Chemical formula: C₂₀H₁₅BrN₆O Molecular mass: 435.277 g/mol PubChem compound: 193962
Etravirine interacts in the following cases:
Effects on drug levels – Least Squares Mean Ratio (90% CI; 1.00 = No effect):
Sildenafil 50 mg single dose – Tadalafil – Vardenafil:
Note: In drug-drug interaction studies, different formulations and/or doses of etravirine were used which led to similar exposures and, therefore, interactions relevant for one formulation are relevant for the other.
Recommendations concerning co-administration: Concomitant use of PDE-5 inhibitors with etravirine may require dose adjustment of the PDE-5 inhibitor to attain the desired clinical effect.
Combination not recommended.
Not studied. St John’s wort is expected to decrease the plasma concentrations of etravirine.
Etravirine is primarily metabolised and eliminated by the liver and highly bound to plasma proteins. Effects on unbound exposure could be expected (has not been studied) and therefore caution is advised in patients with moderate hepatic impairment.
The pharmacokinetics of etravirine have not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, etravirine is not recommended in patients with severe hepatic impairment.
It is not recommended to co-administer etravirine with other NNRTIs.
Combining two NNRTIs has not been shown to be beneficial. Concomitant use of etravirine with efavirenz or nevirapine may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of etravirine.
Concomitant use of etravirine with rilpivirine may cause a decrease in the plasma concentration of rilpivirine and loss of therapeutic effect of rilpivirine.
Etravirine is metabolised by CYP3A4, CYP2C9 and CYP2C19 followed by glucuronidation of the metabolites by uridine diphosphate glucuronosyl transferase (UDPGT). Medicinal products that induce CYP3A4, CYP2C9 or CYP2C19 may increase the clearance of etravirine, resulting in lowered plasma concentrations of etravirine.
Co-administration of etravirine and medicinal products that inhibit CYP3A4, CYP2C9 or CYP2C19 may decrease the clearance of etravirine and may result in increased plasma concentrations of etravirine.
Etravirine is a weak inhibitor of CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein. Co-administration with medicinal products primarily metabolised by CYP2C9 or CYP2C19, or transported by P-glycoprotein, may result in increased plasma concentrations of such medicinal products, which could increase or prolong their therapeutic effect or alter their adverse events profile.
Etravirine is a weak inducer of CYP3A4. Co-administration of etravirine with medicinal products primarily metabolised by CYP3A4 may result in decreased plasma concentrations of such medicinal products, which could decrease or shorten their therapeutic effects.
Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with etravirine.
Not studied. Etravirine is expected to decrease plasma concentrations of these antiarrhythmics.
Effects on drug levels – Least Squares Mean Ratio (90% CI; 1.00 = No effect):
Artemether/Lumefantrine 80/480 mg, 6 doses at 0, 8, 24, 36, 48, and 60 hours:
Note: In drug-drug interaction studies, different formulations and/or doses of etravirine were used which led to similar exposures and, therefore, interactions relevant for one formulation are relevant for the other.
Recommendations concerning co-administration: Close monitoring of antimalarial response is warranted when co-administering etravirine and artemether/lumefantrine as a significant decrease in exposure of artemether and its active metabolite, dihydroartemisinin, may result in decreased antimalarial efficacy. No dose adjustment is needed for etravirine.
Co-administration of etravirine with atazanavir/cobicistat or darunavir/cobicistat is not recommended.
Not studied. Co-administration of etravirine with atazanavir/cobicistat or darunavir/cobicistat may decrease plasma concentrations of the PI and/or cobicistat, which may result in loss of therapeutic effect and development of resistance.
Effects on drug levels – Least Squares Mean Ratio (90% CI; 1.00 = No effect):
Atorvastatin 40 mg once daily:
Note: In drug-drug interaction studies, different formulations and/or doses of etravirine were used which led to similar exposures and, therefore, interactions relevant for one formulation are relevant for the other.
Recommendations concerning co-administration: The combination of etravirine and atorvastatin can be given without any dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.
Effects on drug levels – Least Squares Mean Ratio (90% CI; 1.00 = No effect):
Boceprevir 800 mg 3 times daily + etravirine 200 mg every 12 hours:
Note: In drug-drug interaction studies, different formulations and/or doses of etravirine were used which led to similar exposures and, therefore, interactions relevant for one formulation are relevant for the other.
