Professional Information

Antidepressants, Monoamine Oxidase (MAO Inhibitor Systemic )

This monograph includes information on the following:

1) Isocarboxazid ^†
2) Phenelzine
3) Tranylcypromine

VA CLASSIFICATION
Primary: CN602
Secondary: CN900

Commonly used brand name(s): Marplan¹; Nardil²; Parnate³.

Note: This monograph does not cover other MAO inhibitors, such as furazolidone and procarbazine, which are not used as antidepressants, and selegiline, which has its own monograph.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:

Antidepressant—

antipanic agent—

headache (vascular; tension) prophylactic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Depression, major (treatment)—Isocarboxazid is indicated for the treatment of major depression^{125}. Because of its potentially serious side effects, it is not recommended as a first choice treatment of newly diagnosed depressed patients^{125}.
—Phenelzine is effective in the treatment of patients with major depression with or without melancholia ^{04} ^{61} ^{115}, or with atypical, nonendogenous depression, or depressive neurosis ^{39} ^{61} ^{65} ^{115}. These patients often have mixed anxiety and depression with phobic or hypochondriacal features ^{61} ^{65} ^{115}. Phenelzine is more often used as a second-line antidepressant in patients who have failed to respond to other antidepressants ^{01} ^{61} ^{115}. Nevertheless, many clinicians may consider phenelzine the first choice for treatment of certain dysphorias and minor periodic or chronic depressions ^{04} (dysthymic disorders) ^{20}.
—Tranylcypromine is indicated for treatment of major depression [ with or] without melancholia in closely supervised adult patients not responding to or unable to tolerate other antidepressants ^{62} ^{113}. [It is also used to treat the depressed phase of bipolar disorder and depressive neurosis ^{39} of moderate to severe intensity ^{63} .]

[Panic disorder (treatment)]¹—Phenelzine and, to a lesser extent, tranylcypromine are used in conjunction with psychotherapy and behavioral therapy in the treatment of panic disorder, with or without agoraphobia ^{04} ^{20} ^{66} ^{70} ^{89} ^{90} ^{91} ^{100}.

[Headache, vascular (prophylaxis) ]¹or
[Headache, tension (prophylaxis)]¹—Monoamine oxidase inhibitors are used in the prophylaxis of vascular headaches (including migraine) ^{92} ^{93} ^{94} ^{95} ^{96} ^{97} ^{98} ^{99}, tension-type headaches ^{96} ^{97}, and mixed headache syndrome ^{92} ^{95} ^{96}. However, due to potentially severe side effects, these agents are not considered first-line therapy ^{92} ^{95} ^{96}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Isocarboxazid: 231.26
    Phenelzine sulfate: 234.27
    Tranylcypromine sulfate: 364.46

Mechanism of action/Effect:

The exact mechanism of antidepressant effect is unknown; however, it is established that the activity of the enzyme monoamine oxidase (MAO) is inhibited. MAO subtypes A and B are involved in the metabolism of serotonin and catecholamine neurotransmitters such as epinephrine, norepinephrine, and dopamine ^{54}. Phenelzine, isocarboxazid, and tranylcypromine, as nonselective MAO inhibitors, bind irreversibly to monoamine oxidase–A (MAO-A) and monoamine oxidase–B (MAO-B). ^{04} ^{08}^{125} The reduced MAO activity results in an increased concentration of these neurotransmitters in storage sites throughout the central nervous system (CNS) ^{62} ^{63} ^{113} and sympathetic nervous system ^{40}. This increased availability of one or more monoamines has been thought to be the basis for the antidepressant activity of MAO inhibitors. The effects of the nonselective MAO inhibitors isocarboxazid, phenelzine, and tranylcypromine lead to downregulation (desensitization) of alpha ₂- or beta-adrenergic and serotonin receptors. It is thought that changes in receptor characteristics produced by chronic administration of MAO inhibitors correlate better with antidepressant action than does the increased activity of the neuron secondary to increased neurotransmitter concentrations ^{20}, and may also account for the delay of 2 to 4 weeks in therapeutic response. ^{08} ^{09}

Other actions/effects:

MAO inhibitors exhibit a hypotensive effect, which varies with the specific agent; the hypotensive mechanism of action is probably mediated through central inhibition of vasomotor centers ^{04}, or it may be due to chronic accumulation of the false neurotransmitter octopamine in adrenergic terminals ^{69} ^{109}.

