FDA label 77868099-e4d6-5098-e053-2991aa0acd54

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. Post-marketing cases of liver injury, including some fatalities, have been reported. ( 5.2 ) Skin reactions ranging from mild to severe, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms and acute generalized exanthematous pustulosis, have been reported. Discontinue treatment if severe reaction develops. ( 5.3 ) 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 or immune reconstitution syndrome. ( 5.7 , 5.8 ) Patients with hemophilia may develop increased bleeding events. ( 5.9 ) PREZISTA/ritonavir is not recommended in pediatric patients below 3 years of age in view of toxicity and mortality observed in juvenile rats dosed with darunavir up to days 23 to 26 of age. ( 5.10 ) 5.1 Importance of Co-administration with Ritonavir 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 (less than 0.1%) reported during the clinical development program. During post-marketing experience toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported. Discontinue PREZISTA/ritonavir 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/ritonavir [ 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/ritonavir was 0.5%. Rash occurred more commonly in treatment-experienced subjects receiving regimens containing PREZISTA/ritonavir + raltegravir compared to subjects receiving PREZISTA/ritonavir without raltegravir or raltegravir without PREZISTA/ritonavir. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash. 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 were similar in subjects with or without a history of sulfonamide allergy. 5.5 Risk of Serious Adverse Reactions due to Drug Interactions Initiation of PREZISTA/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PREZISTA/ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of PREZISTA/ritonavir, respectively. These interactions may lead to: Clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications. Clinically significant adverse reactions from greater exposures of PREZISTA/ritonavir. Loss of therapeutic effect of PREZISTA/ritonavir and possible development of resistance. See Table 11 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7) ] . Consider the potential for drug interactions prior to and during PREZISTA/ritonavir therapy; review concomitant medications during PREZISTA/ritonavir therapy; and monitor for the adverse reactions associated with the concomitant drugs [see Contraindications (4) and Drug Interactions (7) ] . 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 Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including PREZISTA. 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. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral 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 Not Recommended in Pediatric Patients Below 3 Years of Age PREZISTA/ritonavir in pediatric patients below 3 years of age is not recommended 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) and Clinical Pharmacology (12.3) ] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of labeling: Hepatotoxicity [see Warnings and Precautions (5.2) ] Severe Skin Reactions [see Warnings and Precautions (5.3) ] Diabetes Mellitus/Hyperglycemia [see Warnings and Precautions (5.6) ] Fat Redistribution [see Warnings and Precautions (5.7) ] Immune Reconstitution Syndrome [see Warnings and Precautions (5.8) ] Hemophilia [see Warnings and Precautions (5.9) ] 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 greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, nausea, rash, headache, abdominal pain and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) 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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Treatment Naïve-Adults: 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 162.5 and 153.5 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 (greater than or equal to 5%) of at least moderate intensity (greater than or equal to 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 (greater than or equal to Grade 2) in antiretroviral treatment-naïve HIV-1-infected adult subjects are presented in Table 7 and subsequent text below the table. Table 7: 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 (Trial 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; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate Gastrointestinal Disorders Abdominal pain 6% 6% Diarrhea 9% 16% Nausea 4% 4% Vomiting 2% 4% General Disorders and Administration Site Conditions Fatigue <1% 3% Metabolism and Nutrition Disorders Anorexia 2% <1% Nervous System Disorders Headache 7% 6% Skin and Subcutaneous Tissue Disorders Rash 6% 7% Less Common Adverse Reactions Treatment-emergent ADRs of at least moderate intensity (greater than or equal to 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, immune reconstitution syndrome Metabolism and Nutrition Disorders : diabetes mellitus Musculoskeletal and Connective Tissue Disorders : myalgia, osteonecrosis 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 8. Table 8: 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. (Trial TMC114-C211) Laboratory parameter % 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; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate Biochemistry Alanine Aminotransferase Grade 2 >2.5 to ≤5.0 × ULN 9% 9% Grade 3 >5.0 to ≤10.0 × ULN 3% 3% Grade 4 >10.0 × ULN <1% 3% Aspartate Aminotransferase Grade 2 >2.5 to ≤5.0 × ULN 7% 10% Grade 3 >5.0 to ≤10.0 × ULN 4% 2% Grade 4 >10.0 × ULN 1% 3% Alkaline Phosphatase Grade 2 >2.5 to ≤5.0 × ULN 1% 1% Grade 3 >5.0 to ≤10.0 × ULN 0% <1% Grade 4 >10.0 × ULN 0% 0% Hyperbilirubinemia Grade 2 >1.5 to ≤2.5 × ULN <1% 5% Grade 3 >2.5 to ≤5.0 × ULN <1% <1% Grade 4 >5.0 × ULN 0% 0% Triglycerides Grade 2 5.65–8.48 mmol/L 500–750 mg/dL 3% 10% Grade 3 8.49–13.56 mmol/L 751–1200 mg/dL 2% 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 23% 27% 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% 12% Grade 3 ≥4.91 mmol/L ≥191 mg/dL 9% 6% Elevated Glucose Levels Grade 2 6.95–13.88 mmol/L 126–250 mg/dL 11% 10% Grade 3 13.89–27.75 mmol/L 251–500 mg/dL 1% <1% Grade 4 >27.75 mmol/L >500 mg/dL 0% 0% Pancreatic Lipase Grade 2 >1.5 to ≤3.0 × ULN 3% 2% Grade 3 >3.0 to ≤5.0 × ULN <1% 1% Grade 4 >5.0 × ULN 0% <1% Pancreatic Amylase Grade 2 >1.5 to ≤2.0 × ULN 5% 2% Grade 3 >2.0 to ≤5.0 × ULN 5% 4% Grade 4 >5.0 × ULN 0% <1% Treatment-Experienced Adults: 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 (greater than or equal to 5%) of at least moderate intensity (greater than or equal to 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 (greater than or equal to Grade 2) in antiretroviral treatment-experienced HIV-1-infected adult subjects are presented in Table 9 and subsequent text below the table. Table 9: 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 (Trial 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 (greater than or equal to 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 : acute 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 10. Table 10: 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 (Trial TMC114-C214) Laboratory parameter, % 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 × ULN 7% 5% Grade 3 >5.0 to ≤10.0 × ULN 2% 2% Grade 4 >10.0 × ULN 1% 2% Aspartate Aminotransferase Grade 2 >2.5 to ≤5.0 × ULN 6% 6% Grade 3 >5.0 to ≤10.0 × ULN 2% 2% Grade 4 >10.0 × ULN <1% 2% Alkaline Phosphatase Grade 2 >2.5 to ≤5.0 × ULN <1% 0% Grade 3 >5.0 to ≤10.0 × ULN <1% <1% Grade 4 >10.0 × ULN 0% 0% Hyperbilirubinemia Grade 2 >1.5 to ≤2.5 × ULN <1% 2% Grade 3 >2.5 to ≤5.0 × ULN <1% <1% Grade 4 >5.0 × 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 × ULN 3% 4% Grade 3 >3.0 to ≤5.0 × ULN 2% <1% Grade 4 >5.0 × ULN <1% 0% Pancreatic Amylase Grade 2 >1.5 to ≤2.0 × ULN 6% 7% Grade 3 >2.0 to ≤5.0 × ULN 7% 3% Grade 4 >5.0 × ULN 0% 0% Serious ADRs The following serious ADRs of at least moderate intensity (greater than or equal to Grade 2) occurred in the Phase 2b and Phase 3 trials 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. 