2.0
Background
2.1
Indication
There
are almost 20 drugs approved as antidepressant medications in the U.S.A. Most of the antidepressants marketed are
thought to have their therapeutic action by inhibition of re-uptake of
norepinephrine or serotonin or by inhibition of monoamine oxidase. Approximately 75 per cent of depressed
patients who are treated with an antidepressant medication have good clinical
responses to the treatments. Rigorous
dietary restrictions associated with monoamine oxidase inhibitors and
significant levels of unwelcome side effects associated with most of the
tricyclic and tetracyclic antidepressants and with serotonin-selective reuptake
inhibitors limit the range of usefulness of these medications. Bupropion is an aminoketone in a class by
itself among the antidepressants, though it is structurally related to the
anoretic agent diethylpropion, a sympathomimetic with stimulant
properties. Bupropion is capable of
reducing firing rates of noradrenergic neurons in the locus ceruleus and, with
one exception, demonstrates a mild side effect profile. Clinical use of the drug is limited,
primarily, by the occurrence of seizures, particularly associated with high
serum levels of the substance and with patients with a predilection to seizures
or with histories of anorexia or bulimia.
To reduce the risk of seizures, bupropion is currently labeled for
prescription on a t.i.d. schedule that reduces the risk of seizure but also
makes compliance with medication intake difficult. Development of a sustained-release form of bupropion is expected
to allow for reduction of peak levels of bupropion and, therefore, reduce the
risk of seizures being induced by the medication. Provision of the medication on a b.i.d. instead of a t.id. basis
may allow for increased compliance with the treatment.
2.2
Related INDs and NDAs
See
section 1.2 above.
2.3
Administrative History
The
original IND for bupropion sustained-release was submitted 7/17/86. In a letter dated 3/25/91, the Division went
on record as stating that a clinical study demonstrating the safety and
efficacy of a sustained-release formulation of bupropion would not be
required. Data comparing the
pharmacokinetics of bupropion sustained-release and its active metabolites,
however, was still required.
At
a meeting with representatives of the firm on 1/28/1992, the Division stated
that any change in labeling regarding the incidence of seizure while on
bupropion sustained-release could only be considered if the sustained-release
formulation decreased Cmax demonstrated bioequivalency, and if the
firm could demonstrate convincingly that seizure incidence is directly
correlated with Cmax. In a
letter to the sponsor dated 3/16/93, the Division stated that transfer of
labeling regarding seizures from the Warnings to the Precautions section could
only be considered if the sponsor conducted a large enough study to conclude
reasonably that the incidence of seizure was less than 0.3%. If the firm could not demonstrate improved
or equivalent bioavailability, they would need to conduct two adequate and well
controlled clinical trials to support approval of the formulation.
2.4
Proposed Directions for Use
In
the proposed labeling, specified contraindications are seizure disorder,
current or past history of bulimia or anorexia nervosa, intake within the prior
two weeks of a monoamine oxidase inhibitor, or history of hypersensitivity to
the sustained-release or immediate release formulations of the compound. To reduce the potential risk of seizures
further, the proposed labeling encourages prescription of a maximum of 300
mg/day of the sustained-release formulation, avoiding single doses of the
compound that exceed 150 mg, and very gradual incrementation [incrimination]
of dose. The labeling further
discourages the use of the compound in patients who might be at higher risk of
seizure. Such patients might have a
history of seizure or cranial trauma, concurrent receipt of other psychoactive
medications that might reduce the seizure threshold, recent history of abrupt
discontinuation of benzodiazepine treatment, or other predispositions toward
seizure. When used as recommended by
the sponsor, the incidence of seizure with the
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