ADVERSE REACTIONS
The safety assessment is based on all safety data from the Studies TMC114-C213 and TMC114-C202 and the TMC114-C215/C208 analysis reported with the recommended dose PREZISTA/rtv 600/100 mg b.i.d. in the 458 subjects who initiated treatment with the recommended dose (de novo subjects). In Studies TMC114-C213 and TMC114-C202, the mean exposure in weeks for subjects in the PREZISTA/rtv 600/100 mg b.i.d. arm and comparator PI arm was 63.5 and 31.5, respectively. The mean exposure in weeks for subjects in the TMC114-C215/C208 analysis was 23.9.
The most common treatment-emergent adverse events (> 10%) reported in the de novo subjects, regardless of causality or frequency, were diarrhea, nausea, headache, and nasopharyngitis.
For subjects in the PREZISTA/rtv 600/100 mg b.i.d. arm and the comparator PI arm in the pooled analysis for Studies TMC114-C213 and TMC114-C202, diarrhea was reported in 19.8% and 28.2%, nausea in 18.3% and 12.9%, headache in 15.3% and 20.2%, and nasopharyngitis in 13.7% and 10.5%, of subjects, respectively. In the randomized trials, rates of discontinuation of therapy due to adverse events were 9% in subjects receiving PREZISTA/rtv and in 5% of subjects in the comparator PI arm.
Due to the need for co-administration of PREZISTA with 100 mg of ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions.
Drug-related clinical adverse events of moderate or severe intensity (≥ Grade 2) occurring in ≥ 2% of subjects treated with PREZISTA/rtv for 1 to 96 weeks are presented in Table 12.
Table 12: Percentage of Subjects with Selected Treatment Emergent, Drug-Related^ Adverse Events of at least Moderate Intensity (Grades 2-4) in ≥ 2% of Adult Subjects in Any PREZISTA/rtv Treatment Groups† System Organ Class, Preferred Term,
% | Randomized Studies TMC114-C213 and TMC114-C202 | Non-randomized TMC114-C215/C208 Analysis |
|---|
PREZISTA/rtv 600/100 mg b.i.d. +OBR
N = 131 | Comparator PI +OBR
N = 124 | PREZISTA/rtv 600/100 mg b.i.d.+OBR
N = 327 |
|---|
| ^ Includes adverse events at least possibly, probably, or very likely related to the drug |
| N=total number of subjects per treatment group |
| † Excludes laboratory abnormalities that were reported as Adverse Events (see Table 13: Treatment Emergent Grade 2 to 4 Laboratory Abnormalities Reported in ≥ 2% of Subjects) |
| Gastrointestinal Disorders |
| Diarrhea | 2.3% | 3.2% | 2.8% |
| Vomiting | 1.5% | 1.6% | 2.4% |
| Abdominal Pain | 2.3% | 0.8% | 1.2% |
| Constipation | 2.3% | 0.8% | 0.6% |
| Nervous System Disorders |
| Headache | 3.8% | 2.4% | 0.9% |
Treatment-emergent adverse events occurring in less than 2% of de novo subjects (n=458) receiving PREZISTA/rtv, considered at least possibly related to treatment and of at least moderate intensity are listed below by body system:
Body as a Whole:
folliculitis, asthenia, pyrexia, fatigue, rigors, hyperthermia, peripheral edema
Cardiovascular System:
myocardial infarction, tachycardia, hypertension
Digestive System:
flatulence, abdominal distension, dry mouth, dyspepsia, abdominal pain, nausea, constipation
Metabolic and Nutritional Disorders:
anorexia, hypercholesterolemia, hyperlipidemia, diabetes mellitus, decreased appetite, obesity, fat redistribution, hyponatremia, polydipsia
Musculoskeletal System:
arthralgia, pain in extremity, myalgia, osteopenia, osteoporosis
Nervous System:
peripheral neuropathy, hypoesthesia, memory impairment, paresthesia, somnolence, transient ischemic attack, confusional state, disorientation, irritability, altered mood, nightmare, anxiety, headache
Respiratory System:
dyspnea, cough, hiccups
Skin and Appendages:
lipoatrophy, night sweats, allergic dermatitis, eczema, toxic skin eruption, alopecia, dermatitis medicamentosa, hyperhidrosis, skin inflammation, maculopapular rash,
Special Senses:
vertigo
Urogenital System:
acute renal failure, renal insufficiency, nephrolothiasis, polyuria, gynecomastia
Laboratory abnormalities
The percentages of adult subjects treated with PREZISTA/rtv 600/100 mg b.i.d. with treatment-emergent Grade 2 to 4 laboratory abnormalities are presented in Table 13.
