Atripla approved in Europe as switch option for suppressed patients
On 18 October 2007, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) issued a positive opinion on the Marketing Authorisation Application for the fixed-dose triple combination Atripla (efavirenz600mg/FTC200mg/tenofovir300mg).
Specifically, the CHMP indication is for ‘adults with virologic suppression to HIV 1 RNA levels of <50 copies/mL on their current combination antiretroviral therapy for more than three months’. It is unclear why patients should not have experienced virological failure on ‘any’ prior ARV therapy, although not having resistance to any of the three individual drugs in Atripla prior to starting their first regimen, is clearly important.
The CHMP’s positive recommendation will be reviewed by the European Commission, which has the authority to approve medicinal products for use in the 27 countries of the European Union. The companies (Atripla is a result of a collaboration between BMS, Merck and Gilead) expect the European Commission to issue its decision on the marketing authorisation for Atripla toward the end of the year.
In the US, the FDA also granted approval of an identical alternate formulation (it is a white rather than pink-coloured tablet) for distribution in developing countries. In March 2007, the World Health Organization added Atripla to its Model List of Essential Medicines.
The option of a one-pill, once-daily combination is popular with patients, especially those who are more recently diagnosed, even though caution needs to be taken concerning the side effect profile of efavirenz.
The EMEA have not commented on why approval of Atripla seems to have been so problematic it was approved by the FDA in the US in July 2006.
One issue is likely to be the currently conflicting food recommendations for tenofovir. In the US, Atripla is recommended to be taken ‘on an empty stomach’ and tenofovir is recommended to be taken ‘without regard to food’.
In Europe, the food interaction that increases tenofovir levels (AUC by 40% and Cmax by 14%) when taken with a high fat meal (700-1000kcal, including 40-50% fat), led to the recommendation is to take tenofovir with a ‘light meal or snack’.
However, this information is actually inconsistent with pharmacokinetic data included in the tenofovir Summary of Product Specifications (SPC), which states that ‘a light meal or snack’ has no effect on drug levels.
For years the EMEA and Gilead have therefore been supporting conflicting information about dosing.
Meanwhile, the potential importance of increased drug levels from taking tenofovir with a high fat meal for some patients is still unknown.
There are still no comparative data on the virological impact of higher drugs levels when starting treatment, especially in experienced patients, or in those who have higher baseline viral load.
Anecdotally, tenofovir is commonly taken without regard to food, following the US indication. This is less likely to matter in patients who are virologically suppressed.
There is therefore a theoretical basis for the approval of Atripla as a switch option in suppressed patients, whether or not the strict indication is followed in practice.
Someone at the EMEA needs to recognise that ‘take with a light meal’ and ‘administration with a light meal did not have a significant effect on the pharmacokinetics of tenofovir’ are incompatible in the same SPC.
Studies that show the virological and clinical impact of ‘not taking tenofovir with a high fat meal’ might also be a good idea.