Recommendations concerning co-administration: The clinical significance of the reductions in etravirine pharmacokinetic parameters and boceprevir Cmin in the setting of the combination therapy with HIV antiretroviral medicines which also affect the pharmacokinetics of etravirine and/or boceprevir has not been directly assessed. Increased clinical and laboratory monitoring for HIV and HCV suppression is recommended.
Combination not recommended.
Not studied. Carbazamepine, phenobarbital and phenytoin are expected to decrease plasma concentrations of etravirine.
Co-administration with systemic immunosuppressants should be done with caution because plasma concentrations of cyclosporin, sirolimus and tacrolimus may be affected when co-administered with etravirine.
Not studied. Etravirine is expected to decrease plasma concentrations of cyclosporine, sirolimus and tacrolimus.
Effects on drug levels – Least Squares Mean Ratio (90% CI; 1.00 = No effect):
Note: In drug-drug interaction studies, different formulations and/or doses of etravirine were used which led to similar exposures and, therefore, interactions relevant for one formulation are relevant for the other.
Recommendations concerning co-administration: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
As a precaution it is recommended that concomitant use of etravirine and clopidogrel should be discouraged.
In vitro data show that etravirine has inhibitory properties on CYP2C19. It is therefore possible that etravirine may inhibit the metabolism of clopidogrel to its active metabolite by such inhibition of CYP2C19 in vivo. The clinical relevance of this interaction has not been demonstrated.
Co-administration of etravirine and daclatasvir is not recommended.
Not studied. Co-administration of etravirine with daclatasvir may decrease daclatasvir concentrations.
Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for chronic use.
Not studied. Dexamethasone is expected to decrease plasma concentrations of etravirine.
Alternatives to diazepam should be considered.
Not studied. Etravirine is expected to increase plasma concentrations of diazepam.
Effects on drug levels – Least Squares Mean Ratio (90% CI; 1.00 = No effect):
Digoxin 0.5 mg single dose:
Note: In drug-drug interaction studies, different formulations and/or doses of etravirine were used which led to similar exposures and, therefore, interactions relevant for one formulation are relevant for the other.
Recommendations concerning co-administration: Etravirine and digoxin can be used without dose adjustments. It is recommended that digoxin levels be monitored when digoxin is combined with etravirine.
Effects on drug levels – Least Squares Mean Ratio (90% CI; 1.00 = No effect):
Dolutegravir 50 mg once daily:
Dolutegravir + darunavir/ritonavir 50 mg once daily + 600/100 mg twice daily:
Dolutegravir + Lopinavir/ritonavir 50 mg once daily + 400/100 mg twice daily:
a Comparison based on historic control.
Note: In drug-drug interaction studies, different formulations and/or doses of etravirine were used which led to similar exposures and, therefore, interactions relevant for one formulation are relevant for the other.
Recommendations concerning co-administration:
Etravirine significantly reduced plasma concentrations of 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.
Etravirine should only be used with dolutegravir when co-administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. This combination can be used without dose adjustment.
Dose adjustments for these HMG Co-A reductase inhibitors may be necessary. Not studied.
Lovastatin, rosuvastatin and simvastatin are CYP3A4 substrates and co-administration with etravirine may result in lower plasma concentrations of the HMG Co-A reductase inhibitor. Fluvastatin, and rosuvastatin are metabolised by CYP2C9 and co-administration with etravirine may result in higher plasma concentrations of the HMG Co-A reductase inhibitor.
Effects on drug levels – Least Squares Mean Ratio (90% CI; 1.00 = No effect):
Fosamprenavir/ritonavir 700/100 mg twice daily:
a Comparison based on historic control.
Note: In drug-drug interaction studies, different formulations and/or doses of etravirine were used which led to similar exposures and, therefore, interactions relevant for one formulation are relevant for the other.
Recommendations concerning co-administration: Amprenavir/ritonavir and fosamprenavir/ritonavir may require dose reduction when co-administered with etravirine. Using the oral solution may be considered for dose reduction.
It is not recommended to co-administer etravirine with indinavir.
Concomitant use of etravirine with indinavir may cause a significant decrease in the plasma concentration of indinavir and loss of therapeutic effect of indinavir.
Etravirine and these antifungals can be used without dose adjustments.
Not studied. 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 etravirine may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by etravirine.
