PREZISTA (Page 3 of 12)

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, Guillain-Barré syndrome, and autoimmune hepatitis) 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:

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

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 * 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/FTCN=343 lopinavir/ritonavir 800/200 mg per day + TDF/FTCN=346
N=total number of subjects per treatment group; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate
*
Excluding laboratory abnormalities reported as ADRs.
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 * (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
*
Grade 4 data not applicable in Division of AIDS grading scale.
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 * 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 + OBRN=298 lopinavir/ritonavir 400/100 mg twice daily + OBRN=297
N=total number of subjects per treatment group; OBR=optimized background regimen
*
Excluding laboratory abnormalities reported as ADRs
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 * (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
*
Grade 4 data not applicable in Division of AIDS grading scale
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.

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