Etravirine approved in Europe

30 October 2008. Related: Antiretrovirals.

On 29 August 2008 the European Medicines Agency (EMEA) has granted marketing authorisation for etravirine , a new NNRTI previously called TMC-125 (tradename Intelence).

This indication is based on week 24 results from two randomised, double-blind, placebo-controlled phase III trials in highly treatment-experienced patients with resistance to NNTRIs and protease inhibitors, where etravirine was investigated in combination with an optimised background regimen (OBR) which included darunavir/ritonavir. [2, 3]

The data showed that significantly more patients in the etravirine arm achieved undetectable viral load (less than 50 copies/mL) compared to placebo (59% vs. 41% [p<0.0001]). Etravirine was generally safe and well tolerated. Rash, which was mainly mild to moderate, was also the most common adverse event of moderate intensity or greater (. grade 2); etravirine 9% vs placebo 3.2%.

• Severe skin rash has been reported with etravirine; Stevens-Johnson Syndrome has been rarely (<0.1%) reported. Treatment with etravirine should be discontinued if severe rash develops. In general, rash was mild to moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within 1-2 weeks on continued therapy. discontinuation rate due to rash was 2 percent.
• No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). The pharmacokinetics of etravirine have not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, etravirine should be used with caution in patients with severe hepatic impairment.
• Based upon the safety profile, no dose adjustment is necessary in patients co-infected with hepatitis B and/or C virus.
• Redistribution and/or accumulation of body fat have been observed in patients receiving. ARV therapy. The causal relationship, mechanism, and long-term consequences of these events have not been established.
• Immune reconstitution syndrome has been reported in patients treated with ARV therapy, including etravirine.
• The most frequently reported adverse events (>10%) of any intensity that occurred at a higher rate than placebo were rash (17%), diarrhoea (15%) and nausea (13.9%).

The recommended oral dose of etravirine tablets is 200 mg (two 100mg tablets) twice daily following a meal. Patients may also disperse the tablets in a glass of water.

Etravirine is marketed in Europe by Tibotec, a division of Janssen-Cilag.

Please see full Prescribing Information for more details.

Comment

Etravirine received US approval in January this year and has been available on expanded access in the UK for at least the last year. It is the first NNRTI to show activity against a broad range of (but not all) NNRTI-associated mutations. Etravirine sensitivity in patients with existing NNRTI mutations can be guided using a new resistance mutation algorithm to predict sensitivity to etravirine. [4]

Etravirine should not be given with other NNRTIs, tipranavir/ritonavir, unboosted atazanavir, saquinavir, indinavir or full-dose ritonavir and with caution with boosted fosamprenavir. While many of these interactions are less relevant for prescriptions in 2008, the broad interactions between etravirine and other NNRTIs and PIs is likely to increase confidence in prescribing etravirine together with darunavir/r as in the DUET studies.

In addition to the product information, an excellent summary of these interactions has been developed by the pharmacology department at Liverpool University and is available online. [5]

References

1. Tibotec press release “INTELENCE (etravirine) Receives Marketing Authorisation In The European Union For HIV Combination Therapy. INTELENCE is the first NNRTI to show antiviral activity in patients with NNRTI-resistant virus.” (29 August).
   Link to press release.
2. Madruga JV et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. The Lancet 370(9581): 29-38. July 7, 2007.
   http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61047-2 
3. Lazzarin A et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. The Lancet 370(9581): 39-48. July 7, 2007.
   http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61048-4
4. Understanding etravirine susceptibility: new weighted genotype score and phenotypic cut-offs. HIV Treatment Bulletin July/August 2008.
   http://www.i-base.info/htb/v9/htb9-7-8/Understanding.html