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The overall safety profile of PREZISTA/ritonavir 800/100 mg once daily and PREZISTA/ritonavir 600/100 mg twice daily is based on clinical trials and post-marketing data, and is consistent with the data presented below.

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.

Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions.

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 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* of at Least Moderate Intensity ( ≥ Grade 2) Occurring in ≥ 2% of Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects

System Organ Class, Preferred Term, %  Randomized Study TMC114-C211 
PREZISTA/ritonavir 800/100 mg once daily + TDF/FTC
N = 343 
lopinavir/ritonavir 800/200 mg per day + TDF/FTC
N = 346 
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%
N=total number of subjects per treatment group
TDF = tenofovir disoproxil fumarate
FTC = emtricitabine
* Excluding laboratory abnormalities reported as ADRs

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-1Infected Adult Subjects*

Laboratory Parameter Preferred Term, %  Limit  Randomized Study TMC114-C211 
PREZISTA/ ritonavir 800/100 mg once daily + TDF/FTC  lopinavir/ ritonavir 800/200 mg per day + TDF/FTC 
Biochemistry 
Alanine Aminotransferase 
  Grade 2  > 2.5 to ≤ 5.0 X ULN  9% 9%
  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  7% 10%
  Grade 3  > 5.0 to ≤ 10.0 X ULN  4% 2%
  Grade 4  > 10.0 X ULN  1% 3%
Alkaline Phosphatase 
  Grade 2  > 2.5 to ≤ 5.0 X ULN  1% 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%  5%
  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% 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 X ULN  3% 2%
  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  5% 4%
  Grade 4  > 5.0 X ULN  0% < 1% 
N=total number of subjects per treatment group
TDF = tenofovir disoproxil fumarate
FTC = emtricitabine
* Grade 4 data not applicable in Division of AIDS grading scale.

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 (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* of at Least Moderate Intensity ( ≥ Grade 2) Occurring in ≥ 2% of Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjects

System Organ Class, Preferred Term, %  Randomized Study TMC114-C214 
PREZISTA/ ritonavir 600/100 mg twice daily + OBR
N = 298 
lopinavir/ ritonavir 400/100 mg twice daily + OBR
N = 297 
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%
N=total number of subjects per treatment group
OBR = optimized background regimen
* Excluding laboratory abnormalities reported as ADRs

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*

Laboratory Parameter Preferred Term, %  Limit  Randomized Study TMC114-C214 
PREZISTA/ ritonavir 600/100 mg twice daily + OBR  lopinavir/ ritonavir 400/100 mg twice daily + OBR 
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%
N=total number of subjects per treatment group
OBR = optimized background regimen
* Grade 4 data not applicable in Division of AIDS grading scale

Serious ADRs

The following serious ADRs of at least moderate intensity (greater than or equal to Grade 2) occurred in the Phase 2b studies and Phase 3 studies 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]. 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 II trials. TMC114C212, 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 and Clinical Studies]. Frequency, type, and severity of ADRs in pediatric subjects were comparable to those observed in adults.

Study 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%).

Study 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 study.

Study 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 study.

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].