Effects on drug levels – Least Squares Mean Ratio (90% CI; 1.00 = No effect):
Maraviroc 300 mg twice daily:
Maraviroc/darunavir/ritonavir 150/600/100 mg twice daily:
* compared to maraviroc 150 mg twice daily
Note: In drug-drug interaction studies, different formulations and/or doses of etravirine were used which led to similar exposures and, therefore, interactions relevant for one formulation are relevant for the other.
Recommendations concerning co-administration: The recommended dose for maraviroc when combined with etravirine and a PI is 150 mg twice daily, except for fosamprenavir/ritonavir which is not recommended with maraviroc. No dose adjustment for etravirine is necessary.
It is not recommended to co-administer etravirine with nelfinavir.
Not studied. Etravirine is expected to increase nelfinavir plasma concentrations.
Effects on drug levels – Least Squares Mean Ratio (90% CI; 1.00 = No effect):
With an associated boosted PI:
No interaction study has been performed. Based on historical data, a decrease in etravirine exposure may be expected whereas an increase in rifabutin exposure and especially in 25-O-desacetyl-rifabutin may be expected.
With no associated boosted PI (out of the recommended indication for etravirine):
Note: In drug-drug interaction studies, different formulations and/or doses of etravirine were used which led to similar exposures and, therefore, interactions relevant for one formulation are relevant for the other.
Recommendations concerning co-administration: The combination of etravirine with a boosted PI and rifabutin should be used with caution due to the risk of decrease in etravirine exposure and the risk of increase in rifabutin and 25-O-desacetyl-rifabutin exposures. Close monitoring for virologic response and for rifabutin related adverse reactions is recommended. Please refer to the product information of the associated boosted PI for the dose adjustment of rifabutin to be used.
Combination not recommended.
Not studied. Rifampicin and rifapentine are expected to decrease plasma concentrations of etravirine. Etravirine should be used in combination with a boosted PI. Rifampicin is contraindicated in combination with boosted PIs.
Co-administration of Intelence and simeprevir is not recommended.
Not studied. Concomitant use of etravirine with simeprevir may decrease plasma concentrations of simeprevir.
Effects on drug levels – Least Squares Mean Ratio (90% CI; 1.00 = No effect):
Tipranavir/ritonavir 500/200 mg twice daily:
Note: In drug-drug interaction studies, different formulations and/or doses of etravirine were used which led to similar exposures and, therefore, interactions relevant for one formulation are relevant for the other.
Recommendations concerning co-administration: It is not recommended to co-administer tipranavir/ritonavir and etravirine.
It is recommended that the international normalised ratio (INR) be monitored when warfarin is combined with etravirine.
Not studied. Etravirine is expected to increase plasma concentrations of warfarin.
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
Rash has been reported with etravirine. Most frequently, rash was mild to moderate, occurred in the second week of therapy, and was infrequent after week 4. Rash was mostly self-limiting and generally resolved within 1 to 2 weeks on continued therapy. When prescribing etravirine to females, prescribers should be aware that the incidence of rash was higher in females.
Severe cutaneous adverse reactions have been reported with etravirine. In clinical trials, Stevens-Johnson Syndrome and erythema multiforme have been rarely (<0.1%) reported. Treatment with etravirine should be discontinued if a severe cutaneous reaction develops.
The clinical data are limited and an increased risk of cutaneous reactions in patients with a history of NNRTI-associated cutaneous reactions cannot be excluded. Caution should be observed in such patients, especially in case of history of a severe cutaneous drug reaction.
Cases of severe hypersensitivity syndromes, including DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and TEN (toxic epidermal necrolysis), sometimes fatal, have been reported with the use of etravirine. The DRESS syndrome is characterised by rash, fever, eosinophilia and systemic involvement (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and eosinophilia). Time to onset is usually around 3-6 weeks and the outcome in most cases is favourable upon discontinuation and after initiation of corticosteroid therapy.
Patients should be informed to seek medical advice if severe rash or hypersensitivity reactions occur. Patients who are diagnosed with a hypersensitivity reaction whilst on therapy must discontinue etravirine immediately.
Delay in stopping etravirine treatment after the onset of severe rash may result in a life-threatening reaction.
Patients who have stopped treatment due to hypersensitivity reactions should not restart therapy with etravirine.
In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Caution should be exercised in patients co-infected with hepatitis B or C virus due to the current limited data available. A potential increased risk of liver enzymes increase cannot be excluded.
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women, and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account in order to characterise the safety for the foetus.