MAO inhibitors prevent the inactivation of tyramine by hepatic and gastrointestinal monoamine oxidase. Circulating tyramine releases norepinephrine from the sympathetic nerve terminals and produces a sudden increase in blood pressure. ^{24} ^{108}

Absorption:

Well absorbed from the gastrointestinal tract ^{32} ^{69}.

Biotransformation:

Hepatic ^{32} ^{72}; rapid; by oxidation; possible active metabolites.

Onset of action:

As early as 7 to 10 days with appropriate dosage in some patients, but may take up to 4 to 8 weeks to achieve full therapeutic effect.

Time to peak plasma concentration

Phenelzine—2 to 4 hours after oral dose ^{08}.

Tranylcypromine—1 to 3.5 hours ^{21}.

Duration of action:

At least 10 days ^{36} ^{62} ^{64} ^{113} for MAO activity to be recovered because of irreversible binding.

Elimination:
    Renal, as metabolites ^{33}.

Precautions to Consider

Tumorigenicity

Phenelzine ^{20}, like other hydrazine derivatives, has been reported in an uncontrolled lifetime study to induce pulmonary and vascular tumors in mice ^{61}.

Pregnancy/Reproduction

Pregnancy—
Tranylcypromine ^{62} ^{113} (and probably phenelzine) crosses the placenta. A limited study in humans reported an increased risk of fetal malformations when these medications were administered in the first trimester ^{73}.

Animal studies have shown that MAO inhibitors, in doses much higher than the maximum recommended human dose (MRHD), cause hyperexcitability ^{60} ^{114} and a reduced rate of growth in the neonate ^{60} ^{61} ^{114} ^{115}.

For isocarboxazid: FDA Pregnancy Category C^{125}

For phenelzine: FDA Pregnancy Category C ^{115}.

For tranylcypromine: FDA pregnancy category not currently included in product labeling ^{113} ^{114}.

Breast-feeding

Tranylcypromine is distributed into human breast milk ^{62} ^{72} ^{113}; it is not known whether phenelzine or isocarboxazid is distributed into human breast milk ^{32}^{125}. Problems in humans have not been documented.

Pediatrics

Appropriate studies on the relationship of age to the effects of MAO inhibitors have not been performed in children younger than 16 years of age. Safety and efficacy have not been established. ^{36} ^{60} ^{61} ^{65} ^{114} ^{115}^{125} Animal studies have shown that these medications may cause growth retardation in the young ^{60} ^{61} ^{114} ^{115}.

Geriatrics

Experience with the use of MAO inhibitors in the elderly is relatively limited. However, there have been reports that phenelzine is safe and effective in the treatment of elderly depressed patients with a history of atypical depression or depressive neurosis. ^{04} ^{20} MAO inhibitors may also be useful for anergic or apathetic retarded depressions ^{04} ^{05}. The potential for increased vascular accidents ^{62} ^{113} (especially in the event of sudden hypertensive episodes), increased sensitivity to hypotensive effects, and reduced metabolic capacity discourages the first-time use of MAO inhibitors in patients over 60 years of age. When an MAO inhibitor is prescribed for an elderly patient, the patient's history of depression ^{20}, ability to comply with prescribing instructions, and any potential drug interactions must also be considered. ^{04} ^{05}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol ^{61} ^{62} ^{63} ^{65} ^{67} ^{113} ^{115}^{125} or
» CNS depression–producing medications, other, ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{67} ^{68} ^{113} ^{114} ^{115}^{125} (see Appendix II )    (concurrent use with MAO inhibitors may increase CNS depressant effects )

