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The following adverse drug reactions are discussed in other sections of the labeling:

  • Lactic Acidosis/Severe Hepatomegaly with Steatosis [See BOXED WARNING, WARNINGS AND PRECAUTIONS].
  • Severe Acute Exacerbations of Hepatitis B [See BOXED WARNING, WARNINGS AND PRECAUTIONS].
  • New Onset or Worsening Renal Impairment [See WARNINGS AND PRECAUTIONS].
  • Depressive Disorders [See WARNINGS AND PRECAUTIONS].
  • Hepatotoxicity [See WARNINGS AND PRECAUTIONS].
  • Bone Effects of Tenofovir DF [See WARNINGS AND PRECAUTIONS].
  • Immune Reconstitution Syndrome [See WARNINGS AND PRECAUTIONS].

Adverse Reactions From 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 practice.

In HIV-1-Infected Subjects With No Antiretroviral Treatment History

Studies C209 and C215 – Treatment-Emergent Adverse Drug Reactions: The safety assessment of rilpivirine, used in combination with other antiretroviral drugs, is based on the Week 96 pooled data from 1368 subjects in the Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve HIV-1-infected adult subjects. A total of 686 subjects received rilpivirine in combination with other antiretroviral drugs as background regimen; most (N=550) received emtricitabine/tenofovir DF as background regimen. The number of subjects randomized to the control arm efavirenz was 682, of which 546 received emtricitabine/tenofovir DF as background regimen [See Clinical Studies]. The median duration of exposure for subjects in either treatment arm was 104 weeks.

Adverse drug reactions (ADR) observed at Week 96 in subjects who received rilpivirine or efavirenz plus emtricitabine/tenofovir DF as background regimen are shown in Table

1. No new types of adverse reactions were identified between Week 48 and Week 96. The adverse drug reactions observed in this subset of subjects were generally consistent with those seen for the overall patient population participating in these studies (refer to the prescribing information for Edurant).

The proportion of subjects who discontinued treatment with rilpivirine or efavirenz + emtricitabine/tenofovir DF due to ADR, regardless of severity, was 2% and 5%, respectively. The most common ADRs leading to discontinuation were psychiatric disorders: 9 (1.6%) subjects in the rilpivirine + emtricitabine/tenofovir DF arm and 12 (2.2%) subjects in the efavirenz + emtricitabine/tenofovir DF arm. Rash led to discontinuation in 1 (0.2%) subject in the rilpivirine + emtricitabine/tenofovir DF arm and 10 (1.8%) subjects in the efavirenz + emtricitabine/tenofovir DF arm.

Common Adverse Drug Reactions

Clinical ADRs to rilpivirine or efavirenz of at least moderate intensity ( ≥ Grade 2) reported in at least 2% of adult subjects are shown in Table 1.

Table 1 : Selected Treatment-Emergent Adverse Drug Reactionsa (Grades 2-4) Reported in ≥ 2% of Subjects Receiving Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215(Week 96 analysis)

  Rilpivirine + FTC/TDF
N=550
Efavirenz + FTC/TDF
N=546
Gastrointestinal Disorder
  Nausea 1% 2%
Nervous System Disorders
  Headache 2% 2%
  Dizziness 1% 7%
Psychiatric Disorders
  Depressive disordersb 2% 2%
  Insomnia 2% 2%
  Abnormal dreams 1% 3%
Skin and Subcutaneous Tissue Disorders
  Rash 1% 5%
a Frequencies of adverse reactions are based on all Grades 2-4 treatment-emergent adverse events assessed to be related to study drug.
b Includes adverse drug reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation.

Rilpivirine: Treatment-emergent adverse drug reactions of at least moderate intensity ( ≥ Grade 2) that occurred in less than 2% of subjects treated with rilpivirine plus any of the allowed background regimens (N=686) in clinical studies C209 and C215 include (grouped by Body System): vomiting, diarrhea, abdominal discomfort, abdominal pain, fatigue, cholecystitis, cholelithiasis, decreased appetite, somnolence, sleep disorders, anxiety, glomerulonephritis membranous, glomerulonephritis mesangioproliferative, and nephrolithiasis.

In Virologically-Suppressed HIV-1-Infected Subjects

No new adverse reactions to COMPLERA were identified in stable, virologicallysuppressed subjects switching to COMPLERA from a regimen containing a ritonavirboosted protease inhibitor; however the frequency of adverse reactions increased by 20% (Study 106) after switching to COMPLERA.

Emtricitabine and Tenofovir Disoproxil Fumarate: The following adverse reactions were observed in clinical trials of emtricitabine or tenofovir DF in combination with other antiretroviral agents:

The most common adverse drug reactions occurring in at least 10% of HIV-1-infected treatment-naïve adult subjects in a Phase 3 clinical trial of emtricitabine and tenofovir DF in combination with another antiretroviral agent are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. In addition, adverse drug reactions that occurred in at least 5% of treatment-experienced or treatment-naïve subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials include abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis.

Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

Laboratory Abnormalities: The percentage of subjects treated with rilpivirine + emtricitabine/tenofovir DF or efavirenz + emtricitabine/tenofovir DF in studies C209 and C215 with selected treatment-emergent laboratory abnormalities (Grades 1 to 4), representing worst grade toxicity, are presented in Table 2.

