"The U.S. Food and Drug Administration today approved Tivicay (dolutegravir), a new drug to treat HIV-1 infection.
Tivicay is an integrase strand transfer inhibitor that interferes with one of the enzymes necessary for HIV to multiply. "...
The following adverse drug reactions (ADRs) are discussed in greater detail in other sections of the package insert:
- Skin and Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
- 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-na´ve 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-Na´ve HIV-1 Infected Adult Subjects (Week 96
|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-na´ve 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
Metabolism and Nutrition Disorders: decreased appetite
Nervous System Disorders: somnolence
Psychiatric Disorders: sleep disorders, anxiety
Laboratory Abnormalities in Treatment-Na´ve 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-Na´ve 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 (-30.85; -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.
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*
|Mean (95% CI)||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 (mg/dL)||Mean (mg/dL)||Mean Change† (mg/dL)||Mean (mg/dL)||Mean (mg/dL)||Mean Change† (mg/dL)|
|Total Cholesterol (fasted)||546||161||166||5||507||160||187||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 postmarketing experience 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)
Read the Edurant (rilpivirine tablets) Side Effects Center for a complete guide to possible side effects
Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Co-administration of EDURANT and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs.
Co-administration of EDURANT and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Co-administration of EDURANT with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs.
EDURANT at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes.
Table 4 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of EDURANT and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with EDURANT are also included in Table 4.
Table 4: Established and Other Potentially Significant
Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on
Drug Interaction Studies or Predicted Interaction [see CLINICAL
|Concomitant Drug Class: Drug Name||Effect on Concentration of Rilpivirine or Concomitant Drug||Clinical Comment|
|HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)|
|No dose adjustment is required when EDURANT is co-administered with didanosine. Didanosine is to be administered on an empty stomach and at least two hours before or at least four hours after EDURANT (which should be administered with a meal).|
|HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)|
|NNRTI (delavirdine) Other NNRTIs (efavirenz, etravirine, nevirapine)||↑ rilpivirine
↔ other NNRTIs
|It is not recommended to co-administer EDURANT with delavirdine and other NNRTIs.|
|HIV-Antiviral Agents: Protease Inhibitors (PIs)-Boosted (i.e., with co-administration of low-dose ritonavir) or Unboosted (i.e., without co-administration of low-dose ritonavir)|
↔ boosted darunavir
|Concomitant use of EDURANT with darunavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is co-administered with darunavir/ritonavir.|
↔ boosted lopinavir
|Concomitant use of EDURANT with lopinavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is co-administered with lopinavir/ritonavir.|
|other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir) unboosted PIs (atazanavir, fosamprenavir, indinavir, nelfinavir)||↑ rilpivirine
↔ boosted PI
↔ unboosted PI
|Concomitant use of EDURANT with boosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of co-administered PIs.
Concomitant use of EDURANT with unboosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of co-administered PIs.
|Antacids: antacids (e.g., aluminum or magnesium hydroxide, calcium carbonate)||↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine)
↓ rilpivirine (concomitant intake)
|The combination of EDURANT and antacids should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after EDURANT.|
|Antimycobacterials: rifabutin*||↓ rilpivirine||Concomitant use of EDURANT with rifabutin may cause a decrease in the plasma concentrations of rilpivirine (induction of CYP3A enzymes). Throughout co-administration of EDURANT with rifabutin, the EDURANT dose should be increased from 25 mg once daily to 50 mg once daily. When rifabutin co-administration is stopped, the EDURANT dose should be decreased to 25 mg once daily.|
|Azole Antifungal Agents:
|Concomitant use of EDURANT with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No rilpivirine dose adjustment is required when EDURANT is co-administered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are co-administered with EDURANT.|
|H2 -Receptor Antagonists:
|↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine)
↓ rilpivirine (famotidine taken 2 hours before rilpivirine)
|The combination of EDURANT and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after EDURANT.|
|Macrolide or ketolide antibiotics:
|Concomitant use of EDURANT with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.|
|Narcotic Analgesics: methadone*||↓ R(-) methadone
↓ S(+) methadone
|No dose adjustments are required when initiating co-administration of methadone with EDURANT. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.|
|↑ = increase, ↓ =
decrease, ↔ = no change
* The interaction between EDURANT and the drug was evaluated in a clinical study. All other drug-drug interactions shown are predicted.
† This interaction study has been performed with a dose higher than the recommended dose for EDURANT assessing the maximal effect on the co-administered drug. The dosing recommendation is applicable to the recommended dose of EDURANT 25 mg once daily.
In addition to the drugs included in Table 4, the interaction between EDURANT and the following drugs was evaluated in clinical studies and no dose adjustment is needed for either drug [see CLINICAL PHARMACOLOGY]: acetaminophen, atorvastatin, chlorzoxazone, ethinylestradiol, norethindrone, raltegravir, sildenafil, telaprevir and tenofovir disoproxil fumarate. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin. No clinically relevant drug-drug interaction is expected when EDURANT is co-administered with maraviroc, ribavirin or the NRTIs abacavir, emtricitabine, lamivudine, stavudine and zidovudine.
QT Prolonging Drugs
There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram [see CLINICAL PHARMACOLOGY]. EDURANT should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.
Read the Edurant Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 5/19/2015
This monograph has been modified to include the generic and brand name in many instances.
Additional Edurant Information
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