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. Clinical Trials Experience: Pediatric Patients PREZISTA/ritonavir has been studied in combination with other antiretroviral agents in 3 Phase 2 trials. TMC114-C212, in which 80 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 6 to less than 18 years of age and weighing at least 20 kg were included, TMC114-C228, in which 21 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 3 to less than 6 years of age and weighing at least 10 kg were included, and TMC114-C230 in which 12 antiretroviral treatment-naïve HIV-1 infected pediatric patients aged from 12 to less than 18 years and weighing at least 40 kg were included. The TMC114-C212 and C228 trials evaluated PREZISTA/ritonavir twice daily dosing and the TMC114-C230 trial evaluated PREZISTA/ritonavir once daily dosing [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. TMC114-C212 Clinical ADRs to PREZISTA/ritonavir (all grades, greater than or equal to 3%), 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%). TMC114-C228 Clinical ADRs to PREZISTA/ritonavir (all grades, greater than or equal to 5%), were diarrhea (24%), vomiting (19%), rash (19%), abdominal pain (5%), and anorexia (5%). There were no Grade 3 or 4 laboratory abnormalities considered as ADRs in this trial. TMC114-C230 Clinical ADRs to PREZISTA/ritonavir (all grades, greater than or equal to 3%), were vomiting (33%), nausea (25%), diarrhea (16.7%), abdominal pain (8.3%), decreased appetite (8.3%), pruritus (8.3%), and rash (8.3%). There were no Grade 3 or 4 laboratory abnormalities considered as ADRs in this trial. 6.2 Postmarketing Experience The following events have been identified during post approval use of PREZISTA. Because these events are reported voluntarily from a population of uncertain 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) has been reported. In addition, toxic epidermal necrolysis, acute generalized exanthematous pustulosis and drug rash with eosinophilia and systemic symptoms have been reported rarely [see Warnings and Precautions (5.3) ] .

<table width="75%" ID="table7"> <caption>Table 7: Selected Clinical Adverse Drug Reactions to PREZISTA/ritonavir 800/100 mg Once Daily <footnote ID="tab5a">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 (Trial TMC114-C211) </caption> <col width="52%" align="left" valign="top"/> <col width="25%" align="center" valign="top"/> <col width="23%" align="center" valign="top"/> <thead> <tr> <th styleCode="Lrule">System organ class, preferred term, % </th> <th align="center" 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; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate</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">6%</td> <td styleCode="Rrule">6%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Diarrhea</td> <td styleCode="Rrule">9%</td> <td styleCode="Rrule">16%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Nausea</td> <td styleCode="Rrule">4%</td> <td styleCode="Rrule">4%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Vomiting</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">4%</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">7%</td> <td styleCode="Rrule">6%</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">6%</td> <td styleCode="Rrule">7%</td> </tr> </tbody> </table>

<table width="85%" ID="table8"> <caption>Table 8: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Na&#xEF;ve HIV-1-Infected Adult Subjects <footnote ID="table6a">Grade 4 data not applicable in Division of AIDS grading scale.</footnote> (Trial TMC114-C211) </caption> <col width="30%" align="left" valign="top"/> <col width="30%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <thead> <tr> <th styleCode="Lrule">Laboratory parameter % </th> <th styleCode="Lrule" valign="bottom">Limit</th> <th align="center" 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; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate</td> </tr> </tfoot> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Biochemistry</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td colspan="4" styleCode="Lrule Rrule">Alanine Aminotransferase</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">&gt;2.5 to &#x2264;5.0 &#xD7; ULN</td> <td styleCode="Rrule">9%</td> <td styleCode="Rrule">9%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt;5.0 to &#x2264;10.0 &#xD7; 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 &#xD7; ULN</td> <td styleCode="Rrule">&lt;1%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td colspan="4" styleCode="Lrule Rrule">Aspartate Aminotransferase</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">&gt;2.5 