Table 2 : Selected Laboratory Abnormalities (Grades 1-4) Reported in Subjects WhoReceived Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 (Week 96 Analysis)

Laboratory Parameter Abnormality, (%) DAIDS Toxicity Range Rilpivirine + FTC/TDF
N=550
Efavirenz + FTC/TDF
N=546
BIOCHEMISTRY
Increased Creatinine
  Grade 1 1.1-1.3 x ULNa 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%
Increased AST
  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% 3%
  Grade 4 > 10.0 x ULN 1% 1%
Increased ALT
  Grade 1 1.25-2.5 x ULN 19% 22%
  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 6% < 1%
  Grade 2  > 1.5-2.5 x ULN 3% 1%
  Grade 3 > 2.5-5.0 x ULN 1% < 1%
Increased Total Cholesterol (fasted)
  Grade 1 200-239 mg/dL 14% 31%
  Grade 2 240-300 mg/dL 6% 18%
  Grade 3 > 300 mg/dL < 1% 2%
Increased LDL Cholesterol (fasted)
  Grade 1 130-159 mg/dL 13% 28%
  Grade 2 160-190 mg/dL 5% 13%
  Grade 3 > 190 mg/dL 1% 4%
Increased Triglycerides (fasted)
  Grade 2 500-750 mg/dL 1% 2%
  Grade 3 751-1,200 mg/dL 1% 2%
  Grade 4 > 1,200 mg/dL 0 1%
N = number of subjects per treatment group
a ULN = Upper limit of normal value.
Note: Percentages were calculated versus the number of subjects in ITT population with emtricitabine + tenofovir DF as background regimen.

Emtricitabine or Tenofovir Disoproxil Fumarate: The following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: Grade 3 or 4 laboratory abnormalities of increased pancreatic amylase ( > 2.0 x ULN), increased serum amylase ( > 175 U/L), increased lipase ( > 3.0 x ULN), increased alkaline phosphatase ( > 550 U/L), increased or decreased serum glucose ( < 40 or > 250 mg/dL), increased glycosuria ( ≥ 3+), increased creatine kinase (M: > 990 U/L; F: > 845 U/L), decreased neutrophils ( < 750/mm³) and increased hematuria ( > 75 RBC/HPF) occurred.

Adrenal Function

In the pooled Phase 3 trials of C209 and C215, in subjects treated with rilpivirine plus any of the allowed background regimen (N=686), at Week 96, there was an overall mean change from baseline in basal cortisol of -19.1 (95% CI: -30.9; -7.4) nmol/L in the rilpivirine group, and of -0.6 (95% CI: -13.3; 12.2) nmol/L in the efavirenz group. At Week 96, the mean change from baseline in ACTH-stimulated cortisol levels was lower in the rilpivirine 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. Effects on adrenal function were comparable by background N(t)RTIs.

Serum Creatinine

In the pooled Phase 3 trials of C209 and C215 trials in subjects treated with rilpivirine plus any of the allowed background regimen (N=686), there was a small increase in serum creatinine over 96 weeks of treatment with rilpivirine. 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 through Week 96. 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. Creatinine increases were comparable by background N(t)RTIs.

Serum Lipids

Changes from baseline in total cholesterol, LDL-cholesterol and triglycerides are presented in Table 3.

Table 3 : Lipid Values Reported in Subjects Receiving Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215a

Mean Pooled Data from the Week 96 Analysis of C209 and C215 Trials
Rilpivirine + FTC/TDF
N=550
Efavirenz + FTC/TDF
N=546
N Baseline Week 96 N Baseline Week 96
Mean (mg/dL) Mean (mg/dL) Mean Changeb (mg/dL) Mean (mg/dL) Mean (mg/dL) Mean Changeb (mg/dL)
Total Cholesterol (fasted) 430 162 164 2 401 160 186 26
HDL- cholesterol (fasted) 429 42 45 4 399 40 50 11
LDL- cholesterol (fasted) 427 97 97 -1 397 96 110 14
Triglycerides (fasted) 430 123 109 -14 401 127 133 6
N = number of subjects per treatment group
a Excludes subjects who received lipid lowering agents during the treatment period.
b The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values.

Subjects Coinfected with Hepatitis B and/or Hepatitis C Virus

In patients coinfected with hepatitis B or C virus receiving rilpivirine in studies C209 and C215, the incidence of hepatic enzyme elevation was higher than in subjects receiving rilpivirine who were not coinfected. The same increase was also observed in the efavirenz arm. The pharmacokinetic exposure of rilpivirine in coinfected subjects was comparable to that in subjects without coinfection.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of rilpivirine-or tenofovir DF-containing regimens . Because postmarketing reactions 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.

Rilpivirine

Renal and Urinary Disorders nephrotic syndrome

Emtricitabine

No postmarketing adverse reactions have been identified for inclusion in this section.

Tenofovir Disoproxil Fumarate

Immune System Disorders

allergic reaction, including angioedema

Metabolism and Nutrition Disorders

lactic acidosis, hypokalemia, hypophosphatemia

Respiratory, Thoracic, and Mediastinal Disorders

dyspnea

Gastrointestinal Disorders

pancreatitis, increased amylase, abdominal pain

Hepatobiliary Disorders

hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)

Skin and Subcutaneous Tissue Disorders

rash

Musculoskeletal and Connective Tissue Disorders

rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy

Renal and Urinary Disorders

acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria

General Disorders and Administration Site Conditions

asthenia

The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.