PREZISTA SIDE EFFECTS
- Generic Name: darunavir
- Brand Name: Prezista
- Drug Class: HIV, Protease Inhibitors
SIDE EFFECTS
The following adverse reactions are discussed in other sections of labeling:
- Hepatotoxicity
- Severe Skin Reactions
- Diabetes Mellitus/Hyperglycemia
- Fat Redistribution
- Immune Reconstitution Syndrome
- Hemophilia
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
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 Naive-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-naive 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-naive HIV-1-infected adult subjects are presented in Table 1 and subsequent text below the table.
Table 1: 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-Naive 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 |
| 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; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate * Excluding laboratory abnormalities reported as ADRs. |
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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-naive 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-naive adult subjects treated with PREZISTA/ritonavir 800/100 mg once daily are presented in Table 2.
Table 2: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Naive HIV-1Infected 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 |
| 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; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate * Grade 4 data not applicable in Division of AIDS grading scale. |
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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 3 and subsequent text below the table.
Table 3: 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 + 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 |
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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 4.
Table 4: 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 |
| 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 |
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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. 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-naive 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.
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.
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.
SRC: NLM .