The following adverse drug reactions (ADRs) are discussed in greater detail in other sections of the package insert:
- Depressive Disorders [see WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
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.
The safety assessment is based on the Week 96 pooled data from 1368 patients in the Phase 3 controlled trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve HIV-1 infected adult patients, 686 of whom received EDURANT (25 mg once daily) [see Clinical Studies]. The median duration of exposure for patients in the EDURANT arm and efavirenz arm was 104.3 and 104.1 weeks, respectively. Most ADRs occurred in the first 48 weeks of treatment. The proportion of subjects who discontinued treatment with EDURANT or efavirenz due to ADR, regardless of severity, was 2% and 4%, respectively. The most common ADRs leading to discontinuation were psychiatric disorders: 10 (1%) subjects in the EDURANT arm and 11 (2%) subjects in the efavirenz arm. Rash led to discontinuation in 1 (0.1%) subject in the EDURANT arm and 10 (1.5%) subjects in the efavirenz arm.
Common Adverse Drug Reactions
ADRs of at least moderate intensity ( ≥ Grade 2) reported in at least 2% of adult subjects are presented in Table 1. Selected treatment-emergent laboratory abnormalities are included in Table 2.
Table 1: Selected Treatment-Emergent Adverse Drug Reactions of at least Moderate Intensity* (Grades 2-4) Occurring in at Least 2% of Antiretroviral Treatment-Naïve HIV-1 Infected Adult Subjects (Week 96 Analysis)
|System Organ Class, Preferred Term, %||Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials|
|EDURANT + BR
|Efavirenz + BR
|General Disorders and Administration Site Conditions|
|Nervous System Disorders|
|Skin and Subcutaneous Tissue Disorders|
|N = total number of subjects per treatment group; BR = background regimen
* Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity).
† Includes adverse drug reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation.
No new ADR terms were identified in adult subjects in the Phase 3 TMC278-C209 and TMC278-C215 trials between 48 weeks and 96 weeks nor in the Phase 2b TMC278-C204 trial through 240 weeks. The incidence of adverse events in the Phase 2b TMC278-C204 trial was similar to the Phase 3 trials through 96 weeks.
Less Common Adverse Drug Reactions
Treatment-emergent ADRs of at least moderate intensity ( ≥ Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving EDURANT are listed below by System Organ Class. Some adverse events have been included because of investigator's assessment of potential causal relationship and were considered serious or have been reported in more than 1 subject treated with EDURANT.
Gastrointestinal Disorders: diarrhea, abdominal discomfort
Hepatobiliary Disorders: cholecystitis, cholelithiasis
Metabolism and Nutrition Disorders: decreased appetite
Nervous System Disorders: somnolence
Psychiatric Disorders: sleep disorders, anxiety
Renal and Urinary Disorders: glomerulonephritis membranous, glomerulonephritis mesangioproliferative, nephrolithiasis
Laboratory Abnormalities in Treatment-Naïve Subjects
The percentage of subjects treated with EDURANT or efavirenz in the Phase 3 trials with selected treatment-emergent clinical laboratory abnormalities (Grades 1 to 4), representing worst Grade toxicity are shown in Table 2.
