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| Journal of the New Zealand Medical Association,
15-July-2005, Vol 118 No 1218
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Dihydropyridines, felodipine, and PHARMAC
Stewart Mann
BackgroundDihydropyridine calcium channel
antagonists (DHPs) are powerful vasodilators used as anti-hypertensive and
anti-anginal agents. Although overall benefit in angina has been observed, some
patients experience worsening of symptoms or adverse cardiac
events1 and there has been concern over their
safety in acute coronary syndromes.2,3 Cohort
studies undertaken in patients taking DHPs for hypertension showed increased
rates of myocardial infarction in comparison with those taking drugs from other
pharmaceutical groups.4,5 Although a
substantial number of prospective trials comparing DHPs with other
antihypertensive classes6,7 has now largely
allayed those concerns, there has been lingering doubt over the safety of the
more vasculoselective DHPs and of short-acting
preparations.8 Some uncontrolled studies of
swaps between the different long-acting DHPs have not shown any safety
concerns.9,10
PHARMAC and calcium antagonists, 1997–9In New Zealand in 1997, several DHPs
were freely prescribable: nifedipine (as Adalat, Adalat Retard, and Adalat
OROS), felodipine (as Plendil ER), amlodipine (as Norvasc), and isradipine (as
Dynacirc). Various preparations of verapamil and diltiazem were also available.
For both cost and safety reasons, PHARMAC was concerned that
the use of calcium antagonists as first-line agents in hypertension was growing
inappropriately. PHARMAC issued proposals to treat all calcium antagonists
(excluding verapamil) as an interchangeable class, and use reference pricing to
restrict costs. At that time, the cheapest member of the class was short-acting
diltiazem.
Consultation with various groups (including the Cardiac
Society) occurred in 1998–9 in response to which PHARMAC recognised both
the need to separate diltiazem from the DHP group and took note of concerns over
patients taking DHPs for angina. In mid-1999, subsidies on all DHPs were
referenced to felodipine (Plendil ER, AstraZeneca Pharmaceuticals) but Special
Authority provisions were made for those who were already taking other DHPs for
angina or who could not tolerate felodipine.
Bayer Pharmaceuticals had offered an alternative preparation
of nifedipine (Adalat Coat Core) but PHARMAC’s Pharmacology and
Therapeutics Advisory Committee (PTAC), although not the usual body to assess
this, did not feel its release characteristics were adequate compared with the
current product (Adalat Oros). At that time, felodipine held some 37% market
share of all DHP prescriptions (total around 59,000 patients in New Zealand) so
over 30,000 patients had to change their medication to continue to receive full
subsidy. PHARMAC provided some financial help for GP visits to achieve the
change.
Later in 1999, negotiations with AstraZeneca Pharmaceuticals
led to a reduced price for felodipine (Plendil ER) in return for some subsidised
access for their angiotensin-II receptor blocker, candesartan. This increased
the co-payments of those who had chosen to continue other DHPs.
Generic substitution (and back again, and again), 2001–4By late 2001, the patent protection
on the Plendil ER brand of felodipine had expired, and PHARMAC identified and
awarded a sole-supply contract for a generic (Felo ER, Pacific Pharmaceuticals)
that was available in one other country (Germany).
AstraZeneca obtained results of comparative bioavailability
studies under the Official Information Act and felt there was enough concern
over these to commence judicial review proceedings with the object of having the
approval for Felo withdrawn. While the drug entity was the same, the
slow-release characteristics of Felo were questioned—an important
consideration given concern over the safety of short-acting DHPs.
MEDSAFE’s Generics Subcommittee reviewed the claims
but stood by its original approval decision, further ratified by the Medicines
Assessment Advisory Committee (MAAC) which deemed Plendil ER and Felo ER to be
interchangeable. This stance contrasted with PTAC’s earlier opinion of the
unacceptability of comparative release characteristics of Adalat Coat Core,
although it was based on accepted specific criteria and, in this case, related
to different formulations of the same drug.
The switch to the generic felodipine went ahead. There were
a number of anecdotal concerns from patients via doctors and pharmacists, and
118 notifications to the Centre for Adverse Reactions Monitoring (CARM) in
Felo’s first year compared with 69 over 14 years with Plendil. PHARMAC
dismissed these as the inevitable disgruntlement that accompanies enforced
change. MEDSAFE ascertained that there had been no excess of complaints about
Felo ER in Germany.
In October 2002, it came to light that biostudy tests done
in Europe on Felo ER used to justify its registration could not be relied on and
registration was withdrawn. The 50,000 or so patients taking the drug were
therefore switched back to Plendil ER; Pacific Pharmaceuticals having to
subsidise the consultations necessary to achieve this. However, there was
consequent further disruption11 and patients
had to meet the costs of a new prescription. Bioequivalence tests were then
repeated on each dose of Felo ER (2.5mg, 5mg, and 10mg) and resubmitted to
MEDSAFE.
