DESCRIPTION
Celexa® (citalopram HBr) is an orally administered selective
serotonin reuptake inhibitor (SSRI) with a chemical structure unrelated to that
of other SSRIs or of tricyclic, tetracyclic, or other available antidepressant
agents. Citalopram HBr is a racemic bicyclic phthalane derivative designated
(±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile,
HBr with the following structural formula:
The molecular formula is C20H22BrFN2O and its molecular weight is
405.35.
Citalopram HBr occurs as a fine, white to off-white powder. Citalopram HBr is
sparingly soluble in water and soluble in ethanol.
Celexa (citalopram hydrobromide) is available as tablets or as an oral
solution.
Celexa 10 mg tablets are film-coated, oval tablets containing citalopram HBr
in strengths equivalent to 10 mg citalopram base. Celexa 20 mg and 40 mg tablets
are film-coated, oval, scored tablets containing citalopram HBr in strengths
equivalent to 20 mg or 40 mg citalopram base. The tablets also contain the
following inactive ingredients: copolyvidone, corn starch, crosscarmellose
sodium, glycerin, lactose monohydrate, magnesium stearate, hypromellose,
microcrystalline cellulose, polyethylene glycol, and titanium dioxide. Iron
oxides are used as coloring agents in the beige (10 mg) and pink (20 mg)
tablets.
Celexa oral solution contains citalopram HBr equivalent to 2 mg/mL citalopram
base. It also contains the following inactive ingredients: sorbitol, purified
water, propylene glycol, methylparaben, natural peppermint flavor, and
propylparaben.
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CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of citalopram HBr as an antidepressant is
presumed to be linked to potentiation of serotonergic activity in the central
nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of
serotonin (5-HT). In vitro and in
vivo studies in animals suggest that citalopram is a highly selective
serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE)
and dopamine (DA) neuronal reuptake. Tolerance to the inhibition of 5-HT uptake
is not induced by long-term (14-day) treatment of rats with citalopram.
Citalopram is a racemic mixture (50/50), and the inhibition of 5-HT reuptake by
citalopram is primarily due to the (S)-enantiomer.
Citalopram has no or very low affinity for 5-HT1A,
5-HT2A, dopamine D1 and D2, α1-, α2-, and
β-adrenergic, histamine H1, gamma aminobutyric acid
(GABA), muscarinic cholinergic, and benzodiazepine receptors. Antagonism of
muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be
associated with various anticholinergic, sedative, and cardiovascular effects of
other psychotropic drugs.
Pharmacokinetics
The single- and multiple-dose pharmacokinetics of citalopram are
linear and dose-proportional in a dose range of 10-60 mg/day. Biotransformation
of citalopram is mainly hepatic, with a mean terminal half-life of about 35
hours. With once daily dosing, steady state plasma concentrations are achieved
within approximately one week. At steady state, the extent of accumulation of
citalopram in plasma, based on the half-life, is expected to be 2.5 times the
plasma concentrations observed after a single dose. The tablet and oral solution
dosage forms of citalopram HBr are bioequivalent.
Absorption and Distribution
Following a single oral dose (40 mg tablet) of citalopram, peak
blood levels occur at about 4 hours. The absolute bioavailability of citalopram
was about 80% relative to an intravenous dose, and absorption is not affected by
food. The volume of distribution of citalopram is about 12 L/kg and the binding
of citalopram (CT), demethylcitalopram (DCT) and didemethylcitalopram (DDCT) to
human plasma proteins is about 80%.
Metabolism and Elimination
Following intravenous administrations of citalopram, the fraction
of drug recovered in the urine as citalopram and DCT was about 10% and 5%,
respectively. The systemic clearance of citalopram was 330 mL/min, with
approximately 20% of that due to renal clearance.
Citalopram is metabolized to demethylcitalopram (DCT), didemethylcitalopram
(DDCT), citalopram-N-oxide, and a deaminated propionic acid derivative. In
humans, unchanged citalopram is the predominant compound in plasma. At steady
state, the concentrations of citalopram's metabolites, DCT and DDCT, in plasma
are approximately one-half and one-tenth, respectively, that of the parent drug.
In vitro studies show that citalopram is at least 8
times more potent than its metabolites in the inhibition of serotonin reuptake,
suggesting that the metabolites evaluated do not likely contribute significantly
to the antidepressant actions of citalopram.
