US approve a lower-dose efavirenz (400 mg) based generic FDC (Simfi Lo)

9 February 2018. Related: Antiretrovirals.

Simon Collins, HIV i-Base

On 7 February 2018, the US FDA approved a new generic fixed dose combination (FDC) that uses a lower dose of efavirenz (400 mg rather than 600 mg) together with lamivudine and tenofovir DF. [1]

Approval is primarily based on results from the randomised double-blind ENCORE1 study in 630 treatment-naive individuals that reported results three years ago. ENCORE1 reported similar efficacy with slightly fewer side effects in the 400 mg vs 600 mg efavirenz group. [2]

The most common psychiatric side effects were: abnormal dreams (8.7% vs 11.3%), insomnia (6.2% vs 6.5%), somnolence (3.1% vs 3.9%), depression (3.1% vs 1.6%), nightmare (1.9% vs 2.6%), sleep disorder (2.2% vs 1.3%), and anxiety (1.2% vs 1.3%), in the 400 mg vs 600 mg groups respectively.

Central nervous system (CNS) symptoms were reported by 40% vs 48% with dizziness (27% vs 35%) and headache (11% vs 11%) in the 400 mg vs 600 mg groups respectively. Different types of rash occurred in 32% vs 26%, with grade 3-4 rash reported in 3% vs 1% (all 600 mg vs 400 mg).

Approval is for adults and children weighing >35 kg.

The FDC is manufactured by Mylan and will be marketed with the brand name Simfi Lo.

For full details see the produced information for the FDC and for the individual drug components. [3]

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The option to use this new reduced dose efavirenz-based FDC is welcome – and reducing the dose of a drug that was still under patent protection is an achievement – but results from ENCORE1 were first presented almost five years ago. [4]

Although this new formulation might improve quality of life for some people, the reduction in side effects with the 400 mg dose was modest. For this reason, efavirenz is no-longer recommended as a preferred first-line combination in UK guidelines.

Earlier this month Mylan also announced approval in the US and EU of their generic 600 mg efavirenz, that comes with 180 days marketing exclusivity. [5]

The Mylan low dose efavirenz FDC was granted FDA tentative approval (for use outside the US, in association with PEPFAR, even where there is still patent or exclusivity market protection for the product in the US) in March 2017. [6]

References

1. FDA HIV listserv. FDA approves SYMFI LO Tablets (Fixed Dose Combination). (07 February 2018)
2. ENCORE1 study group. Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial. Lancet. 2014 Apr 26;383(9927):1474-1482. doi: 10.1016/S0140-6736(13)62187-X. Epub 2014 Feb 10.
   http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62187-X/fulltext
3. Simfi Lo. Highlights of prescribing information.
   https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208255s000lbl.pdf (PDF)
4. Puls R et al. A daily dose of 400mg efavirenz (EFV) is non-inferior to the standard 600mg dose: week 48 data from the ENCORE1 study, a randomised, double-blind, placebo controlled, non-inferiority trial. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 30 June – 3 July 2013, Kuala Lumpur. Oral late breaker abstract WELBB01.
   http://pag.ias2013.org/Abstracts.aspx?SID=74&AID=3137
5. Mylan PR. Mylan expands access to HIV/AIDS medicines with launch of first generic Sustiva tablets. (01 February 2018).
   http://newsroom.mylan.com/2018-02-01-Mylan-Expands-Access-to-HIV-AIDS-Medicines-with-Launch-of-First-Generic-Sustiva-R-Tablets
6. US FDA. FDA antiretrovirals approved and tentatively approved in association with the President’s Emergency Plan Expedited Review Process. 193. Tentative approval 10 March 2017.
   https://www.fda.gov/InternationalPrograms/PEPFAR/ucm119231.htm