    (also, possible tyramine content in some alcoholic beverages, especially beer, wine, or ale, may induce hypertensive reactions)

    (in addition to additive CNS depressant effects caused by some antihypertensives such as clonidine, guanabenz, methyldopa, metyrosine, and pargyline, postural hypotension may be aggravated ^{04}^{125})

» Anesthetics, local, with epinephrine or levonordefrin ^{60} ^{61} ^{62} ^{65} ^{70} ^{113} ^{114} ^{115}^{125} or
» Cocaine ^{60} ^{61} ^{62} ^{65} ^{70} ^{83} ^{113} ^{114} ^{115}^{125}    (concurrent use with MAO inhibitors may cause severe hypertension due to sympathomimetic effects)

    (cocaine should not be administered during or within 14 days following administration of an MAO inhibitor; phenelzine also inhibits cholinesterase activity and may reduce or slow cocaine metabolism, thereby increasing the risk of cocaine toxicity ^{25})

Anesthetics, spinal ^{60} ^{61} ^{65} ^{114} ^{115}^{125}    (use of MAO inhibitors in patients receiving local anesthetics via subarachnoid block may increase the risk of hypotension ^{60} ^{61} ^{114} ^{115}; discontinuation of MAO inhibitors 10 days before elective surgery may be advisable ^{60} ^{61} ^{62} ^{113} ^{114} ^{115}; however, to avoid interruption of antidepressant therapy, patients receiving long-term MAO inhibition may undergo surgery without discontinuation of the MAO inhibitor; dosages of the anesthetic must be adjusted carefully ^{44} ^{45})

Anticholinergics or other medications with anticholinergic activity ^{64} ^{93} ^{101} (see Appendix II ) or
Antidyskinetic agents ^{63} or
Antihistamines ^{50} ^{62} ^{66} ^{113}^{125}    (concurrent use with MAO inhibitors may intensify the anticholinergic effects of these medications because of secondary anticholinergic activities of MAO inhibitors)

    (also, concurrent use with MAO inhibitors may block detoxification of anticholinergics, thus potentiating their action ^{49}; patients should be advised to report occurrence of gastrointestinal problems promptly since paralytic ileus may occur with concurrent therapy)

    (concurrent use with MAO inhibitors may also prolong and intensify the CNS depressant and anticholinergic effects of antihistamines; concurrent use is not recommended ^{50})

Anticoagulants, coumarin- or indandione-derivative    (concurrent use may increase anticoagulant activity; although the mechanism of action and clinical significance are unknown, caution is recommended)

Anticonvulsants    (in addition to increasing CNS depressant effects, concurrent use with MAO inhibitors may cause a change in the pattern of epileptiform seizures; dosage adjustment of anticonvulsant may be necessary)

» Antidepressants, tricyclic ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{67} ^{68} ^{69} ^{70} ^{83} ^{112} ^{113} ^{114} ^{115}^{125} or
» Fluoxetine ^{40} ^{59} ^{62} ^{112} ^{113} ^{114} ^{115}^{125} or
» Paroxetine ^{124}^{125} or
» Sertraline ^{116} ^{117} ^{118} ^{119} ^{120} ^{121} ^{122}^{125} or
» Trazodone ^{112}    (a potentially lethal hyperserotonergic state known as the serotonin syndrome may occur as the result of combining serotonergic agents [such as amitriptyline, clomipramine, doxepin, or imipramine; fluoxetine, paroxetine, or sertraline; or trazodone] with MAO inhibitors. The syndrome may be manifested by mental status changes [confusion, hypomania], restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, and/or fever. If recognized early, the syndrome usually resolves quickly upon withdrawal of the offending agents ^{111})

