Edurant Adverse Reactions

Adverse Reaction Overview: The safety assessment of EDURANT (rilpivirine) at Week 48 and Week 96 is based on pooled data from 686 patients in the Phase III controlled trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve HIV-1 infected adult patients who received EDURANT (25 mg once daily) (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions). In the Week 96 analysis, the median duration of exposure was 104.3 weeks. The proportion of subjects who discontinued treatment with EDURANT due to adverse drug reactions (ADRs) was 1.7%. The most frequently reported ADRs (≥ 2%) that were at least Grade 2 in severity were depression (4.1%), insomnia (3.5%), headache (3.5%), rash (2.3%), and abdominal pain (2.0%) (see Table 8). Most ADRs occurred during the first 48 weeks of treatment and no new ADR terms were identified between 48 weeks and 96 weeks (Phase III trials TMC278-C209 and TMC278-C215) and in the Phase IIb trial (TMC278-C204) through 240 weeks.
Clinical Trial Adverse Reactions: Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Clinical ADRs of at least moderate intensity or greater (≥ Grade 2) reported in adult subjects treated with EDURANT are presented in Table 8. (See Table 8.)

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Less Common Clinical Trial Adverse Reactions: Treatment-emergent ADRs of at least moderate intensity (≥ Grade 2) occurring in less than 1% of antiretroviral treatment-naïve subjects receiving EDURANT are listed as follows 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: abdominal discomfort.
Hepatobiliary Disorders: cholecystitis*, cholelithiasis*.
Nervous System Disorders: somnolence.
Psychiatric Disorders: anxiety, depressed mood.
Renal and Urinary Disorders: glomerulonephritis membranous*, glomerulonephritis mesangioproliferative*, nephrolithiasis*.
Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data: Selected treatment-emergent clinical laboratory abnormalities (Grade 3 or Grade 4), considered as ADRs, reported in EDURANT-treated subjects are shown in Table 9. (See Table 9.)

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Adrenal Function: In the pooled analysis of Phase III trials, at Week 48, the overall mean change from baseline in basal cortisol showed a decrease of 13.1 nmol/L in the EDURANT group and an increase of 9.0 nmol/L in the efavirenz (control) group. At Week 96, the overall mean change from baseline in basal cortisol showed a decrease of 19.1 nmol/L in the EDURANT group and a decrease of 0.6 nmol/L in the efavirenz group. At Week 48 and Week 96, the mean change from baseline in ACTH-stimulated cortisol levels was lower in the EDURANT group (+16.5 ± 6.14 nmol/L and +18.4 ± 8.36 nmol/L, respectively) than in the efavirenz group (+58.1 ± 6.66 nmol/L and +54.1 ± 7.24 nmol/L, respectively). Mean values for both basal and ACTH-stimulated cortisol values at Week 48 and 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 III 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 10. The mean changes from baseline were smaller in the EDURANT arm versus the comparator (efavirenz) arm. The impact of such findings has not been demonstrated. (See Table 10.)

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Bone Effects: Dual Energy X-ray Absorptiometry (DEXA) scans were performed in substudies of the Phase III clinical trials, primarily to evaluate changes in body fat distribution; changes in bone mineral density and content were also evaluated. Both treatment groups showed a small but statistically significant median decrease from baseline in bone mineral density (1.4% and 1.5% in the EDURANT group and 1.4% and 1.5% in the efavirenz (control) group at Week 48 and Week 96, respectively), and bone mineral content (1.8% and 2.1% in the EDURANT group and 2.0% and 2.5% in the efavirenz group at Week 48 and Week 96, respectively). These changes were not considered to be clinically relevant. No statistically significant differences were observed between treatment groups.
Fat Redistribution: As evaluated in the DEXA substudy, both treatment groups showed a small but statistically significant median increase from baseline in limb fat (11.6% and 10.9% in the EDURANT and the control (efavirenz) group, respectively), trunk fat (15.5% and 13.9%, respectively), and total body fat (13.5% and 11.4%, respectively) at Week 96. No statistically significant differences were observed between treatment groups.
Patients Co-infected with Hepatitis B and/or Hepatitis C Virus: In HIV patients co-infected with hepatitis B and/or C virus receiving EDURANT, the incidence of hepatic enzyme elevation was higher than in patients who were not co-infected. The pharmacokinetic exposure of rilpivirine in co-infected patients was comparable to that in patients without co-infection.
Electrocardiogram Findings: A pooled analysis of data from two Phase III clinical trials of antiretroviral-naïve HIV-1 infected patients who received either EDURANT 25 mg once daily or control (efavirenz), showed statistically significant mean increase from baseline in the QTc interval at Weeks 48 and 96. During treatment with EDURANT, the mean change from baseline in QTc increased through Week 48 without reaching plateau and remained stable between Week 48 and Week 96 (11.4 ms [95% CI 10.1, 12.8] and 12.4 ms [95% CI 11.0, 13.7], respectively). These trials excluded patients with high risk factors for proarrhythmia. The clinical relevance of these findings is unknown (see Cardiovascular under Precautions, QT Prolonging Drugs under Interactions, and Pharmacology: Pharmacodynamics: Effect on Electrocardiogram under Actions).
Clinical Trial Adverse Reactions (Pediatrics): Adverse Drug Reactions from a Clinical Trial in Pediatric Patients (12 to less than 18 Years of Age and weighing at least 35 kg): The safety assessment is based on the Week 48 analysis of the single-arm, open-label, Phase II trial, TMC278-C213, in which 36 antiretroviral treatment-naïve HIV-1 infected patients 12 to less than 18 years of age and weighing at least 35 kg received EDURANT (25 mg once daily) in combination with other antiretroviral agents (see Pharmacology: Pharmacodynamics: Clinical Trials: Study Results: Treatment-Naïve Pediatric Patients (12 years to less than 18 years of age): Trial TMC278-C213 under Actions). The median duration of exposure was 63.5 weeks. There were no patients who discontinued treatment due to ADRs. No new ADRs were identified compared to those seen in adults.
ADRs were reported in nineteen pediatric subjects (52.8%). Most ADRs were Grade 1 or 2. The most common ADRs (all grades, in at least two subjects) were headache (19.4%), depression (19.4%), somnolence (13.9%), and nausea (11.1%), dizziness (8.3%), abdominal pain (8.3%), vomiting (5.6%) and rash (5.6%). Observed laboratory abnormalities were comparable to those in adults.
Adrenal Function: In trial TMC278-C213, at Week 48, the overall mean change from baseline in basal cortisol showed an increase of 1.59 (0.24, 2.93) micrograms/dL.
Six of 30 (20%) subjects with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level < 18.1 micrograms/dL) during the trial. Three of these subjects had an abnormal 250 micrograms ACTH stimulation test at Week 48. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the abnormal 250 micrograms ACTH stimulation tests is not known.
Post-Market Adverse Reactions: 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.
Skin and Subcutaneous Tissue Disorders: severe skin and hypersensitivity reactions including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms).