Protriptyline Hydrochloride

PROTRIPTYLINE HYDROCHLORIDE- protriptyline hydrochloride tablet
West-Ward Pharmaceuticals Corp.

Suicidality and Antidepressant Drugs

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of protriptyline hydrochloride or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Protriptyline hydrochloride is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)

DESCRIPTION

Protriptyline HCl is N -methyl-5H dibenzo[a,d ]-cycloheptene-5-propanamine hydrochloride. Its molecular formula is C19 H21 N•HCl and its structural formula is:

Protriptyline.jpg
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Protriptyline hydrochloride, a dibenzocycloheptene derivative, has a molecular weight of 299.84. It is a white crystalline powder that is freely soluble in water and soluble in dilute HCl. Protriptyline Hydrochloride Tablets USP are available for oral administration containing either 5 mg or 10 mg of protriptyline hydrochloride USP. Each tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, magnesium stearate and microcrystalline cellulose.

CLINICAL PHARMACOLOGY

Protriptyline hydrochloride is an antidepressant agent. The mechanism of its antidepressant action in man is not known. It is not a monoamine oxidase inhibitor, and it does not act primarily by stimulation of the central nervous system.

Protriptyline has been found in some studies to have a more rapid onset of action than imipramine or amitriptyline. The initial clinical effect may occur within one week. Sedative and tranquilizing properties are lacking. The rate of excretion is slow.

INDICATIONS AND USAGE

Protriptyline hydrochloride is indicated for the treatment of symptoms of mental depression in patients who are under close medical supervision. Its activating properties make it particularly suitable for withdrawn and anergic patients.

CONTRAINDICATIONS

Protriptyline hydrochloride is contraindicated in patients who have shown prior hypersensitivity to it.

It should not be given concomitantly with a monoamine oxidase inhibiting compound. Hyperpyretic crises, severe convulsions, and deaths have occurred in patients receiving tricyclic antidepressant and monoamine oxidase inhibiting drugs simultaneously. When it is desired to substitute protriptyline for a monoamine oxidase inhibitor, a minimum of 14 days should be allowed to elapse after the latter is discontinued. Protriptyline should then be initiated cautiously with gradual increase in dosage until optimum response is achieved.

Protriptyline hydrochloride is contraindicated in patients taking cisapride because of the possibility of adverse cardiac interactions including prolongation of the QT interval, cardiac arrhythmias and conduction system disturbances.

This drug should not be used during the acute recovery phase following myocardial infarction.

WARNINGS

Clinical Worsening and Suicide Risk

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 (ages 18 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 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.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see ADVERSE REACTIONS: Withdrawal Symptoms for a description of the risks of discontinuation of protriptyline).

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 protriptyline should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

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