The US FDA has approved the first combination of an angiotensin
receptor blocker (ARB)--valsartan--with a calcium-channel blocker
(CCB)--amlodipine--for the initial treatment of hypertension. The
product, known as Exforge, was given the additional indication along
with another combination containing valsartan and
hydrochlorothiazide, Diovan HCT [1]. Both are marketed by Novartis.

The products were already available for the second-line treatment of
high blood pressure--Exforge having first been approved just last
year. Hypertension expert Dr Franz Messerli (St Luke's Roosevelt
Hospital, New York) told heartwire that the new indication for
Exforge "is by far the more important of the two, because valsartan
and amlodipine are the most commonly prescribed ARB/CCB combination,
and this is the first time such a combination has been approved for
initial therapy."

Messerli welcomes the approval--"I think this is a major progress"--
but cautions that "patient selection is crucial when it comes to
using fixed-dose combinations, because they are not for every
patient. A decade ago the pharmaceutical companies were taking out
full-page ads stating that 80% of patients can be controlled on drug
X monotherapy, and now they are saying that more than 80% of
patients need combination therapy. I suspect the truth is somewhere
in between, with around 50% to 65% of patients needing
combinations."

Approval sanctions off-label use, allows companies to market as
first-line

Messerli says the FDA has "been fairly trigger-happy to approve
diuretic-based combinations" but slightly more reluctant to grant
approvals of other fixed-dose combinations, particularly for initial
therapy, for the simple reason that it fears that some patients will
be exposed unnecessarily to combination treatment.

But he believes that physicians have been erring on the side of
caution in this regard, "as they are a bit reluctant to be too
aggressive in lowering blood pressure too fast." However, "the
ACCOMPLISH study really has put fixed combinations on the map, and
therefore physicians have been using them, which is not surprising,"
and some doctors have been using Exforge off-label for the initial
treatment of hypertension, "so in some ways the FDA is belatedly
blessing what many physicians have been doing for quite some time."

Another expert, Dr Elizabeth Ofili (Morehouse School of Medicine,
Atlanta, GA), agrees, adding that "it is important to get the first-
line approval for a number of reasons, one of which is managed care.
The FDA is moving toward this area and recognizing that high blood
pressure is a complex process." Messerli says such approvals also
allow the companies to market their products as first-line therapy,
something they have previously been unable to do.

"There are two main advantages of fixed-dose combinations for the
patient," he says. "First, the pill burden is reduced, and second,
the patient only has one copayment instead of two."

Both Messerli and Ofili said that there would not be too much
competition from generics for the new Exforge product or for other
similar combinations at the present time. Although amlodipine has
recently become available generically in the US, it is not that
cheap, they point out.

"Once amlodipine becomes a Wal-Mart $4 drug, it's obvious that cost
will become an issue," says Messerli. None of the ARBs are yet
available generically in the US, he adds, although losartan will be
available next year.

Novartis. Single-pill combinations Diovan HCT and Exforge approved
in US as first-line treatments for high blood pressure press
release]. August 4, 2008. Available at:
http://www.novartis.com/newsroom/media-
releases/en/2008/1239786.shtml.