    (in addition to increased anticholinergic effects, concurrent use of tricyclic antidepressants with MAO inhibitors has resulted in an increased risk of hyperpyretic episodes, hypertensive crises, severe convulsions, and death; however, recent studies have shown that some tricyclic antidepressants can be used concurrently with MAO inhibitors for refractory depression with no adverse effects if both medications are initiated simultaneously at lower than usual doses and the doses raised gradually, or if the MAO inhibitor is gradually added to the tricyclic, also at low doses; tricyclics should not be added to an established MAO inhibitor regimen; clomipramine, desipramine, imipramine, nortriptyline, and protriptyline are not recommended for use in such a regimen ^{35} ^{83}; careful monitoring for side effects of either medication is necessary ^{20})

    (concurrent use of fluoxetine with MAO inhibitors may result in confusion, agitation, restlessness, and gastrointestinal symptoms, or possibly hyperpyretic episodes, severe convulsions, and hypertensive crises. Based on experience with tricyclic antidepressants, at least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of fluoxetine. ^{40} ^{113}^{125} However, because of the long half-lives of fluoxetine and its active metabolite, at least 5 weeks [approximately 5 half-lives of norfluoxetine] should elapse between discontinuation of fluoxetine and initiation of therapy with an MAO inhibitor ^{59} ^{62} ^{113} ^{114} ^{115}^{125}. Administration of an MAO inhibitor within 5 weeks of discontinuation of fluoxetine may increase the risk of serious events. While a causal relationship to fluoxetine has not been established, death has been reported following the initiation of an MAO inhibitor shortly after fluoxetine administration was stopped ^{59})

» Antidiabetic agents, oral ^{66} ^{67} ^{68} or
» Insulin ^{64} ^{66} ^{68} ^{70}    (hypoglycemic effects may be enhanced by MAO inhibitors; reduction in dosage of hypoglycemic medication may be necessary during and after concurrent therapy )

Antihypertensive medications^{125}    (isocarboxazid may have a marked potentiating effect on antihypertensive drugs, resulting in hypotension^{125})

Beta-adrenergic blocking agents ^{61} ^{67} ^{68} ^{81} ^{115}    (a few cases of significant bradycardia have been reported in elderly patients receiving a beta-adrenergic blocking agent concurrently with phenelzine; monitoring of pulse rate during concurrent administration has been recommended ^{81})

Bromocriptine    (concurrent use may increase serum prolactin concentrations and interfere with effects of bromocriptine; dosage adjustment of bromocriptine may be necessary )

» Bupropion    (concurrent use of MAO inhibitors with bupropion may increase the risk of acute bupropion toxicity and is contraindicated; a medication-free interval of at least 2 weeks should elapse between discontinuation of the MAO inhibitor and initiation of bupropion therapy ^{115} ^{123}^{125})

» Buspirone    (concurrent use with MAO inhibitors is not recommended because elevation of blood pressure may occur ^{46} ^{47} ^{60} ^{61} ^{62} ^{63} ^{113} ^{114} ^{115}^{125}; at least 10 days should elapse between discontinuation of one medication and initiation of the other ^{60} ^{61} ^{62} ^{113} ^{114} ^{115}^{125})

» Caffeine-containing medications ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{83} ^{113} ^{114} ^{115}^{125}    (concurrent use of excessive amounts of caffeine, consumed in coffee, tea, cola, chocolate, or ``stay awake"" products, with MAO inhibitors may produce dangerous cardiac arrhythmias or severe hypertension because of sympathomimetic side effects of caffeine)

» Carbamazepine ^{60} ^{61} ^{62} ^{63} ^{113} ^{114} ^{115}^{125} or
» Cyclobenzaprine ^{60} ^{61} ^{62} ^{63} ^{66} ^{68} ^{113} ^{114} ^{115}^{125} or
» Maprotiline ^{60} ^{61} ^{62} ^{63} ^{113} ^{114} ^{115}^{125} or
» Monoamine oxidase (MAO) inhibitors, other ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{68} ^{113} ^{114} ^{115}^{125} , including furazolidone, procarbazine ^{61} ^{62} ^{113} ^{115}^{125} , or selegiline    (concurrent use with MAO inhibitors has resulted in hyperpyretic crises, hypertensive crises, severe convulsions, and death; a medication-free interval of at least 2 weeks should elapse between discontinuation of one medication and initiation of another; for patients switching from one MAO inhibitor to another, an interval of 2 weeks is recommended)

