"The U.S. Food and Drug Administration today approved Genvoya (a fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) as a complete regimen for the treatment of HIV-1 infection in adults and "...
The following adverse reactions are described in greater detail in other sections:
- Severe skin and hypersensitivity reactions [see WARNINGS AND PRECAUTIONS].
Clinical Trials Experience: Adults
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.
The safety assessment is based on all data from 1203 subjects in the Phase 3 placebo-controlled trials, TMC125C206 and TMC125-C216, conducted in antiretroviral treatment-experienced HIV-1-infected adult subjects, 599 of whom received INTELENCE® (200 mg twice daily). In these pooled trials, the median exposure for subjects in the INTELENCE® arm and placebo arm was 52.3 and 51.0 weeks, respectively. Discontinuations due to adverse drug reactions (ADRs) were 5.2% in the INTELENCE® arm and 2.6% in the placebo arm.
The most frequently reported ADR at least Grade 2 in severity was rash (10.0%). Stevens-Johnson syndrome, drug hypersensitivity reaction and erythema multiforme were reported in less than 0.1% of subjects during clinical development with INTELENCE® [see WARNINGS AND PRECAUTIONS]. A total of 2.2% of HIV-1-infected subjects in Phase 3 trials receiving INTELENCE® discontinued due to rash. In general, in clinical trials, rash was mild to moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within 1 to 2 weeks on continued therapy. The incidence of rash was higher in women compared to men in the INTELENCE® arm in the Phase 3 trials (rash ≥ Grade 2 was reported in 9/60 [15.0%] women versus 51/539 [9.5%] men; discontinuations due to rash were reported in 3/60 [5.0%] women versus 10/539 [1.9%] men) [see WARNINGS AND PRECAUTIONS]. Patients with a history of NNRTI-related rash did not appear to be at increased risk for the development of INTELENCE®-related rash compared to patients without a history of NNRTI-related rash.
Common Adverse Reactions
Clinical ADRs of moderate intensity or greater (greater than or equal to Grade 2) and reported in at least 2% of subjects treated with INTELENCE® and occurring at a higher rate compared to placebo (excess of 1%) are presented in Table 1. Laboratory abnormalities considered ADRs are included in Table 2.
Table 1: Treatment-Emergent Adverse Reactions* of at
least Moderate Intensity† (Grades 2 to 4) in at least 2% of Adult
Subjects in the INTELENCE® Treatment Groups and at a higher rate compared to
placebo (excess of 1%)
|System Organ Class, Preferred Term, %||Pooled TMC125-C206 and TMC125-C216 Trials|
|INTELENCE® + BR
|Placebo + BR
|Nervous System Disorders|
|Skin and Subcutaneous Tissue Disorders|
|N=total number of subjects per treatment group, BR=background
* Includes adverse reactions at least possibly, probably, or very likely related to the drug.
† Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity).
Less Common Adverse Reactions
Treatment-emergent ADRs occurring in less than 2% of subjects (599 subjects) receiving INTELENCE® and of at least moderate intensity (greater than or equal to Grade 2) are listed below by body system:
Ear and Labyrinth Disorders: vertigo
Eye Disorders: blurred vision
General Disorders and Administration Site Conditions: sluggishness
Immune System Disorders: drug hypersensitivity, immune reconstitution syndrome
Renal and Urinary Disorders: acute renal failure
Reproductive System and Breast Disorders: gynecomastia
Respiratory, Thoracic and Mediastinal Disorders: exertional dyspnea, bronchospasm
Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic edema, erythema multiforme and haemorrhagic stroke, each reported in no more than 0.5% of subjects.
Laboratory Abnormalities in Treatment-Experienced Patients
Selected Grade 2 to Grade 4 laboratory abnormalities that represent a worsening from baseline observed in adult subjects treated with INTELENCE® are presented in Table 2.
