bit 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 interaction may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the ssri involved. nevertheless, caution is indicated in the coadministration 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 of particular importance, sufficient time must elapse before initiating tca treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).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 furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required.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. the plasma concentration of imipramine hydrochloride 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 hydrochloride may therefore be necessary. 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 imipramine hydrochloride is administered concomitantly with anticholinergic drugs. avoid the use of preparations, such as decongestants and local anesthetics, that 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 hydrochloride may potentiate the effects of cns depressant drugs. patients should be warned that imipramine hydrochloride may enhance the cns depressant effects of alcohol. (see warnings .)

major depressive disorder (mdd) and other psychiatric disorders. short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. the pooled analyses of placebo-controlled trials in children and adolescents with mdd, obsessive compulsive disorder (ocd), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. the pooled analyses of placebo-controlled trials in adults with mdd or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. there was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. there were differences in absolute risk of suicidality across the different indications, with the highest incidence in mdd. the risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. these risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in table 1 . table 1 age range drug-placebo difference in number of cases of suicidality per 1000 patients treated increases compared to placebo < 18 14 additional cases 18 to 24 5 additional cases decreases compared to placebo 25 to 64 1 fewer case ≥ 65 6 fewer cases no suicides occurred in any of the pediatric trials. there were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. it is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. however, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. all patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. the following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. such monitoring should include daily observation by families and caregivers. prescriptions for imipramine hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. screening patients for bipolar disorder: a major depressive episode may be the initial presentation of bipolar disorder. it is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. whether any of the symptoms described above represent such a conversion is unknown. however, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. it should be noted that imipramine hydrochloride is not approved for use in treating bipolar depression. angle-closure glaucoma the pupillary dilation that occurs following use of many antidepressant drugs including imipramine hydrochloride tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. children : a dose of 2.5 mg/kg/day of imipramine hydrochloride should not be exceeded in childhood. ecg changes of unknown significance have been reported in pediatric patients with doses twice this amount. extreme caution should be used when this drug is given to: patients with cardiovascular disease because of the possibility of conduction defects, arrhythmias, congestive heart failure, myocardial infarction, strokes and tachycardia. these patients require cardiac surveillance at all dosage levels of the drug; patients with history of urinary retention, or history of narrow-angle glaucoma because of the drug’s anticholinergic properties; hyperthyroid patients or those on thyroid medication because of the possibility of cardiovascular toxicity; patients with a history of seizure disorder because this drug has been shown to lower the seizure threshold; patients receiving guanethidine, clonidine, or similar agents, since imipramine hydrochloride may block the pharmacologic effects of these drugs; patients receiving methylphenidate hydrochloride. since methylphenidate hydrochloride may inhibit the metabolism of imipramine hydrochloride, downward dosage adjustment of imipramine hydrochloride may be required when given concomitantly with methylphenidate hydrochloride. imipramine hydrochloride may enhance the cns depressant effects of alcohol. therefore, it should be borne in mind that the dangers inherent in a suicide attempt or accidental overdosage with the drug may be increased for the patient who uses excessive amounts of alcohol. (see precautions .) since imipramine hydrochloride may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned accordingly.

day should be tried in children aged 6 and older. medication should be given one hour before bedtime. if a satisfactory response does not occur within one week, increase the dose to 50 mg nightly in children under 12 years; children over 12 may receive up to 75 mg nightly. a daily dose greater than 75 mg does not enhance efficacy and tends to increase side effects. evidence suggests that in early night bedwetters, the drug is more effective given earlier and in divided amounts, i.e., 25 mg in midafternoon, repeated at bedtime. consideration should be given to instituting a drug-free period following an adequate therapeutic trial with a favorable response. dosage should be tapered off gradually rather than abruptly discontinued; this may reduce the tendency to relapse. children who relapse when the drug is discontinued do not always respond to a subsequent course of treatment. a dose of 2.5 mg/kg/day should not be exceeded. ecg changes of unknown significance have been reported in pediatric patients with doses twice this amount. the safety and effectiveness of imipramine hydrochloride as temporary adjunctive therapy for nocturnal enuresis in children less than 6 years of age has not been established.

isturbances of accommodation, mydriasis; constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract. allergic : skin rash, petechiae, urticaria, itching, photosensitization; edema (general or of face and tongue); drug fever; cross-sensitivity with desipramine. hematologic : bone marrow depression including agranulocytosis; eosinophilia; purpura; thrombocytopenia. gastrointestinal : nausea and vomiting, anorexia, epigastric distress, diarrhea; peculiar taste, stomatitis, abdominal cramps, black tongue. endocrine : gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido, impotence; testicular swelling; elevation or depression of blood sugar levels; inappropriate antidiuretic hormone (adh) secretion syndrome. other: jaundice (simulating obstructive); altered liver function; weight gain or loss; perspiration; flushing, urinary frequency; drowsiness, dizziness, weakness and fatigue; headache; parotid swelling; alopecia; proneness to falling. withdrawal symptoms : though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache and malaise. note: in enuretic children treated with imipramine hydrochloride, the most common adverse reactions have been nervousness, sleep disorders, tiredness, and mild gastrointestinal disturbances. these usually disappear during continued drug administration or when dosage is decreased. other reactions which have been reported include constipation, convulsions, anxiety, emotional instability, syncope, and collapse. all of the adverse effects reported with adult use should be considered. postmarketing experience the following adverse drug reaction has been reported during post-approval use of imipramine. because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency. eye disorders: angle-closure glaucoma

bit 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 interaction may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the ssri involved. nevertheless, caution is indicated in the coadministration 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. the plasma concentration of imipramine hydrochloride 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 hydrochloride may therefore be necessary. 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 imipramine hydrochloride is administered concomitantly with anticholinergic drugs. avoid the use of preparations, such as decongestants and local anesthetics, that 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 hydrochloride may potentiate the effects of cns depressant drugs. patients should be warned that imipramine hydrochloride may enhance the cns depressant effects of alcohol. (see warnings .)

ide. patients should be advised that taking imipramine hydrochloride tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. open-angle glaucoma is not a risk factor for angle-closure glaucoma. patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. clinical worsening and suicide risk: patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.