Table 2: Selected Treatment-Emergent Changes in Laboratory Parameters (Grades 1 to 4) Observed in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects (Week 96 Analysis)
|Laboratory Parameter Abnormality, (%)||DAIDS Toxicity Range||Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials|
|EDURANT + BR
|Efavirenz + BR
|Grade 1||≥ 1.1 ≤ 1.3 x ULN||6%||1%|
|Grade 2||> 1.3 ≤ 1.8 x ULN||1%||1%|
|Grade 3||> 1.8 ≤ 3.4 x ULN||< 1%||0|
|Grade 4||> 3.4 x ULN||0||< 1%|
|Grade 1||≥ 1.25 ≤ 2.5 x ULN||16%||19%|
|Grade 2||> 2.5 ≤ 5.0 x ULN||4%||7%|
|Grade 3||> 5.0 ≤ 10.0 x ULN||2%||2%|
|Grade 4||> 10.0 x ULN||1%||1%|
|Grade 1||≥ 1.25 ≤ 2.5 x ULN||18%||20%|
|Grade 2||> 2.5- ≤ 5.0 x ULN||5%||7%|
|Grade 3||> 5.0 ≤ 10.0 x ULN||1%||2%|
|Grade 4||> 10.0 x ULN||1%||1%|
|Increased Total Bilirubin|
|Grade 1||≥ 1.1- ≤ 1.5 x ULN||5%||< 1%|
|Grade 2||> 1.5- ≤ 2.5 x ULN||3%||1%|
|Grade 3||> 2.5- ≤ 5.0 x ULN||1%||< 1%|
|Grade 4||> 5.0 x ULN||0||0|
|Increased Total Cholesterol (fasted)|
|Grade 1||5.18-6.19 mmol/L 200-239 mg/dL||17%||31%|
|Grade 2||6.20-7.77 mmol/L 240-300 mg/dL||7%||19%|
|Grade 3||> 7.77 mmol/L > 300 mg/dL||< 1%||3%|
|Increased LDL Cholesterol (fasted)|
|Grade 1||3.37-4.12 mmol/L 130-159 mg/dL||14%||26%|
|Grade 2||4.13-4.90 mmol/L 160-190 mg/dL||5%||13%|
|Grade 3||≥ 4.91 mmol/L ≥ 191 mg/dL||1%||5%|
|Increased Triglycerides (fasted)|
|Grade 2||5.65-8.48 mmol/L 500-750 mg/dL||2%||2%|
|Grade 3||8.49-13.56 mmol/L 751-1,200 mg/dL||1%||3%|
|Grade 4||> 13.56 mmol/L > 1,200 mg/dL||0||1%|
|BR = background regimen; ULN = upper limit of normal
N = number of subjects per treatment group
Note: Percentages were calculated versus the number of subjects in ITT.
In the pooled Phase 3 trials, at Week 96, there was an overall mean change from baseline in basal cortisol of 19.1 (-30.87; -7.39) nmol/L in the EDURANT group and of +0.1 (-12.63; 12.80) nmol/L in the efavirenz group. At Week 96, the mean change from baseline in ACTH-stimulated cortisol levels was lower in the EDURANT group (+18.4 ± 8.36 nmol/L) than in the efavirenz group (+54.1 ± 7.24 nmol/L). Mean values for both basal and ACTH-stimulated cortisol values at Week 96 were within the normal range. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency.
In the pooled Phase 3 trials, an increase in serum creatinine was observed over the 96 weeks of treatment with EDURANT. Most of this increase occurred within the first four weeks of treatment, with a mean change of 0.1 mg/dL (range: -0.3 mg/dL to 0.6 mg/dL) observed after 96 weeks of treatment. In subjects who entered the trial with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in subjects with normal renal function. These changes are not considered to be clinically relevant and no subject discontinued treatment due to increases in serum creatinine. Serum creatinine increases occurred regardless of the background N(t)RTI regimen.
Changes from baseline in total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides are presented in Table 3. The clinical benefit of these findings has not been demonstrated.
Table 3: Lipid Values, Mean Change from Baseline*
|Pooled Data from the Week 96 Analysis of the Phase 3 TMC278-C209 and TMC278-C215 Trials|
|Mean (95% CI)||EDURANT + BR||Efavirenz + BR|
|N||Baseline Mean (mg/dL)||Week 96||N||Baseline Mean (mg/dL)||Week 96|
|Mean (mg/dL)||Mean Change† (mg/dL)||Mean (mg/dL)||Mean Change† (mg/dL)|
|Total Cholesterol (fasted)||584||161||167||5||549||161||190||28|
|N = number of subjects per treatment group; BR = background regimen
* Excludes subjects who received lipid lowering agents during the treatment period
† The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values
Subjects co-infected with hepatitis B and/or hepatitis C virus
In subjects co-infected with hepatitis B or C virus receiving EDURANT, the incidence of hepatic enzyme elevation was higher than in subjects receiving EDURANT who were not co-infected. This observation was the same in the efavirenz arm. The pharmacokinetic exposure of rilpivirine in co-infected subjects was comparable to that in subjects without co-infection.
Adverse reactions have been identified during post-marketing in patients receiving a rilpivirine containing regimen. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Renal and Genitourinary Disorders: nephrotic syndrome