needed, ecg monitoring should be maintained during the initiation of therapy and at appropriate intervals during stabilization of dose 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 the 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., 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 of particular importance, sufficient time must elapse before initiating tca treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).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 furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required.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. monoamine oxidase inhibitors (maois) (see contraindications , warnings , and dosage and administration .) serotonergic drugs (see contraindications , warnings , and dosage and administration .)

h 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 analysis of placebo-controlled trials in children and adolescents with mdd, obsessive compulsive disorder (ocd) or other psychiatric disorders including 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 with age strada 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 non-psychiatric, 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 trimipramine maleate should be written for the smallest quantity of capsules 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 depression 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 trimipramine maleate is not approved for use in treating bipolar depression. serotonin syndrome the development of a potentially life-threatening serotonin syndrome has been reported with snris and ssris, including trimipramine maleate, alone, but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and st. john’s wort) and with drugs that impair metabolism of serotonin (in particular, maois, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g, nausea, vomiting, diarrhea). patients should be monitored for the emergence of serotonin syndrome. the concomitant use of trimipramine maleate with maois intended to treat psychiatric disorders is contraindicated. trimipramine maleate should also not be started in a patient who is being treated with maois such as linezolid or intravenous methylene blue. all reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. no reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. there may be circumstances when it is necessary to initiate treatment with an maoi such as linezolid or intravenous methylene blue in a patient taking trimipramine maleate. trimipramine maleate should be discontinued before initiating treatment with the maoi (see contraindications and dosage and administration ). if concomitant use of trimipramine maleate with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and st. john’s wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. treatment with trimipramine maleate and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. angle-closure glaucoma the pupillary dilation that occurs following use of many antidepressant drugs including trimipramine maleate may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. general consideration for use extreme caution should be used when this drug is given to patients with any evidence of cardiovascular disease because of the possibility of conduction defects, arrhythmias, myocardial infarction, strokes, and tachycardia. caution is advised in patients with history of urinary retention 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 or similar agents, since trimipramine maleate may block the pharmacologic effects of these drugs. since the drug 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.

uld be used with caution in patients with impaired liver function. chronic animal studies showed occasional occurrence of hepatic congestion, fatty infiltration, or increased serum liver enzymes at the highest dose of 60 mg/kg/day. both elevation and lowering of blood sugar have been reported with tricyclic antidepressants.

to four weeks before a therapeutic response is noted. increasing the dose will not shorten this period but rather increase the incidence of adverse reactions. usual adult dose outpatients and office patients—initially, 75 mg/day in divided doses, increased to 150 mg/day. dosages over 200 mg/day are not recommended. maintenance therapy is in the range of 50 to 150 mg/day. for convenient therapy and to facilitate patient compliance, the total dosage requirement may be given at bedtime. hospitalized patients—initially, 100 mg/day in divided doses. this may be increased gradually in a few days to 200 mg/day, depending upon individual response and tolerance. if improvement does not occur in 2 to 3 weeks, the dose may be increased to the maximum recommended dose of 250 to 300 mg/day. adolescent and geriatric patients—initially, a dose of 50 mg/day is recommended, with gradual increments up to 100 mg/day, depending upon patient response and tolerance. maintenance—following remission, maintenance medication may be required for a longer period of time, at the lowest dose that will maintain remission. maintenance therapy is preferably administered as a single dose at bedtime. to minimize relapse, maintenance therapy should be continued for about three months. switching a patient to or from a monoamine oxidase inhibitor (maoi) intended to treat psychiatric disorders: at least 14 days should elapse between discontinuation of an maoi intended to treat psychiatric disorders and initiation of therapy with trimipramine maleate. conversely, at least 14 days should be allowed after stopping trimipramine maleate before starting an maoi intended to treat psychiatric disorders (see contraindications ). use of trimipramine maleate with other maois, such as linezolid or methylene blue : do not start trimipramine maleate in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. in a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see contraindications ). in some cases, a patient already receiving therapy with trimipramine maleate may require urgent treatment with linezolid or intravenous methylene blue. if acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, trimipramine maleate should be stopped promptly, and linezolid or intravenous methylene blue can be administered. the patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. therapy with trimipramine maleate may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see warnings ). the risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with trimipramine maleate is unclear. the clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see warnings ).

riasis, constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract. allergic skin rash, petechiae, urticaria, itching, photosensitization, edema of face and tongue. hematologic bone-marrow depression including agranulocytosis, eosinophilia; purpura; thrombocytopenia. leukocyte and differential counts should be performed in any patient who develops fever and sore throat during therapy; the drug should be discontinued if there is evidence of pathological neutrophil depression. 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. other jaundice (simulating obstructive); altered liver function; weight gain or loss; perspiration; flushing; urinary frequency; drowsiness, dizziness, weakness, and fatigue; headache; parotid swelling; alopecia. withdrawal symptoms though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise.

needed, ecg monitoring should be maintained during the initiation of therapy and at appropriate intervals during stabilization of dose 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 the 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., 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. monoamine oxidase inhibitors (maois) (see contraindications , warnings , and dosage and administration .) serotonergic drugs (see contraindications , warnings , and dosage and administration .)

ontainer as defined in the usp. preserve in tight container. protect from excessive heat. store at 20° to 25°c (68° to 77°f) [see usp controlled room temperature]. protect from moisture. keep this and all medication out of the reach of children. keep tightly closed. manufactured by: elite laboratories, inc. northvale, nj 07647 rev. 09/22 in0523

l 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. patients should be advised that taking trimipramine maleate 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.