Four cases where patients went into cardiogenic shock within a few hours of
being switched from mibefradil to other calcium-channel blockers (CCBs) will
be reported in the July 8 issue of the Journal of the American Medical
Association. Mibefradil's market withdrawal on June 8 (see Lancet June 13, p
1791) prompted the early release of the article because of its public-health
importance --thousands of people worldwide will be changing from mibefradil
to other drugs in the next few weeks.

The article reports four cases of patients who were switched from
mibefradil to
other CCBs because their blood pressure was not being adequately
controlled by
mibefradil. The patients began taking their new drug within a day of
stopping
mibefradil. One patient died. The other three survived after treatment in
intensive care (JAMA 1998; 280: 157-58).

About 200 000 people in the USA alone will need to change from mibefradil to
another CCB, so many more of these newly reported life-threatening drug-drug
interactions could occur. Michael Mullins (Oregon Poison Center, Portland,
OR,
USA), an author on the new report, notes that the possibility of
interactions between mibefradil and other CCBs was not included in the June
8 warning, which focused on mibefradil's effect on the activity of liver
detoxifying enzymes.

In a supplementary letter issued on June 12, Roche advises a delay of 7 days
between discontinuing mibefradil and taking most other CCBs and
ß-blockers. A
14-day delay is recommended before switching to felopidine or timolol.

---------------------------------------------------------------------------
What lessons can be learnt from withdrawal of mibefradil from the market?
----------------------------------------------------------------------

Roche announced on June 8 its withdrawal of the calcium antagonist,
mibefradil
(Posicor), from the market, almost exactly a year after the drug had been
given
marketing approval in Europe and the USA. The withdrawal was based on new
reports about serious interactions with other drugs. Is it yet another
example of overprecipitous approval by licensing agencies,1 whose
livelihoods in some
cases depend on fees from pharmaceutical companies? Companies would argue
that the withdrawal shows just how risky investment in the pharmaceutical
industry is. Where does the truth lie and what lessons can be learnt from
this episode?

Drug research is expensive and there is no reliable way of ensuring that the
investment required will yield the blockbuster drugs that the major
pharmaceutical companies need to keep going. Bringing a drug such as
mibefradil to the market costs on average several hundred million pounds.2,3
Withdrawal of mibefradil, which was projected to account for 1-3% of Roche's
sales in the next few years, led to a 2% drop in its market value.4 The
chief executive of SmithKline Beecham has suggested that his company needs
to produce three products with potential annual sales of £250 million each
year between 1998 and 2000 and six thereafter to maintain the 10% sales
growth that investors expect.5 Given this financial pressure, it is not
surprising that companies market their products vigorously.

Advertisements for mibefradil suggest that there was little modesty in the
promotion of the drug, which was claimed to be a first-line therapeutic
agent for hypertension and angina. Given the absence of long-term studies
such as those that have established thiazide diuretics and ß-blockers as
truly first-line therapy for hypertension, objective observers would
classify mibefradil as a second-line agent that deserves a black triangle
(to indicate limited experience) in the British National Formulary.6 How did
the industry's advertising authority allow this claim to pass through? With
this experience, perhaps the advertising of the newer antihypertensive
agents, such as the angiotensin II antagonists (the "sartans"), needs
re-examination.

Mibefradil was withdrawn from the market because "the combination of Posicor
and
some other commonly used drugs, among them cardiovascular agents, may
increase the frequency of side-effects of these other medications. In
principle drug interactions can be addressed by appropriate labelling;
however, with respect to Posicor, Roche Laboratories believes that the
complexity of such prescribing information would make it too difficult to
implement". The interactions were predictable from the pharmacology of the
drug. Mibefradil inhibits the action of cytochrome P450 3A4. Therefore when
given concurrently with drugs that are metabolised by this enzyme,
concentrations of these drugs would be expected to increase. With drugs
possessing a narrow therapeutic window, such as cyclosporin and tacrolimus
(panel), toxic concentrations could be reached with normal doses. Roche's
decision suggests that drug-regulatory authorities ought to review urgently
the licensing of current and future drugs with this potential for
interaction.

Mibefradil is, pharmacologically, an exciting new molecule that has opened
up
many new avenues for research. Its selective T-channel-blocker activity led
to its classification as a new category of calcium antagonist. This
classification perhaps led to the perception that somehow it was above the
problems associated with older calcium antagonists.7,8 Pharmacological
plausibility plays a large part in the licensing of drugs, as is evidenced
by the wide use of surrogate outcomes. Perhaps it is time to be less
enamoured by pharmacological rationale and to accept that the true value of
a drug and whether it should be a first-line agent can be assessed only
through properly conducted randomised controlled trials with hard outcomes.

As for patients stabilised on mibefradil, they should not be withdrawn from
treatment abruptly, but care must be taken to ensure that they are not
taking interacting drugs concurrently. Alternative antihypertensives should
be prescribed as soon as possible, but at least on this score, there is no
cause for panic.
(http://www.thelancet.com/newlancet/sub/issues/vol351no9119/commentary1829.ht
ml)