Journal of the New Zealand Medical Association, 15-July-2005, Vol 118 No 1218
Dihydropyridines, felodipine, and PHARMAC
Dihydropyridine 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, 1997–9
In 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), 2001–4
By 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.
What 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: email@example.com
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