In occasional susceptible patients or in those receiving anticholinergic drugs (including antiparkinsonism agents)
in addition, the atropine-like effects may become more pronounced (e.g., paralytic ileus).
Close supervision and careful adjustment of dosage is required when this drug is administered concomitantly with
Avoid the use of preparations such as decongestants and local anesthetics which contain any sympathomimetic amine
(e.g., epinephrine, norepinephrine), since it has been reported that tricyclic antidepressants can potentiate the
effects of catecholamines.
Caution should be exercised when imipramine hydrochloride is used with agents that lower blood pressure.
Imipramine Hcl hydrochloride may potentiate the effects of CNS depressant drugs.
The plasma concentration of imipramine may increase when the drug is given concomitantly with hepatic enzyme
inhibitors (e.g., cimetidine, fluoxetine) and decrease by concomitant administration of hepatic enzyme inducers
(e.g., barbiturates, phenytoin), and adjustment of the dosage of imipramine may therefore be necessary.
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 to 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 p.o.
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., 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 TCA5 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 cotherapy, 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.