    (in addition, MAO inhibitors cause a change in the pattern of epileptiform seizures in patients receiving carbamazepine as an anticonvulsant ^{48})

» Dextromethorphan ^{60} ^{61} ^{62} ^{63} ^{67} ^{113} ^{114} ^{115}^{125}    (concurrent use with MAO inhibitors may cause excitation, hypertension ^{52}, and hyperpyrexia)

Diuretics ^{60} ^{61} ^{62} ^{64} ^{65} ^{113} ^{114} ^{115}    (concurrent use with MAO inhibitors may result in an increased hypotensive effect)

» Doxapram ^{67}    (concurrent use may increase the pressor effects of either doxapram or the MAO inhibitor)

» Guanadrel ^{68}^{125} or
» Guanethidine ^{61} ^{62} ^{63} ^{65} ^{67} ^{68} ^{83} ^{113} ^{114} or
» Rauwolfia alkaloids ^{60} ^{61} ^{63} ^{65} ^{67} ^{83} ^{115}    (concurrent use with these agents may result in moderate to severe hypertension due to release of catecholamines; withdrawal of MAO inhibitor at least 1 week prior to initiation of therapy with these agents is recommended)

    (when an MAO inhibitor is added to existing therapy with a rauwolfia alkaloid, serious potentiation of CNS depressant effects may result; however, if a rauwolfia alkaloid is added to an MAO inhibitor regimen, CNS excitation and hypertension may result from release of excessive amounts ^{04} of accumulated norepinephrine and serotonin ^{02})

Haloperidol or
Loxapine or
Molindone or
Phenothiazines ^{62} ^{63} ^{67} ^{113}^{125} or
Pimozide or ^{37}
Thioxanthenes    (concurrent use may prolong and intensify the sedative, hypotensive, and anticholinergic effects of either these medications or MAO inhibitors)

» Levodopa ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{66} ^{67} ^{68} ^{83} ^{113} ^{114} ^{115}^{125}    (concurrent use with MAO inhibitors is not recommended, as the combination may result in sudden moderate to severe hypertensive crisis; it is recommended that MAO inhibitors be discontinued for 2 to 4 weeks prior to initiation of levodopa therapy ^{68})

» Meperidine, and possibly other opioid (narcotic) analgesics ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{67} ^{68} ^{70} ^{71} ^{83} ^{113} ^{114} ^{115}^{125}    (concurrent use with MAO inhibitors may produce immediate excitation, sweating, rigidity, and severe hypertension; in some patients, hypotension, severe respiratory depression, coma, convulsions, hyperpyrexia, vascular collapse, and death may occur; reactions may be due to accumulation of serotonin resulting from MAO inhibition; avoidance of meperidine use within 2 to 3 weeks following MAO inhibition is recommended ^{62} ^{113}; other opioid analgesics such as morphine are not likely to cause such severe reactions and may be used cautiously in reduced dosage in patients receiving MAO inhibitors; however, it is recommended that a small test dose [1/4 of the usual dose] or several small incremental test doses over a period of several hours should first be administered to permit observation of any adverse effects ^{12}; caution is also recommended in the use of alfentanil, fentanyl, or sufentanil as an adjunct to anesthesia if the patient has received an MAO inhibitor within 14 days; although the risk of a significant interaction has been questioned, the use of a small test dose is advised to detect any possible interaction)

» Methyldopa ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{83} ^{113} ^{114} ^{115}^{125}    (may cause hyperexcitability in patients receiving an MAO inhibitor; also headache, severe hypertension, and hallucinations have been reported with concurrent use)

» Methylphenidate ^{61} ^{66} ^{68} ^{83} ^{115}^{125}    (concurrent use with MAO inhibitors may potentiate the CNS stimulant effects of methylphenidate, possibly resulting in a hypertensive crisis; methylphenidate should not be administered during or within 14 days following the administration of MAO inhibitors)

