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The availability of a generic version of a branded drug is usually
cause for quiet celebration. The generic product is invariably substantially
less expensive than the trade name version and regulatory requirements
ensure bioequivalence. Pharmacists then have available to them a cheaper
drug that presents no risk to patient welfare. Everyone but the original
manufacturer benefits from this process.
In the treatment of schizophrenia, the introduction of clozapine was
a significant breakthrough. Authorisation for the marketing of generic
versions of clozapine has recently been given and so automatic switching
from branded to generic clozapine might be expected. However, the unique
nature of clozapine’s pharmacology calls for some caution and,
in our view, some careful reflection and planning.
Schizophrenia is the most severe and disabling psychiatric illness. About
a quarter of patients with this devastating illness have little or no
response to the currently available antipsychotic agents. Clozapine is
the only antipsychotic that has been demonstrated to be effective in
this group of treatment refractory patients. However, clozapine is associated
with severe haematological side effects that necessitate regular blood
monitoring. This regular monitoring of clozapine treatment has, without
doubt, substantially reduced the risk of clozapine-related deaths. The
success in reducing mortality and morbidity is due, at least in part,
to the centralised national registry maintained by the Clozaril Patient
Monitoring Service (CPMS). With the introduction of generic clozapine,
the benefit of a single, centralised database is lost. Also, we will
move from using a well proven monitoring scheme to a variety of untested
schemes often with no UK track record.
Clearly, before national and international regulatory authorities approve
generic drugs, the generic drug must demonstrate bioequivalence to the
reference drug. But what exactly is bioequivalence in this context and
what does it mean? The key parameters used to determine bioequivalence
include the area under the concentration-time curve, time to peak plasma
concentration and the peak plasma concentration. From these data, a generic
drug is deemed bioequivalent to a reference brand product if the bioavailability
lies between 80 per cent and 125 per cent of the reference drug. The
implication of this is that two products may vary considerably in their
bioavailability. For the overwhelming majority of drugs, this variability
is of little clinical significance, but for a small number of drugs and
patient groups, this could have huge implications. We believe that clozapine
is in the latter category.
Clozapine dose is a poor predictor of therapeutic response. One possible
reason is the wide inter-patient variability in plasma levels. This variation
may be as high as 45-fold in different individuals. Conversely, there
is a good correlation between plasma levels and therapeutic response.
Proposed therapeutic levels associated with clinical response range from
350 to 504µg/L. However, the degree of variation that is allowed
between generic and branded products may in the case of clozapine be
sufficient to cause subtle changes in plasma levels that may result in
relapse or re-emergence of symptoms. There are certainly case reports
of psychotic relapses when Clozaril was switched to a generic product
that substantiate the above assertion.1
Our experience with clozapine suspension is perhaps a useful pointer.
When we identified the need for a liquid clozapine preparation, we formulated
a suspension using paediatric base as a vehicle for the Clozaril tablets.
This suspension passed vigorous stability testing and we used it in many
of our patients. Shortly after its introduction we found that plasma
levels achieved with the suspension were significantly lower than those
achieved with the tablets.
What do the data say?
Generic versions of clozapine have been available in the US since 1997
and the debate about interchangeability has continued ever since. The
key question is, in routine clinical practice, can one switch a patient
from branded clozapine to generic clozapine without any risk to the
patient? Unfortunately most data available on the subject are tinged
by bias and by strong competing financial interests. Two Novartis-sponsored
studies suggest that branded and generic clozapine are not interchangeable.
In the first study, Lam et al2 investigated 21 patients randomised
to branded or generic clozapine. They found differences in some pharmacokinetic
parameters between the two preparations in almost 40 per cent of patients.
In the second study, Kluznik et al3 randomised 45 patients to either
generic or branded clozapine in a crossover design. Five patients experienced
a relapse when switched from Clozaril to generic clozapine. Eleven
patients worsened short of full relapse, nine while receiving generic
and two while on Clozaril.
Against this backdrop of negative reports, we have studies sponsored
by generic manufacturers that dispute the claim that generic and branded
clozapine are dissimilar. Goldfinger4 assessed over 14,000 patients on
a clozapine database. Approximately 90 per cent of these patients did
not require a dosage adjustment after switching. Other studies, such
as that by Makela et al,5 although this only included small numbers (n=20),
found no deterioration in clinical status after the switch. These reports
indicate successful switching from branded to generic clozapine.
It is arguably clear from the foregoing that switching from Clozaril
to generic clozapine is neither simple nor straightforward. At the same
time, possible cost saving from this switch is an enticing prospect for
budget holders. However, it must be remembered that it is the safety
of the patient that is paramount. Currently, the monthly cost of Clozaril
at a dose of 300mg is £147.84. Generic clozapine is likely to be
at least 30 per cent cheaper than the list price of Clozaril. If a patient
were to relapse as a result of generic switch, the cost of hospital care
is about £300 per day, which is approximately 55 times more expensive
than Clozaril. The cost advantage of generic clozapine therefore is more
than lost. Moreover, the financial impact is nothing compared with the
cost to patients and their families.
A successful switch from branded to generic clozapine can be implemented
with careful planning in stable patients. Baseline assessments should
include mental state and clozapine plasma levels. Patients should be
closely monitored and dose adjustments made according to clinical status
and plasma levels. For patients newly started on clozapine there are
no special requirements. Trusts currently switching patients from branded
to generic clozapine might note those recommendations. To our knowledge,
many are switching without any form of monitoring in place.
In summary, clozapine is a unique drug in the treatment of schizophrenia.
Correlation between therapeutic effects and plasma levels is well documented.
For most patients, switching from Clozaril to generic clozapine will
be uneventful. For some patients, the subtle differences in pharmacokinetic
profile may result in precipitous relapse. Careful planning is needed
if the process is to be successful. References
1. Mofsen R, Balter J. Case reports of the emergence of psychotic symptoms
after conversion from brand-name clozapine to a generic formulation.
Clinical Therapeutics 2001;10:1720–31.
2. Lam YWF, Ereshefsky L, Toney GB et al. Branded versus generic clozapine:
bioavailability comparison and interchangeability issues. Journal
of Clinical Psychiatry 2001;62(Suppl 5):18–22.
3. Kluznik JC, Walbek NH, Farnsworth MG et al. Clinical effects of a
randomised switch of patients from Clozaril to generic clozapine. Journal
of Clinical Psychiatry 2001;62(Suppl 5):14–7.
4. Goldfinger SM. The interchangeability of brand and generic clozapine.
41st NCDEU poster abstract 2001.
5. Makela EH, Cutlip WD, Stevenson JM et al. Branded versus generic clozapine
for treatment of schizophrenia. Annals of Pharmacotherapy 2003;37:350–3. |
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