Phenelzine for Depression

INDICATIONS AND USAGE Phenelzine Sulfate Tablets, USP has been found to be effective in depressed patients clinically characterized as "atypical," "nonendogenous," or "neurotic." These patients often have mixed anxiety and depression and phobic or hypochondriacal features. There is less conclusive evidence of its usefulness with severely depressed patients with endogenous features. Phenelzine Sulfate Tablets should rarely be the first antidepressant drug used. Rather, it is more suitable for use with patients who have failed to respond to the drugs more commonly used for these conditions.

DOSAGE AND ADMINISTRATION Initial dose The usual starting dose of Phenelzine Sulfate Tablets is one tablet (15 mg) three times a day. Early phase treatment Dosage should be increased to at least 60 mg per day at a fairly rapid pace consistent with patient tolerance. It may be necessary to increase dosage up to 90 mg per day to obtain sufficient MAO inhibition. Many patients do not show a clinical response until treatment at 60 mg has been continued for at least 4 weeks. Maintenance dose After maximum benefit from Phenelzine Sulfate Tablets is achieved, dosage should be reduced slowly over several weeks. Maintenance dose may be as low as one tablet, 15 mg, a day or every other day, and should be continued for as long as is required.

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 18–24) 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 18–24 5 additional cases Decreases Compared to Placebo 25–64 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 Phenelzine Sulfate Tablets 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 Phenelzine Sulfate Tablets are not approved for use in treating bipolar depression. It should be noted that Phenelzine Sulfate Tablets are not approved for use in treating any indications in the pediatric population. Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including Phenelzine Sulfate Tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. The most serious reactions to Phenelzine Sulfate Tablets involve changes in blood pressure. Hypertensive Crises The most important reaction associated with Phenelzine Sulfate Tablets administration is the occurrence of hypertensive crises, which have sometimes been fatal. These crises are characterized by some or all of the following symptoms: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea, vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin), dilated pupils, and photophobia. Either tachycardia or bradycardia may be present and can be associated with constricting chest pain. NOTE: Intracranial bleeding has been reported in association with the increase in blood pressure. Blood pressure should be observed frequently to detect evidence of any pressor response in all patients receiving Phenelzine Sulfate Tablets. Therapy should be discontinued immediately upon the occurrence of palpitation or frequent headaches during therapy. Recommended treatment in hypertensive crisis If a hypertensive crisis occurs, Phenelzine Sulfate Tablets should be discontinued immediately and therapy to lower blood pressure should be instituted immediately. On the basis of present evidence, phentolamine is recommended. (The dosage reported for phentolamine is 5 mg intravenously.) Care should be taken to administer this drug slowly in order to avoid producing an excessive hypotensive effect. Fever should be managed by means of external cooling. Warning to the Patient All patients should be warned that the following foods, beverages, and medications must be avoided while taking Phenelzine Sulfate Tablets, and for two

Drug Interactions In patients receiving nonselective monoamine oxidase (MAO) inhibitors in combination with serotoninergic agents (e.g., dexfenfluramine, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxine) there have been reports of serious, sometimes fatal, reactions. Because Phenelzine Sulfate Tablets is a monoamine oxidase (MAO) inhibitor, Phenelzine Sulfate Tablets should not be used concomitantly with a serotoninergic agent (See CONTRAINDICATIONS ). Administration of guanethidine to patients receiving an MAO inhibitor can produce moderate to severe hypertension due to release of catecholamines. At least two weeks should elapse between withdrawal of the MAO inhibitor and the initiation of guanethidine. (see CONTRAINDICATIONS ) Geriatric Use Clinical studies of Phenelzine Sulfate Tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS Phenelzine Sulfate Tablets is a potent inhibitor of monoamine oxidase. Because this enzyme is widely distributed throughout the body, diverse pharmacologic effects can be expected to occur. When they occur, such effects tend to be mild or moderate in severity (see below), often subside as treatment continues, and can be minimized by adjusting dosage; rarely is it necessary to institute counteracting measures or to discontinue Phenelzine Sulfate Tablets. Common side effects include: Nervous System —Dizziness, headache, drowsiness, sleep disturbances (including insomnia and hypersomnia), fatigue, weakness, tremors, twitching, myoclonic movements, hyperreflexia. Gastrointestinal —Constipation, dry mouth, gastrointestinal disturbances, elevated serum transaminases (without accompanying signs and symptoms). Metabolic —Weight gain. Cardiovascular —Postural hypotension, edema. Genitourinary —Sexual disturbances, eg, anorgasmia and ejaculatory disturbances and impotence. Less common mild to moderate side effects (some of which have been reported in a single patient or by a single physician) include: Nervous System —Jitteriness, palilalia, euphoria, nystagmus, paresthesias. Genitourinary —Urinary retention. Metabolic —Hypernatremia. Dermatologic —Pruritus, skin rash, sweating. Special Senses —Blurred vision, angle-closure glaucoma. Although reported less frequently, and sometimes only once, additional severe side effects include: Nervous System —Ataxia, shock-like coma, toxic delirium, manic reaction, convulsions, acute anxiety reaction, precipitation of schizophrenia, transient respiratory and cardiovascular depression following ECT. Gastrointestinal —To date, fatal progressive necrotizing hepatocellular damage has been reported in very few patients. Reversible jaundice. Hematologic —Leukopenia. Immunologic —Lupus-like syndrome Metabolic —Hypermetabolic syndrome (which may include, but is not limited to, hyperpyrexia, tachycardia, tachypnea, muscular rigidity, elevated CK levels, metabolic acidosis, hypoxia, coma and may resemble an overdose). Respiratory —Edema of the glottis. General —Fever associated with increased muscle tone. Withdrawal may be associated with nausea, vomiting, and malaise. An uncommon withdrawal syndrome following abrupt withdrawal of Phenelzine Sulfate Tablets has been infrequently reported. Signs and symptoms of this syndrome generally commence 24 to 72 hours after drug discontinuation and may range from vivid nightmares with agitation to frank psychosis and convulsions. This syndrome generally responds to reinstitution of low-dose Phenelzine Sulfate Tablets therapy followed by cautious downward titration and discontinuation.