to &#x2264;5.0 &#xD7; ULN</td> <td styleCode="Rrule">7%</td> <td styleCode="Rrule">10%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt;5.0 to &#x2264;10.0 &#xD7; 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 &#xD7; ULN</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td colspan="4" styleCode="Lrule Rrule">Alkaline Phosphatase</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">&gt;2.5 to &#x2264;5.0 &#xD7; ULN</td> <td styleCode="Rrule">1%</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 &#xD7; 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 &#xD7; ULN</td> <td styleCode="Rrule">0%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td colspan="4" styleCode="Lrule Rrule">Hyperbilirubinemia</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">&gt;1.5 to &#x2264;2.5 &#xD7; ULN</td> <td styleCode="Rrule">&lt;1%</td> <td styleCode="Rrule">5%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt;2.5 to &#x2264;5.0 &#xD7; 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 &#xD7; ULN</td> <td styleCode="Rrule">0%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td colspan="4" styleCode="Lrule Rrule">Triglycerides</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">5.65&#x2013;8.48 mmol/L 500&#x2013;750 mg/dL </td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">10%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">8.49&#x2013;13.56 mmol/L 751&#x2013;1200 mg/dL </td> <td styleCode="Rrule">2%</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"> 1%</td> <td styleCode="Rrule"> 1%</td> </tr> <tr styleCode="Botrule"> <td colspan="4" styleCode="Lrule Rrule">Total Cholesterol</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">6.20&#x2013;7.77 mmol/L 240&#x2013;300 mg/dL </td> <td styleCode="Rrule">23%</td> <td styleCode="Rrule">27%</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 colspan="4" styleCode="Lrule Rrule">Low-Density Lipoprotein Cholesterol</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">4.13&#x2013;4.90 mmol/L 160&#x2013;190 mg/dL </td> <td styleCode="Rrule">14%</td> <td styleCode="Rrule">12%</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">9%</td> <td styleCode="Rrule">6%</td> </tr> <tr styleCode="Botrule"> <td colspan="4" styleCode="Lrule Rrule">Elevated Glucose Levels</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">6.95&#x2013;13.88 mmol/L 126&#x2013;250 mg/dL </td> <td styleCode="Rrule">11%</td> <td styleCode="Rrule">10%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">13.89&#x2013;27.75 mmol/L 251&#x2013;500 mg/dL </td> <td styleCode="Rrule"> 1%</td> <td styleCode="Rrule">&lt;1%</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 colspan="4" styleCode="Lrule Rrule">Pancreatic Lipase</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">&gt;1.5 to &#x2264;3.0 &#xD7; ULN</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 3</td> <td styleCode="Rrule">&gt;3.0 to &#x2264;5.0 &#xD7; ULN</td> <td styleCode="Rrule">&lt;1%</td> <td styleCode="Rrule"> 1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 4</td> <td styleCode="Rrule">&gt;5.0 &#xD7; ULN</td> <td styleCode="Rrule">0%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td colspan="4" styleCode="Lrule Rrule">Pancreatic Amylase</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Grade 2</td> <td styleCode="Rrule">&gt;1.5 to &#x2264;2.0 &#xD7; 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 &#xD7; ULN</td> <td styleCode="Rrule">5%</td> <td styleCode="Rrule">4%</td> </tr> <tr> <td styleCode="Lrule Rrule"> Grade 4</td> <td styleCode="Rrule">&gt;5.0 &#xD7; ULN</td> <td styleCode="Rrule">0%</td> <td styleCode="Rrule">&lt;1%</td> </tr> </tbody> </table>

<table width="75%" ID="table9"> <caption>Table 9: Selected Clinical Adverse Drug Reactions to PREZISTA/ritonavir 600/100 mg Twice Daily <footnote ID="table9a">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 (Trial TMC114-C214) </caption> <col width="50%" align="left" valign="top"/> <col width="25%" align="center" valign="top"/> <col width="25%" align="center" valign="top"/> <thead> <tr> <th styleCode="Lrule" valign="bottom">System organ class, preferred term, % </th> <th align="center" 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>