Table 2: Selected Grade 2 to 4 Laboratory
Abnormalities Observed in Treatment-Experienced Subjects
|Laboratory Parameter Preferred Term, %||DAIDS Toxicity Range||Pooled TMC125-C206 and TMC125-C216 Trials|
|INTELENCE® + BR
|Placebo + BR
|Grade 2||> 1.5-2 x ULN||7%||8%|
|Grade 3||> 2-5 x ULN||7%||8%|
|Grade 4||> 5 x ULN||2%||1%|
|Grade 2||> 1.5-3 x ULN||4%||6%|
|Grade 3||> 3-5 x ULN||2%||2%|
|Grade 4||> 5xULN||1%||< 1%|
|Grade 2||> 1.4-1.8 x ULN||6%||5%|
|Grade 3||> 1.9-3.4 x ULN||2%||1%|
|Grade 4||> 3.4 x ULN||0%||< 1%|
|Grade 2||90-99 g/L||2%||4%|
|Grade 3||70-89 g/L||< 1%||< 1%|
|Grade 4||< 70 g/L||< 1%||< 1%|
|White blood cell count|
|Grade 4||< 1,000/mm³||1%||< 1%|
|Grade 4||< 500/mm³||2%||3%|
|Grade 4||< 25,000/mm³||< 1%||< 1%|
|LIPIDS AND GLUCOSE|
|Grade 2||> 6.20-7.77 mmol/L 240-300 mg/dL||20%||17%|
|Grade 3||> 7.77 mmol/L > 300 mg/dL||8%||5%|
|Low density lipoprotein|
|Grade 2||4.13-4.9 mmol/L 160-190 mg/dL||13%||12%|
|Grade 3||> 4.9 mmol/L > 190 mg/dL||7%||7%|
|Grade 2||5.65-8.48 mmol/L 500 -750 mg/dL||9%||7%|
|Grade 3||8.49-13.56 mmol/L 751 - 1200 mg/dL||6%||4%|
|Grade 4||> 13.56 mmol/L > 1200 mg/dL||4%||2%|
|Elevated glucose levels|
|Grade 2||6.95-13.88 mmol/L 161-250 mg/dL||15%||13%|
|Grade 3||13.89-27.75 mmol/L 251 - 500 mg/dL||4%||2%|
|Grade 4||> 27.75 mmol/L > 500 mg/dL||0%||< 1%|
|Alanine amino transferase|
|Grade 2||2.6-5 x ULN||6%||5%|
|Grade 3||5.1-10 x ULN||3%||2%|
|Grade 4||> 10 x ULN||1%||< 1%|
|Aspartate amino transferase|
|Grade 2||2.6-5 x ULN||6%||8%|
|Grade 3||5.1-10 x ULN||3%||2%|
|Grade 4||> 10 x ULN||< 1%||< 1%|
|ULN=Upper Limit of Normal, BR=background regimen|
Patients Co-infected With Hepatitis B and/or Hepatitis C Virus
In Phase 3 trials TMC125-C206 and TMC125-C216, 139 subjects (12.3%) with chronic hepatitis B and/or hepatitis C virus co-infection out of 1129 subjects were permitted to enroll. AST and ALT abnormalities occurred more frequently in hepatitis B and/or hepatitis C virus co-infected subjects for both treatment groups. Grade 2 or higher laboratory abnormalities that represent a worsening from baseline of AST, ALT or total bilirubin occurred in 27.8%, 25.0% and 7.1% respectively, of INTELENCE®-treated co-infected subjects as compared to 6.7%, 7.5% and 1.8% of non-co-infected INTELENCE®-treated subjects. In general, adverse events reported by INTELENCE®treated subjects with hepatitis B and/or hepatitis C virus co-infection were similar to INTELENCE®-treated subjects without hepatitis B and/or hepatitis C virus co-infection.
