1 INDICATIONS AND USAGE PREZISTA, co-administered with ritonavir (PREZISTA/ritonavir), in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection in adult and pediatric patients 3 years of age and older [see Use in Specific Populations (8.4) and Clinical Studies (14) ] .

PREZISTA is a human immunodeficiency virus (HIV-1) protease inhibitor indicated for the treatment of HIV-1 infection in adult and pediatric patients 3 years of age and older.

PREZISTA must be co-administered with ritonavir (PREZISTA/ritonavir) and with other antiretroviral agents.

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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 6 and subsequent text below the table.

Table 6: 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 7.

Table 7: 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 8 and subsequent text below the table.

Table 8: 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 9.

Table 9: 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 adverse reactions have been identified during post-approval use of PREZISTA.

Because these reactions 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.

Metabolism and Nutrition Disorders: Redistribution of body fat Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors and PREZISTA/ritonavir) Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms [see Warnings and Precautions (5.3) ] Renal and Urinary Disorders: Crystal nephropathy, crystalluria