Table 13: Treatment Emergent Grade 2 to 4 Laboratory Abnormalities Reported in ≥ 2% of Subjects | Randomized Studies TMC114-C213 and TMC114-C202 | Non-randomized TMC114-C215/C208 Analysis |
|---|
Laboratory Parameter Preferred Term,
% | Limit | PREZISTA/rtv 600/100 mg b.i.d. + OBR
N = 131 | Comparator PI + OBR
N = 124 | PREZISTA/rtv 600/100 mg b.i.d.
N = 327 |
|---|
| Biochemistry | |
Aspartate
Aminotransferase | > 2.5 X ULN | 10.0% | 13.0% | 5.3% |
Alanine
Aminotransferase | > 2.5 X ULN | 6.9% | 9.8% | 5.6% |
Gamma Glutamyl
Transferase | > 2.5 X ULN | 9.2% | 8.9% | 8.4% |
| Hyperbilirubinemia | > 1.5 X ULN | 2.3% | 15.4% | 0.9% |
Alkaline
Phosphatase | > 2.5 X ULN | 4.6% | 0% | 2.8% |
| Pancreatic Amylase | > 1.5 X ULN | 16.9% | 8.9% | 10.8% |
| Pancreatic Lipase | > 1.5 X ULN | 8.5% | 4.1% | 6.2% |
| Hyperglycemia | ≥ 161 mg/dL | 2.3% | 8.1% | 5.9% |
| Hypoglycemia | ≤ 54 mg/dL | 1.5% | 1.6% | 3.7% |
| Total Cholesterol | ≥ 240 mg/dL | 9.2% | 3.3% | 8.0% |
| Triglycerides | > 400 mg/dL | 25.4% | 26.0% | 18.9% |
| Hypoalbuminemia | < 3 g/dL | 3.1% | 1.6% | 4.3% |
| Hyperuricemia | ≥ 9.9 mg/dL | 6.9% | 6.5% | 2.2% |
| Bicarbonate | < 15 mmol/L | 3.1% | 4.1% | 3.4% |
| Hypocalcemia | ≤ 7.8 mg/dL | 0% | 0.8% | 4.0% |
| Hyponatremia | ≤ 129 meq/L | 0.8% | 0% | 2.5% |
| Hypernatremia | ≥ 151 meq/L | 2.3% | 0% | 0% |
| Hematology | |
White Blood Cell
Count decrease | < 3000 count/mm3 | 15.4% | 18.7% | 13.0% |
Total Absolute
Neutrophil
Count decrease | ≤ 999 mm3 | 6.9% | 9.8% | 11.5% |
Lymphocytes
decrease | < 1000 count/mm3 | 4.6% | 19.5% | 10.9% |
Partial
Thromboplastin
Time increase | > 1.66 X ULN | 7.8% | 4.1% | 4.3% |
Plasma
Prothrombin Time
increase | > 1.25 X ULN | 3.9% | 0.8% | 0.6% |
Platelet Count
decrease | < 75,000/mm3 | 3.1% | 1.6% | 2.8% |
Additional adverse reactions identified in clinical studies, occurring in less than 1% of the patients, are listed below by body system:
Hepatobiliary System: hepatitis
Skin and Appendages: erythema multiforme, Stevens-Johnson Syndrome
Patients co-infected with hepatitis B and/or hepatitis C virus
In subjects co-infected with hepatitis B or C virus receiving PREZISTA/rtv, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving PREZISTA/rtv 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. Standard clinical monitoring of patients with hepatitis co-infectionis considered adequate.
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