SURMONTIL

Tricyclic antidepressant similar to imipramine, but with more antihistaminic and sedative properties.

For the treatment of depression and depression accompanied by anxiety, agitation or sleep disturbance

Trimipramine is a tricyclic antidepressant.

It was thought that tricyclic antidepressants work by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells.

However, this response occurs immediately, yet mood does not lift for around two weeks.

It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus.

The hippocampus is part of the limbic system, a part of the brain involved in emotions.

Presynaptic receptors are affected: a1 and b1 receptors are sensitized, a2 receptors are desensitised (leading to increased noradrenaline production).

Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain.

A precise mechanism for their analgesic action is unknown, but it is thought that they modulate anti-pain opioid systems in the CNS via an indirect serotonergic route.

They are also effective in migraine prophylaxis, but not in abortion of acute migraine attack.

The mechanism of their anti-migraine action is also thought to be serotonergic.

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Side effects include agitation, coma, confusion, convulsions, dilated pupils, disturbed concentration, drowsiness, hallucinations, high fever, irregular heart rate, low body temperature, muscle rigidity, overactive reflexes, severely low blood pressure, stupor, vomiting.

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (aged to 24) with 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 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 to 24 5 additional cases Decreases Compared to Placebo 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.

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.

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.

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.

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.

Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with trimipramine maleate or within 14 days of stopping treatment with trimipramine maleate is contraindicated because of an increased risk of serotonin syndrome.

The use of trimipramine maleate within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated See WARNINGS and DOSAGE AND ADMINISTRATION.

Starting trimipramine maleate in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome See WARNINGS and DOSAGE AND ADMINISTRTION.

Cross-sensitivity between trimipramine maleate and other dibenzazepines is a possibility.

The drug is contraindicated during the acute recovery period after a myocardial infarction.

Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance.

Lower dosages are recommended for elderly patients and adolescents.

Lower dosages are also recommended for outpatients as compared to hospitalized patients who will be under close supervision.

It is not possible to prescribe a single dosage schedule of trimipramine maleate that will be therapeutically effective in all patients.

The physical psychodynamic factors contributing to depressive symptomatology are very complex; spontaneous remissions or exacerbations of depressive symptoms may occur with or without drug therapy.

Consequently, the recommended dosage regimens are furnished as a guide which may be modified by factors such as the age of the patient, chronicity and severity of the disease, medical condition of the patient, and degree of psychotherapeutic support.

Most antidepressant drugs have a lag period of ten days 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.

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 to 150 mg/day. For convenient therapy and to facilitate patient compliance, the total dosage requirement may be given at bedtime.

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 to 3 weeks, the dose may be increased to the maximum recommended dose of 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.

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.

Capsules equivalent to 50 mg of Trimipramine are #2 Capsules, light blue opaque cap, medium orange opaque body, imprinted “A-294” in black ink on cap and body, filled with white to off-white powder.

Capsules are supplied in bottles of: 30 (NDC 72162-2062-03) with a child-resistant closure.

Dispense in a tight, light-resistant container as defined in the USP.

Preserve in tight container.

Protect from excessive heat.

Store at 20° to 25°C (68° to 77°F) .

Protect from

Keep this and all medication out of the reach of children.

Keep tightly closed.

Trimipramine maleate has shown evidence of embryotoxicity and/or increase incidence of major anomalies in rats or rabbits at doses 20 times the human dose.

There are no adequate and well-controlled studies in pregnant women.

Trimipramine maleate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Safety and effectiveness in the pediatric population have not been established.

Anyone considering the use of trimipramine maleate in a child or adolescent must balance the potential risks with the clinical need.

Clinical studies of trimipramine maleate were not adequate to determine whether subjects aged and over respond differently from younger subjects.

The pharmacokinetics of trimipramine were not substantially altered in the elderly.

Trimipramine maleate is known to be substantially excreted by the kidney.

Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered.

Greater sensitivity (e.g., confusional states, sedation) of some older individuals cannot be ruled out See ADVERSE REACTIONS.

In general, dose selection for an elderly patient should be cautious, usually starting at a lower dose See DOSAGE AND ADMINISTRATION.