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General: Patients should be advised that current antiretroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV to others through blood or sexual contact. Appropriate precautions to prevent the transmission of HIV should continue to be employed.
In the pooled analysis from the Phase III trials, more EDURANT-treated subjects with baseline HIV-1 RNA >100,000 copies/mL experienced virologic failure compared to subjects with HIV-1 RNA ≤100,000 copies/mL at baseline (see Sensitivity/Resistance: Resistance/Cross-resistance as follows and Microbiology: Resistance and Cross-resistance under Actions).
Regardless of HIV-1 RNA at the start of therapy, more EDURANT-treated subjects with CD4+ cell count less than 200 cells/mm3 at the start of therapy experienced virologic failure compared to subjects with CD4+ cell count greater than or equal to 200 cells/mm3 (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions).
The observed virologic failure rate in EDURANT-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to the control (efavirenz) (see Sensitivity/Resistance: Resistance/Cross-resistance as follows and Microbiology: Resistance and Cross-resistance under Actions).
More subjects treated with EDURANT developed tenofovir and lamivudine/emtricitabine associated resistance compared to the control (see Sensitivity/Resistance: Resistance/Cross-resistance as follows and Microbiology: Resistance and Cross-resistance under Actions).
Caution should be exercised when prescribing EDURANT (rilpivirine) with drugs that may reduce the exposure of rilpivirine (see Contraindications and Interactions).
As with other antiretroviral medicinal products, resistance testing should guide the use of EDURANT (see Microbiology under Actions).
Carcinogenesis and Mutagenesis: Rilpivirine induced benign and malignant tumors in the liver of mice and rats. These tumors are caused by the enzyme induction that rilpivirine caused in these species which may be rodent-specific. In rats rilpivirine caused benign and malignant tumors of the thyroid follicular cells. These tumors are the result of continuous stimulation of the follicular cells due to the increased clearance of thyroxine caused by rilpivirine in this species. This effect is considered rat-specific.
Cardiovascular: EDURANT should be administered with caution to patients who are suspected to be at an increased risk of experiencing proarrhythmic conditions such as hypokalemia, clinically significant bradycardia, acute myocardial ischemia, congestive heart failure or congenital prolongation of QTc interval (see Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data: Electrocardiogram Findings under Adverse Reactions, QT Prolonging Drugs under Interactions, and Pharmacology: Pharmacodynamics: Effect on Electrocardiogram under Actions).
In healthy subjects, rilpivirine has been associated with prolongation of the QT interval of the electrocardiogram at doses of 75 mg and 300 mg once daily. In antiretroviral naïve, HIV-1 infected patients receiving EDURANT 25 mg once daily in Phase III clinical trials, which excluded subjects with high risk factors for proarrhythmia, the mean QTc interval increased gradually over 48 weeks and remained stable through Week 96. An increase of >60 ms in QTcF interval resulting in abnormal values of > 480 ms was reported in one patient. Prolongation of QT interval may increase the risk of cardiac arrhythmias.
There is limited information available on the potential for a pharmacodynamic interaction between EDURANT and drugs that prolong the QTc interval of the electrocardiogram.
EDURANT should be used with caution when co-administered with drugs with a known risk of Torsade de Pointes.
Depressive Disorders: During the Phase III trials (N=686), the incidence of depressive disorder adverse drug reactions (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) of at least moderate intensity (Grades 2 to 4) was 5%. The incidence of discontinuation due to depressive disorders was 1%. Suicide attempt was reported in 2 subjects while suicide ideation was reported in 4 subjects taking in EDURANT. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to EDURANT, and if so, to determine whether the risks of continued therapy outweigh the benefits. The incidence of these events was similar in the control (efavirenz) group.
During the Phase II trial in pediatric subjects 12 to less than 18 years of age (N = 36) receiving EDURANT through 48 weeks, the incidence of depressive disorders (regardless of causality, severity) was 19.4% (7/36). Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 5.6% (2/36). None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 subject.
Endocrine and Metabolism: Serum Lipids and Blood Glucose: Serum lipids and blood glucose may increase during antiretroviral therapy. Disease control and lifestyle changes may also be contributing factors. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders and blood glucose elevations should be managed as clinically appropriate.