Placental transfer has been seen in pregnant rats, but it is not known whether placental transfer of etravirine also occurs in pregnant women. Studies in animals do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Based on animal data the malformative risk is unlikely in humans. The clinical data do not raise safety concern but are very limited.
Etravirine is excreted in human milk. As a general rule, it is recommended that mothers infected by HIV do not breastfeed their babies under any circumstances in order to avoid transmission of HIV.
No human data on the effect of etravirine on fertility are available. In rats, there was no effect on mating or fertility with etravirine treatment.
Etravirine has minor influence on the ability to drive and use machines. No studies on the effects of etravirine on the ability to drive or operate machines have been performed. Adverse reactions such as somnolence and vertigo have been reported in etravirine-treated patients and should be considered when assessing a patient’s ability to drive or operate machinery.
The most frequent (incidence ≥10%) adverse reactions of all intensities reported for etravirine were rash, diarrhoea, nausea and headache. In the Phase III studies, the rates of discontinuation due to any adverse reaction were 7.2% in patients receiving etravirine. The most common adverse reaction leading to discontinuation was rash.
Adverse reactions reported in patients treated with etravirine are summarised in below. The adverse reactions are listed by system organ class (SOC) and frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000).
Adverse reactions observed with etravirine in clinical trials and post-marketing experience:
common: thrombocytopaenia, anaemia, decreased neutrophils
uncommon: decreased white blood cell count
common: drug hypersensitivity
uncommon: immune reconstitution syndrome
common: diabetes mellitus, hyperglycaemia, hypercholesterolaemia, increased low density lipoprotein (LDL), hypertriglyceridaemia, hyperlipidaemia, dyslipidaemia, anorexia
common: anxiety, insomnia, sleep disorders
uncommon: confusional state, disorientation, nightmares, nervousness, abnormal dreams
very common: headache
common: peripheral neuropathy, paraesthesia, hypoaesthesia, amnesia, somnolence
uncommon: convulsion, syncope, tremor, hypersomnia, disturbance in attention
common: blurred vision
uncommon: vertigo
common: myocardial infarction
uncommon: atrial fibrillation, angina pectoris
common: hypertension
rare: haemorrhagic strokea
common: exertional dyspnoea
uncommon: bronchospasm
very common: diarrhoea, nausea
common: gastrooesophageal reflux disease, vomiting, abdominal pain, abdominal distension, flatulence, gastritis, constipation, dry mouth, stomatitis, lipase increased, blood amylase increased uncommon pancreatitis, haematemesis, retching
common: increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST)
uncommon: hepatitis, hepatic steatosis, cytolytic hepatitis, hepatomegaly
very common: rash
common: night sweats, dry skin, prurigo
uncommon: angioneurotic oedemaa, swelling face, hyperhidrosis
rare: Stevens-Johnson Syndromea, erythema multiformea
very rare: toxic epidermal necrolysisa, DRESSb
common: renal failure, blood creatinine increased
uncommon: gynaecomastia
common: fatigue uncommon sluggishness
a These adverse reactions were observed in other clinical trials than DUET-1 and DUET-2.
b These adverse reactions have been identified through postmarketing experience with etravirine.
Rash was most frequently mild to moderate, generally macular to maculopapular or erythematous, mostly occurred in the second week of therapy, and was infrequent after week 4. Rash was mostly self-limiting, and generally resolved within 1-2 weeks on continued therapy. The incidence of rash was higher in women compared to men in the etravirine arm in the DUET 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). There was no gender difference in severity or treatment discontinuation due to rash. The clinical data are limited and an increased risk of cutaneous reactions in patients with a history of NNRTI-associated cutaneous reaction cannot be excluded.
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy. The frequency of this is unknown.
In clinical trials, the frequency, type and severity of adverse reactions in paediatric patients were comparable to those observed in adults. 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). Most often, rash was mild to moderate, of macular/papular type, and occurred in the second week of therapy. Rash was mostly self-limiting and generally resolved within 1 week on continued therapy.
In a postmarketing retrospective cohort study aiming at substantiating the long-term safety profile of etravirine in HIV-1-infected children and adolescents receiving etravirine with other HIV-1 antiretrovirals (N=182), Stevens-Johnson Syndrome was reported at a higher incidence (1%) than has been reported in adult clinical trials (<0.1%).
In the pooled analysis for DUET-1 and DUET-2, the incidence of hepatic events tended to be higher in co-infected subjects treated with etravirine compared to co-infected subjects in the placebo group. Etravirine should be used with caution in these patients.
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