Clinical Trials Experience: Pediatric Subjects (6 years to less than 18 years of age)
The safety assessment in children and adolescents is based on the Week 24 analysis of the single-arm, Phase 2 trial TMC125-C213 in which 101 antiretroviral treatment-experienced HIV-1 infected subjects 6 years to less than 18 years of age and weighing at least 16 kg received INTELENCE® in combination with other antiretroviral agents [see Clinical Studies]. The frequency, type and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adult subjects, except for rash which was observed more frequently in pediatric subjects. The most common adverse drug reactions in at least 2% of pediatric subjects were rash and diarrhea. Rash was reported more frequently in female subjects than in male subjects (rash ≥ Grade 2 was reported in 13/64 [20.3%] females versus 2/37 [5.4%] males; discontinuations due to rash were reported in 4/64 [6.3%] females versus 0/37 [0%] males).Rash (greater than or equal to Grade 2) occurred in 15% of pediatric subjects. In the majority of cases, rash was mild to moderate, of macular/papular type, and occurred in the second week of therapy. Rash was self-limiting and generally resolved within 1 week on continued therapy. The safety profile for subjects who completed 48 weeks of treatment was similar to the safety profile for subjects who completed 24 weeks of treatment.
The following events have been identified during postmarketing use of INTELENCE®. Because these events 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.
Immune System Disorders: Severe hypersensitivity reactions including DRESS and cases of hepatic failure have been reported [see WARNINGS AND PRECAUTIONS].
Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis
Read the Intelence (entravirine tablets) Side Effects Center for a complete guide to possible side effects
Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of INTELENCE® with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE® (see Table 3). [See also CLINICAL PHARMACOLOGY]
Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. Therefore, coadministration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-glycoprotein with INTELENCE® may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see Table 3). [See also CLINICAL PHARMACOLOGY]
Table 3 shows the established and other potentially significant drug interactions based on which, alterations in dose or regimen of INTELENCE® and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with INTELENCE® are also included in Table 3.
Table 3: 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 Etravirine or Concomitant Drug||Clinical Comment|
|HIV-Antiviral Agents: Integrase Strand Inhibitors|
|dolutegravir*||↓ dolutegravir ↔ etravirine||Etravirine significantly reduced plasma concentrations of dolutegravir. Using cross-study comparisons to historical pharmacokinetic data for etravirine, dolutegravir did not appear to affect the pharmacokinetics of etravirine.|
|dolutegravir/darunavir /ritonavir* dolutegravir/lopinavir /ritonavir*||↓ dolutegravir
|The effect of etravirine on dolutegravir plasma concentrations was mitigated by co-administration of darunavir/ritonavir or lopinavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. Dolutegravir should only be used with INTELENCE® when co-administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir.|
|HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)|
|↓etravirine||Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and other NNRTIs should not be co-administered.|
|delavirdine||↑ etravirine||Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and delavirdine should not be co-administered.|
|Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and rilpivirine should not be coadministered.|
|HIV-Antiviral Agents: Protease Inhibitors (PIs)|
|atazanavir* (without ritonavir) atazanavir/ritonavir*||↓ atazanavir
|INTELENCE® should not be co-administered with atazanavir without low-dose ritonavir.
Concomitant use of INTELENCE® with atazanavir/ritonavir decreased atazanavir Cmin but it is not considered clinically relevant.. The mean systemic exposure (AUC) of etravirine after coadministration of INTELENCE® with atazanavir/ritonavir in HIV-infected patients was similar to the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir can be coadministered without dose adjustments.
|darunavir/ritonavir*||↓ etravirine||The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE® and darunavir/ritonavir can be coadministered without dose adjustments.|
|fosamprenavir (without ritonavir) fosamprenavir/ritonavir*||↑ amprenavir
|Concomitant use of INTELENCE® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE® should not be coadministered with fosamprenavir without low-dose ritonavir.
Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE® and fosamprenavir/ritonavir have not been established. INTELENCE® and fosamprenavir/ritonavir should not be co-administered.
|indinavir* (without ritonavir)||↓ indinavir||Concomitant use of INTELENCE® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE® should not be coadministered with indinavir without low-dose ritonavir.|
|lopinavir/ritonavir*||↓ etravirine||The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and lopinavir/ritonavir can be co-administered without dose adjustments.|
|nelfinavir (without ritonavir)||↑ nelfinavir||Concomitant use of INTELENCE® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE® should not be coadministered with nelfinavir without low-dose ritonavir.|
|ritonavir*||↓ etravirine||Concomitant use of INTELENCE® with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and ritonavir 600 mg twice daily should not be coadministered.|
|saquinavir/ritonavir*||↓ etravirine||The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and saquinavir/ritonavir can be co-administered without dose adjustments.|
|tipranavir/ritonavir*||↓ etravirine||Concomitant use of INTELENCE® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and tipranavir/ritonavir should not be coadministered.|
|When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE® is needed.|
|maraviroc/darunavir/ ritonavir*^||↔ etravirine
|When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE® is needed.|
|Antiarrhythmics: digoxin*||↔ etravirine
|For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.|
|amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine||↓ antiarrhythmics||Concentrations of these antiarrhythmics may be decreased when coadministered with INTELENCE®. INTELENCE® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.|
|Anticoagulants: warfarin||↑ anticoagulants||Warfarin concentrations may be increased when co-administered with INTELENCE®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE®.|
|Anticonvulsants: carbamazepine, phenobarbital,
|↓ etravirine||Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®.|
|Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE® or fluconazole is needed.
Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE® or voriconazole is needed.
|Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.|
|Antiinfectives: clarithromycin*||↑ etravirine
|Clarithromycin exposure was decreased by INTELENCE®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.|
|Antimalarials: artemether/lumefantrine*||↔ etravirine
|Caution is warranted when co-administering INTELENCE® and artemether/lumefantrine as it is unknown whether the decrease in exposure of artemether or its active metabolite, dihydroartemisinin, could result in decreased antimalarial efficacy. No dose adjustment is needed for INTELENCE®.|
|Antimycobacterials: rifampin, rifapentine||↓ etravirine||Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®.|
|Antimycobacterials: rifabutin*||↓ etravirine
|If INTELENCE® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended.
If INTELENCE® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
|Benzodiazepines: diazepam||↑ diazepam||Concomitant use of INTELENCE® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.|
|Corticosteroids: dexamethasone (systemic)||↓ etravirine||Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.|
|Herbal Products: St. John's wort (Hypericum perforatum)||↓ etravirine||Concomitant use of INTELENCE® with products containing St. John’s wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. INTELENCE® and products containing St. John’s wort should not be co-administered.|
|Hepatitis C Virus (HCV) Direct-Acting Antivirals:
|The combination of INTELENCE® and boceprevir can be used without dose adjustments.
However, co-administration of INTELENCE® and boceprevir is not recommended in the presence of other drugs which may further decrease etravirine exposure. This includes, but is not limited to, darunavir/ritonavir, lopinavir/ritonavir, saquinavir/ritonavir, tenofovir disoproxil fumarate, or rifabutin.
There are insufficient data to make a dosing recommendation for telaprevir when used with INTELENCE®.
|HMG-CoA Reductase Inhibitors:
|The combination of INTELENCE® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.
No interaction between pravastatin, rosuvastatin and INTELENCE® is expected. Lovastatin and simvastatin are CYP3A substrates and coadministration with INTELENCE® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
|↓ immunosuppressant||INTELENCE® and systemic immunosuppressants should be coadministered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.|
|Narcotic Analgesics/Treatment of Opioid Dependence:
|INTELENCE® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients.
INTELENCE® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
|Phosphodiesterase Type 5 (PDE-5) Inhibitors:
|INTELENCE® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.|
|Platelet Aggregation Inhibitors: clopidogrel||↓ clopidogrel (active) metabolite||Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE®. Alternatives to clopidogrel should be considered.|
|↑ = increase, ↓ = decrease, ↔ = no
* The interaction between INTELENCE® and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
† The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir
In addition to the drugs included in Table 3, the interaction between INTELENCE® and the following drugs were evaluated in clinical studies and no dose adjustment is needed for either drug [see CLINICAL PHARMACOLOGY]: didanosine, enfuvirtide (ENF), ethinylestradiol/norethindrone, omeprazole, paroxetine, raltegravir, ranitidine, and tenofovir disoproxil fumarate.
Read the Intelence Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 5/20/2015
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