Brands, Medical Use, Clinical Data
- Anti-anxiety Agents
- Norepinephrine-Reuptake Inhibitors
- Histamine Antagonists
Brands / Synonyms
Adapin; Aponal; Curatin; Doxepin; Doxepin Hcl; Doxepin [Usan]; Doxepin, Hydrochloride; Doxepina [Inn-Spanish]; Doxepine; Doxepinum [Inn-Latin]; Novo-Doxepin; Quitaxon; Sinequan; Triadapin; Zonalon
For the treatment of psychoneurotic patients with depression and/or anxiety
Doxepin, a tricyclic antidepressant of the dibenzoxepin type, is used to treat depression and anxiety and, topically, pruritus associated with eczema. Doxepin has substantial anticholinergic and sedative effects.
Mechanism of Action
The mechanism of action of doxepin is not completely understood. It is thought that Like amitriptyline, doxepin enhances the actions of norepinephrine and serotonin by blocking their reuptake at the neuronal membrane. Doxepin may also act on histamine H1-receptors, resulting in sedative effects, and beta-adrenergic receptors.
well absorbed from the gut
LD50=26 (mg/kg) (in mice, iv); LD50=16 (mg/kg) (in rats, iv); Cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity.
Biotrnasformation / Drug Metabolism
SINEQUAN is contraindicated in individuals who have shown hypersensitivity to the drug. Possibility
of cross sensitivity with other dibenzoxepines should be kept in mind.
SINEQUAN is contraindicated in patients with glaucoma or a tendency to urinary retention. These
disorders should be ruled out, particularly in older patients.
Drugs Metabolized by P450 2D6: The biochemical activity of the drug metabolizing isozyme
cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7-10% of
Caucasians are so-called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme
activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than
expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction
of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase
in plasma AUC of the TCA).
In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble
poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of
these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not
metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other
antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective
serotonin reuptake inhibitors (SSRIs), e.g., citalopram, escitalopram, fluoxetine, sertraline, and paroxetine,
inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose
clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved.
Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from
one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a
patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5
weeks may be necessary).
Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may
require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore,
whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be
required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another
drug known to be an inhibitor of P450 2D6.
Doxepin is primarily metabolized by CYP2D6 (with CYP1A2 & CYP3A4 as minor pathways). Inhibitors or
substrates of CYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors [SSRIs]) may increase the plasma
concentration of doxepin when administered concomitantly. The extent of interaction depends on the variability of
effect on CYP2D6. The clinical significance of this interaction with doxepin has not been systematically
MAO Inhibitors: Serious side effects and even death have been reported following the
concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two
weeks prior to the cautious initiation of therapy with SINEQUAN. The exact length of time may vary and is dependent
upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage
Cimetidine: Cimetidine has been reported to produce clinically significant fluctuations in
steady-state serum concentrations of various tricyclic antidepressants. Serious anticholinergic symptoms (i.e.,
severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of
tricyclic antidepressant when cimetidine therapy is initiated. Additionally, higher than expected tricyclic
antidepressant levels have been observed when they are begun in patients already taking cimetidine. In patients who
have been reported to be well controlled on tricyclic antidepressants receiving concurrent cimetidine therapy,
discontinuation of cimetidine has been reported to decrease established steady-state serum tricyclic antidepressant
levels and compromise their therapeutic effects.
Alcohol: It should be borne in mind that alcohol ingestion may increase the danger inherent in
any intentional or unintentional SINEQUAN overdosage. This is especially important in patients who may use alcohol
Tolazamide: A case of severe hypoglycemia has been reported in a type II diabetic patient
maintained on tolazamide (1 gm/day) 11 days after the addition of doxepin (75 mg/day).