The Generics Subcommittee initially felt the equivalence
fell outside desirable tolerance limits for all doses but, after further
submissions, accepted that their initially proposed standards were unrealistic
and permitted re-registration of the 5mg and 10mg doses but not the 2.5mg dose.
This created a problem for PHARMAC who wished to reintroduce reduced subsidies
based on the generic pricing for these doses in late 2003 but AstraZeneca
refused to provide the Plendil ER 2.5mg dose alone. (Cutting larger tablets in
half destroys the slow release characteristics of either Plendil ER or Felo
ER.)
Given that patients taking this low dose were doing so
because of safety and tolerance concerns, this created a potentially dangerous
situation which was exacerbated by a lack of well-established equivalent low
doses of other DHPs.
The Cardiac Society asked PHARMAC to:
No information
was received to indicate that these requests had been considered, and clearly
the vital question of the 2.5mg dose was subject to brinkmanship.
Thankfully, an eleventh hour agreement between PHARMAC and
AstraZeneca saw the 2.5mg dose of Plendil ER continue to be available with full
funding, but patients taking higher doses had to swap brands yet again to retain
full subsidy. A final twist in the tale occurred in March 2004 when Pacific
Pharmaceuticals were temporarily unable to satisfy the demand for Felo 5mg and,
yet again, patients swapped to Plendil.
CommentWhat lessons can be drawn from this
tale? Reference pricing of a previously available, diverse but pharmacologically
similar group of medications to a single product creates tension for prescribers
who believe that there are significant differences between products based on
therapeutic quality, safety considerations, or on widely disparate levels of
evidence for outcome benefit. The scientifically minded are naturally distraught
that such major ‘experiments’ are forced on a large population with
little formal collection of outcome data and with negligible regulatory and
ethical approval or documentation of outcome compared with the requirements for
clinical trials that may have much less impact on subjects.
In order to retain full subsidy on their medication, some
patients on long-term DHP treatment will have had to swap their medication
several times in recent years to accommodate the pricing objectives of PHARMAC.
There is at least a temporary and sometimes major quality issue here for
patients, particularly for the elderly who easily get confused about their
medication. Interactions with healthcare providers become frustrating on both
sides given the adverse perceptions of change (whether or not these are due to
true organic disturbance), and consequent rebalancing of previously stable
medication.
The importance of this loss of quality will undoubtedly
remain a contentious issue between those representing their patients and a
purchasing agency with a commercial imperative. Dissatisfaction of patients with
the imposed substitute product purely due to the change is an undeniable
phenomenon but one which cannot be interpreted fully in the absence of detailed
data collection or a prospective trial.
Generic substitution is an acceptable and commercially
important practice in reducing consumer costs. However, not all preparations of
the same drug are exactly the same; such factors as release mechanisms having
importance where markedly fluctuating levels of a drug create safety concerns.
Analysis of bioequivalence is complex and studies asserting this frequently do
not use preparations and experimental subjects directly equivalent to the usual
clinical situation.
Extension of reference pricing or generic substitution into
sole-supply arrangements can leave healthcare provision vulnerable in the event
of a quality issue arising which renders the chosen drug formulation temporarily
or permanently unusable. Alternatives may not be readily available when minimal
market share has discouraged suppliers from maintaining infrastructure in the
country necessary to facilitate urgent supply (or resupply) of a product.
By analogy, we would not expect the same quality controls
when buying an imported used car from a second-hand dealer than we would from a
new model bought from a franchised dealer of the original manufacturer. There
may be good reasons for purchasing the former but we have to admit the
compromise and try not to drive all the other dealers out of town so that when
our vehicle breaks down, there are no easy alternatives.
Timeline of various arrangements affecting supply of
dihydropyridines in New Zealand
(CAAs = calcium antagonists,
DHPs = dihydropyridines, GSC = MEDSAFE’s Generics
Subcommittee)
Disclosures:
I acted in the late 1990s as a designated representative on pharmaceutical
policy for the Cardiac Society and from 2002–4 as New Zealand Regional
Chairman of the Society, periods when these issues were very much on the agenda.
I have provided occasional consultancy advice to AstraZeneca Pharmaceuticals.
Since 2004, I have been a member of the cardiovascular subcommittee of the
Pharmacology and Therapeutics Advisory Committee (PTAC) to PHARMAC but have not
participated in this capacity in any discussions on DHPs.
Author information:
Stewart Mann, Associate Professor of Cardiovascular Medicine, Wellington School
of Medicine and Health Sciences, University of Otago, PO Box 7343,
Wellington
Correspondence:
Associate Professor Stewart Mann, Wellington School of Medicine and Health
Sciences, University of Otago, PO Box 7343, Wellington. Fax: (04) 389 5427;
email: stewart.mann@otago.ac.nz
References:
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