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NDA 20-358 |
14 |
LABELLING:
The
following animal data-based portions of the labelling differ from the approved
labelling of the original formulation.
(Note that in most cases the changes are not specific to the sustained
release formulation per se but reflect animal data obtained since
the original labelling was approved):
1) Page 2-3 (“Pharmacodynamics and Pharmacological Actions”)
a) First paragraph
This paragraph was completely rewritten. Not much was said about the mechanism of action of bupropion (B) in the
original labelling. It was active in
the Porsolt and tetrabenazine models of depression, but was a relatively weak
blocker of the neuronal uptake of serotonin, norepinephrine and dopamine. (See my review of NDA 18-644). The sponsor now wishes to state that “the
antidepressant activity of bupropion is presumed to be mediated primarily
through pathways subserved by norepinephrine as evidenced by its ability to
reduce firing rates of norepinephrine-containing neurons in the locus coeruleus at doses which are
active un animal antidepressant models”.
It is not clear if this study has been submitted; the sponsor’s
reference for this paragraph states “Update of Clinical Pharmacology Section to
include information regarding bupropion’s effects on the firing rates of
noradrenergic neurons in locus coeruleus).
There is a brief summary of relevant data in the sponsor’s submission of
1/28/93 to NDA 18-644; according to this, in studies in anesthetized rats, B,
metabolite, 306U73, and imipramine reduced NE firing rate with i.v. ID50s
of 2.7, 1.4, and 0.45 mg/kg, resp. (and an i.p. ID50 of 12.6 mg/kg
for B). It was also stated that B
inhibited the firing rate of A9 and A10 dopamine neurons with i.p. ID50s
of 44 and 43 mg/kg, resp; imipramine at 16 mg/kg was said to be without
effect. (It was also stated that B, but
not its metabolites 306U73 and 494U73 decreased dopaminergic firing rates when
given i.v., but doses used were not stated).
It was further stated that B did not alter firing rates of dorsal raphe
serotonergic neurons up to a cumulative dose of 12.5 mg/kg i.v. or at a dose of
25 mg/kg i.p. (ID50 for imipramine = 16 mg/kg i.p.).
Several antidepressants are known to decrease the
firing rate of NE and/or 5HT neurons; this is though to represent a
compensatory response to increased synaptic levels of the respective
neurotransmitter, in turn caused by blockade of neurotransmitter
re-uptake. The mechanism of the
decreased firing in the case of B is not clear in that it is a relatively weak reuptake
blocker (and somewhat more potent vs DA
than NE). (Furthermore the decreased
firing rate is not a sufficient condition for the clinical antidepressant
effect of antidepressants in that the former occurs after acute dosing whereas
the latter occurs only after repeated dosing.)
However, even granting that the decrease in firing rate may be relevant
to the mechanism of antidepressant action of B, I do not think there are
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