Gastrointestinal: EDURANT contains lactose. This medicine is not recommended for patients with rare hereditary problems of galactose intolerance (severe lactase deficiency or glucose-galactose malabsorption).
Hepatic/Biliary/Pancreatic: Hepatotoxicity: Hepatic adverse events have been reported in patients receiving a rilpivirine containing regimen. Patients with underlying hepatitis B or C, or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of EDURANT. A few cases of hepatic toxicity have been reported in patients receiving a rilpivirine-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with EDURANT is recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in transaminases prior to treatment initiation. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors.
Hepatic Impairment: EDURANT has not been studied in patients with severe hepatic impairment (Child-Pugh score C) and the use of EDURANT is not recommended in this population. No dose adjustment of EDURANT is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. However, given that the metabolism of EDURANT is cytochrome P450-mediated and that clinical experience in patients with mild or moderate hepatic impairment is limited, caution should be exercised when administering EDURANT to this population (see Recommended Dose and Dosage Adjustment: Hepatic Impairment under Dosage & Administration and Pharmacology: Pharmacokinetics: Special Populations and Conditions: Hepatic Insufficiency under Actions).
Immune: Immune Reconstitution Inflammatory Syndrome: Immune reconstitution inflammatory syndrome has been reported in patients treated with combination antiretroviral therapy, including EDURANT. During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP and TB), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease, autoimmune hepatitis, polymyositis and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment. Sometimes there can be an atypical presentation.
Renal: Renal Impairment: EDURANT has not been studied in patients with renal impairment. Caution should be exercised when administering EDURANT to patients with severe renal impairment or end-stage renal disease whose drug absorption, distribution and metabolism may be altered secondary to renal dysfunction. No dose adjustments are required in patients with mild to moderate renal impairment. As 99.7% of rilpivirine is bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis (see Recommended Dose and Dosage Adjustment: Renal Impairment under Dosage & Administration and Pharmacology: Pharmacokinetics: Special Populations and Conditions: Renal Insufficiency under Actions).
Sensitivity/Resistance: Resistance/Cross-resistance: In the pooled analysis from two Phase III trials in adults, the emergence of resistance among subjects was greater in the EDURANT arm as compared to the control (efavirenz) arm at Week 48 (10.6%, 5.3%, respectively) and at Week 96 (14%, 7.6%, respectively). More EDURANT- treated subjects with baseline HIV-1 RNA > 100,000 copies/mL experienced virologic failure compared to subjects with HIV-1 RNA ≤ 100,000 copies/mL at baseline.
The observed virologic failures in EDURANT-treated subjects conferred a higher cross-resistance to the NNRTI class as compared to those in control-treated subjects. More subjects treated with EDURANT developed lamivudine/emtricitabine associated resistance as compared to those treated with the control (see Microbiology: Resistance and Cross-resistance under Actions).
In the 36 adolescents 12 to less 18 years of age, treatment-emergent rilpivirine resistance mutations were detected in 5/8 (62.5%) subjects with virologic failure, treatment-emergent NNRTI resistance mutations were detected in 6 (75%) subjects. In 4/5 subjects, treatment-emergent NRTI resistance was also detected. The observed treatment-emergent rilpivirine, NNRTI and NRTI resistance mutations were previously identified in adults (see Microbiology: Resistance and Cross-resistance under Actions).
In study C213, phenotypic resistance to NRTIs and phenotypic cross-resistance between rilpivirine and other NNRTIs was shown for efavirenz, nevirapine, and etravirine in 4/5 (80%) subjects with rilpivirine associated mutations.
Skin: Severe skin and hypersensitivity reactions have been reported during the post-marketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase III clinical trials, treatment-related rashes with at least Grade 2 severity were reported in 3% of subjects receiving EDURANT. No grade 4 rash was reported. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy (see Adverse Reactions). Discontinue EDURANT immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis or eosinophilia. Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated.
Use in Children: Pediatrics (< 12 years of age): Safety and effectiveness in pediatric patients less than 12 years of age has not been established.
Use in Elderly: Geriatrics (> 65 years of age): Clinical studies of EDURANT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from adult subjects < 65 years of age. EDURANT should be used with caution in this population.
