Edurant (Rilpivirine Hydrochloride) - Side Effects and 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.

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 IntensityIntensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity). (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 N=686	Efavirenz + BR N=682
N = total number of subjects per treatment group; BR = background regimen
Gastrointestinal Disorders
Abdominal pain	2%	2%
Nausea	1%	3%
Vomiting	1%	2%
General Disorders and Administration Site Conditions
Fatigue	2%	2%
Nervous System Disorders
Headache	3%	4%
Dizziness	1%	7%
Psychiatric Disorders
Depressive disordersIncludes adverse drug reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation.	5%	4%
Insomnia	3%	4%
Abnormal dreams	2%	4%
Skin and Subcutaneous Tissue Disorders
Rash	3%	11%

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 N=686	Efavirenz + BR N=682
BIOCHEMISTRY
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.
Increased Creatinine
Grade 1	≥ 1.1–≤ 1.3 × ULN	6%	1%
Grade 2	> 1.3–≤ 1.8 × ULN	1%	1%
Grade 3	> 1.8–≤ 3.4 × ULN	<1%	0
Grade 4	> 3.4 × ULN	0	<1%
Increased AST
Grade 1	≥ 1.25–≤ 2.5 × ULN	16%	19%
Grade 2	> 2.5–≤ 5.0 × ULN	4%	7%
Grade 3	> 5.0–≤ 10.0 × ULN	2%	2%
Grade 4	> 10.0 × ULN	1%	1%
Increased ALT
Grade 1	≥ 1.25–≤ 2.5 × ULN	18%	20%
Grade 2	> 2.5–≤ 5.0 × ULN	5%	7%
Grade 3	> 5.0–≤ 10.0 × ULN	1%	2%
Grade 4	> 10.0 × ULN	1%	1%
Increased Total Bilirubin
Grade 1	≥ 1.1–≤ 1.5 × ULN	5%	<1%
Grade 2	> 1.5–≤ 2.5 × ULN	3%	1%
Grade 3	> 2.5–≤ 5.0 × ULN	1%	<1%
Grade 4	> 5.0 × 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%

Adrenal Function

In the pooled Phase 3 trials, at Week 96, there was an overall mean change from baseline in basal cortisol of -19.1 (-30.85; -7.37) nmol/L in the EDURANT group and of -0.6 (-13.29; 12.17) 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.

Serum Creatinine

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.

Serum Lipids

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 BaselineExcludes subjects who received lipid lowering agents during the treatment period

	Pooled Data from the Week 96 Analysis of the Phase 3 TMC278-C209 and TMC278-C215 Trials
	EDURANT + BR				Efavirenz + BR
	N	Baseline	Week 96		N	Baseline	Week 96
Mean (95% CI)		Mean (mg/dL)	Mean (mg/dL)	Mean Change 1 (mg/dL)		Mean (mg/dL)	Mean (mg/dL)	Mean Change (mg/dL)
N = number of subjects per treatment group; BR = background regimen
Total Cholesterol (fasted)	546	161	166	5	507	160	187	28
HDL-cholesterol (fasted)	545	41	46	4	505	40	51	11
LDL-cholesterol (fasted)	543	96	98	1	503	95	109	14
Triglycerides (fasted)	546	122	116	-6	507	130	141	11