In vitro studies using human liver microsomes
indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the
N-demethylation of citalopram.
Population Subgroups
Age - Citalopram pharmacokinetics in subjects ≥ 60 years of age
were compared to younger subjects in two normal volunteer studies. In a
single-dose study, citalopram AUC and half-life were increased in the elderly
subjects by 30% and 50%, respectively, whereas in a multiple-dose study they
were increased by 23% and 30%, respectively. 20 mg is the recommended dose for
most elderly patients (see
DOSAGE AND
ADMINISTRATION).
Gender - In three pharmacokinetic studies (total N=32), citalopram AUC in
women was one and a half to two times that in men. This difference was not
observed in five other pharmacokinetic studies (total N=114). In clinical
studies, no differences in steady state serum citalopram levels were seen
between men (N=237) and women (N=388). There were no gender differences in the
pharmacokinetics of DCT and DDCT. No adjustment of dosage on the basis of gender
is recommended.
Reduced hepatic function - Citalopram oral clearance was reduced by 37% and
half-life was doubled in patients with reduced hepatic function compared to
normal subjects. 20 mg is the recommended dose for most hepatically impaired
patients (see
DOSAGE AND
ADMINISTRATION).
Reduced renal function - In patients with mild to moderate renal function
impairment, oral clearance of citalopram was reduced by 17% compared to normal
subjects. No adjustment of dosage for such patients is recommended. No
information is available about the pharmacokinetics of citalopram in patients
with severely reduced renal function (creatinine clearance < 20
mL/min).
Drug-Drug Interactions
In vitro enzyme inhibition data did
not reveal an inhibitory effect of citalopram on CYP3A4, -2C9, or -2E1, but did
suggest that it is a weak inhibitor of CYP1A2, -2D6, and -2C19. Citalopram would
be expected to have little inhibitory effect on in
vivo metabolism mediated by these cytochromes. However, in vivo data to address this question are limited.
Since CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of
citalopram, it is expected that potent inhibitors of 3A4 (e.g., ketoconazole,
itraconazole, and macrolide antibiotics) and potent inhibitors of CYP2C19 (e.g.,
omeprazole) might decrease the clearance of citalopram. However,
coadministration of citalopram and the potent 3A4 inhibitor ketoconazole did not
significantly affect the pharmacokinetics of citalopram. Because citalopram is
metabolized by multiple enzyme systems, inhibition of a single enzyme may not
appreciably decrease citalopram clearance. Citalopram steady state levels were
not significantly different in poor metabolizers and extensive 2D6 metabolizers
after multiple-dose administration of Celexa, suggesting that coadministration,
with Celexa, of a drug that inhibits CYP2D6, is unlikely to have clinically
significant effects on citalopram metabolism. See
Drug Interactions
under
PRECAUTIONS
for more detailed information on available
drug interaction data.
Clinical Efficacy Trials
The efficacy of Celexa as a treatment for depression was
established in two placebo-controlled studies (of 4 to 6 weeks in duration) in
adult outpatients (ages 18-66) meeting DSM-III or DSM-III-R criteria for major
depression. Study 1, a 6-week trial in which patients received fixed Celexa
doses of 10, 20, 40, and 60 mg/day, showed that Celexa at doses of 40 and 60
mg/day was effective as measured by the Hamilton Depression Rating Scale (HAMD)
total score, the HAMD depressed mood item (Item 1), the Montgomery Asberg
Depression Rating Scale, and the Clinical Global Impression (CGI) Severity
scale. This study showed no clear effect of the 10 and 20 mg/day doses, and the
60 mg/day dose was not more effective than the 40 mg/day dose. In study 2, a
4-week, placebo-controlled trial in depressed patients, of whom 85% met criteria
for melancholia, the initial dose was 20 mg/day, followed by titration to the
maximum tolerated dose or a maximum dose of 80 mg/day. Patients treated with
Celexa showed significantly greater improvement than placebo patients on the
HAMD total score, HAMD item 1, and the CGI Severity score. In three additional
placebo-controlled depression trials, the difference in response to treatment
between patients receiving Celexa and patients receiving placebo was not
statistically significant, possibly due to high spontaneous response rate,
smaller sample size, or, in the case of one study, too low a dose.
