Low-Density Lipoprotein Cholesterol</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">4.13-4.90 mmol/L 160-190 mg/dL</td> <td styleCode="Rrule">14%</td> <td styleCode="Rrule">10%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&#x2265; 4.91 mmol/L &#x2265; 191 mg/dL</td> <td styleCode="Rrule">5%</td> <td styleCode="Rrule">5%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Elevated Glucose Levels</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">6.95-13.88 mmol/L 126-250 mg/dL</td> <td styleCode="Rrule">7%</td> <td styleCode="Rrule">8%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">13.89-27.75 mmol/L 251-500 mg/dL</td> <td styleCode="Rrule">&lt; 1%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 4</td> <td styleCode="Rrule">&gt; 27.75 mmol/L &gt; 500 mg/dL</td> <td styleCode="Rrule">0%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Pancreatic Lipase</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">&gt; 1.5 to &#x2264; 3.0 X ULN</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt; 3.0 to &#x2264; 5.0 X ULN</td> <td styleCode="Rrule">&lt; 1%</td> <td styleCode="Rrule">&lt; 1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 4</td> <td styleCode="Rrule">&gt; 5.0 X ULN</td> <td styleCode="Rrule">0%</td> <td styleCode="Rrule">&lt; 1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Pancreatic Amylase</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">&gt; 1.5 to &#x2264; 2.0 X ULN</td> <td styleCode="Rrule">5%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt; 2.0 to &#x2264; 5.0 X ULN</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">3%</td> </tr> <tr> <td styleCode="Lrule Rrule"> Grade 4</td> <td styleCode="Rrule">&gt; 5.0 X ULN</td> <td styleCode="Rrule">0%</td> <td styleCode="Rrule">&lt; 1%</td> </tr> </tbody> </table>

<table width="90%" ID="table5"> <caption>Table 5: Selected Clinical Adverse Drug Reactions to PREZISTA/ritonavir 600/100 mg Twice Daily<footnote>Excluding laboratory abnormalities reported as ADRs</footnote> of At Least Moderate Intensity (&#x2265; Grade 2) Occurring in &#x2265; 2% of Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjects</caption> <col width="50%" align="left" valign="top"/> <col width="25%" align="center" valign="top"/> <col width="25%" align="center" valign="top"/> <thead> <tr styleCode="Botrule"> <th styleCode="Lrule"/> <th styleCode="Lrule Rrule" colspan="2">Randomized Study TMC114-C214</th> </tr> <tr> <th styleCode="Lrule">System Organ Class, Preferred Term, %</th> <th styleCode="Lrule">PREZISTA/ritonavir 600/100 mg twice daily + OBR N = 298</th> <th styleCode="Lrule Rrule">lopinavir/ritonavir 400/100 mg twice daily + OBR N = 297</th> </tr> </thead> <tfoot> <tr> <td colspan="3" align="left">N=total number of subjects per treatment group OBR = optimized background regimen</td> </tr> </tfoot> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Gastrointestinal Disorders</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Abdominal distension</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">&lt; 1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Abdominal pain</td> <td styleCode="Rrule">6%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Diarrhea</td> <td styleCode="Rrule">14%</td> <td styleCode="Rrule">20%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Dyspepsia</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Nausea</td> <td styleCode="Rrule">7%</td> <td styleCode="Rrule">6%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Vomiting</td> <td styleCode="Rrule">5%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">General Disorders and Administration Site Conditions</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Asthenia</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Fatigue</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Metabolism and Nutrition Disorders</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Anorexia</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Diabetes mellitus</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">&lt; 1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Nervous System Disorders</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Headache</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Rash</td> <td styleCode="Rrule">7%</td> <td styleCode="Rrule">3%</td> </tr> </tbody> </table>