In two long-term studies, depressed patients who had responded to Celexa
during an initial 6 or 8 weeks of acute treatment (fixed doses of 20 or 40
mg/day in one study and flexible doses of 20-60 mg/day in the second study) were
randomized to continuation of Celexa or to placebo. In both studies, patients
receiving continued Celexa treatment experienced significantly lower relapse
rates over the subsequent 6 months compared to those receiving placebo. In the
fixed-dose study, the decreased rate of depression relapse was similar in
patients receiving 20 or 40 mg/day of Celexa.
Analyses of the relationship between treatment outcome and age, gender, and
race did not suggest any differential responsiveness on the basis of these
patient characteristics.
Comparison of Clinical Trial Results
Highly variable results have been seen in the clinical
development of all antidepressant drugs. Furthermore, in those circumstances
when the drugs have not been studied in the same controlled clinical trial(s),
comparisons among the results of studies evaluating the effectiveness of
different antidepressant drug products are inherently unreliable. Because
conditions of testing (e.g., patient samples, investigators, doses of the
treatments administered and compared, outcome measures, etc.) vary among trials,
it is virtually impossible to distinguish a difference in drug effect from a
difference due to one of the confounding factors just enumerated.
ANIMAL TOXICOLOGY
Retinal Changes in Rats
Pathologic changes (degeneration/atrophy) were observed in the
retinas of albino rats in the 2-year carcinogenicity study with citalopram.
There was an increase in both incidence and severity of retinal pathology in
both male and female rats receiving 80 mg/kg/day (13 times the maximum
recommended daily human dose of 60 mg on a mg/m2 basis).
Similar findings were not present in rats receiving 24 mg/kg/day for two years,
in mice treated for 18 months at doses up to 240 mg/kg/day, or in dogs treated
for one year at doses up to 20 mg/kg/day (4, 20, and 10 times, respectively, the
maximum recommended daily human dose on a mg/m2
basis).
Additional studies to investigate the mechanism for this pathology have not
been performed, and the potential significance of this effect in humans has not
been established.
Cardiovascular Changes in Dogs
In a one-year toxicology study, 5 of 10 beagle dogs receiving
oral doses of 8 mg/kg/day (4 times the maximum recommended daily human dose of
60 mg on a mg/m2 basis) died suddenly between weeks 17
and 31 following initiation of treatment. Although appropriate data from that
study are not available to directly compare plasma levels of citalopram (CT) and
its metabolites, demethylcitalopram (DCT) and didemethylcitalopram (DDCT), to
levels that have been achieved in humans, pharmacokinetic data indicate that the
relative dog-to-human exposure was greater for the metabolites than for
citalopram. Sudden deaths were not observed in rats at doses up to 120
mg/kg/day, which produced plasma levels of CT, DCT, and DDCT similar to those
observed in dogs at doses of 8 mg/kg/day. A subsequent intravenous dosing study
demonstrated that in beagle dogs, DDCT caused QT prolongation, a known risk
factor for the observed outcome in dogs. This effect occurred in dogs at doses
producing peak DDCT plasma levels of 810 to 3250 nM (39-155 times the mean
steady state DDCT plasma level measured at the maximum recommended human daily
dose of 60 mg). In dogs, peak DDCT plasma concentrations are approximately equal
to peak CT plasma concentrations, whereas in humans, steady state DDCT plasma
concentrations are less than 10% of steady state CT plasma concentrations.
Assays of DDCT plasma concentrations in 2020 citalopram-treated individuals
demonstrated that DDCT levels rarely exceeded 70 nM; the highest measured level
of DDCT in human overdose was 138 nM. While DDCT is ordinarily present in humans
at lower levels than in dogs, it is unknown whether there are individuals who
may achieve higher DDCT levels. The possibility that DCT, a principal metabolite
in humans, may prolong the QT interval in dogs has not been directly examined
because DCT is rapidly converted to DDCT in that species.
Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories,
Inc. St. Louis, MO 63045 USA
Licensed from H. Lundbeck A/S
Rev. 01/09
© 2009 Forest Laboratories, Inc.
Relabeling and Repackaging by:
Physicians Total Care, Inc. Tulsa, OK 74146
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