Metrizamide ^{62} ^{63} ^{113}    (concurrent use with MAO inhibitors may lower the seizure threshold and increase the risk of seizures; MAO inhibitors should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours after procedure)

Phenylephrine, nasal or ophthalmic ^{61} ^{64} ^{66} ^{67} ^{70} ^{115}    (if significant systemic absorption of nasal or ophthalmic phenylephrine occurs, concurrent use with MAO inhibitors may potentiate the pressor effect of phenylephrine; nasal or ophthalmic phenylephrine should not be administered during or within 14 days following the administration of an MAO inhibitor )

Succinylcholine ^{67}    (concurrent use with phenelzine may decrease plasma concentrations or activity of pseudocholinesterase, the enzyme that metabolizes succinylcholine, thereby enhancing the neuromuscular blockade of succinylcholine and possibly resulting in prolonged respiratory depression or apnea)

» Sympathomimetics ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{66} ^{67} ^{68} ^{70} ^{83} ^{113} ^{114} ^{115}^{125}    (concurrent use with MAO inhibitors may prolong and intensify cardiac stimulant and vasopressor effects [including headache, cardiac arrhythmias, vomiting, sudden and severe hypertensive and hyperpyretic crises] of these medications because of release of catecholamines that accumulate in intraneuronal storage sites during MAO inhibitor therapy; these medications should not be administered during or within 14 days following the administration of an MAO inhibitor )

» Tryptophan ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{67} ^{113} ^{114} ^{115}^{125}    (concurrent use with MAO inhibitors may cause hyperreflexia, shivering, hyperventilation, hyperthermia, mania or hypomania, and disorientation or confusion; if tryptophan is added to an MAO inhibitor regimen, especially tranylcypromine, it should be started in low dosages and the dose titrated upwards gradually with close monitoring of mental status and blood pressure ^{10} ^{11} ^{12})

» Tyramine- or other high pressor amine–containing foods and beverages ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{67} ^{68} ^{69} ^{70} ^{83} ^{113} ^{114} ^{115}^{125} , such as aged cheese ^{51} ^{83} ^{84} ^{85} ^{86} ^{87}^{125} ; fava or broad bean pods ^{51} ^{83} ^{85} ^{86} ^{87}^{125} ; yeast/protein extracts ^{51} ^{83} ^{84} ^{85} ^{86} ^{87}^{125} ; smoked or pickled meats, poultry, or fish ^{32} ^{51} ^{83} ^{86} ^{87}^{125} ; fermented sausage (bologna, pepperoni, salami, summer sausage) or other fermented meat ^{51} ^{83} ^{85} ^{86}^{125} ; sauerkraut ^{82} ^{85}^{125} ; any overripe fruit ^{51} ^{86} ; beer ^{27} ^{51}^{125}; reduced-alcohol and alcohol-free beer and wine ^{36} ^{37} ^{88}^{125} ; red and white wines ^{36} ^{37} ^{38} ^{39} ^{51}^{125} ; sherry ^{51}^{125} ; and liqueurs ^{51}    (concurrent use with MAO inhibitors may cause sudden and severe hypertensive reactions; reactions are usually limited to a few hours and easily treated with rapidly acting hypotensive agents [such as labetolol, nifedipine, or if necessary in severe cases refractory to other agents, phentolamine] ^{55} ^{74} ^{75} ^{76}; severity depends on amount of tyramine ingested, rate of gastric emptying, and length of interval between dose of MAO inhibitor and ingestion of tyramine ^{24}; when MAO inhibitors are discontinued, dietary restrictions must continue for at least 2 weeks ^{61} ^{64} ^{70} ^{115}; other tyramine- or high pressor amine–containing foods, such as yogurt, sour cream, cream cheese, cottage cheese, chocolate, and soy sauce, if eaten when fresh and in moderation, are considered unlikely to cause serious problems ^{51} ^{83} ^{86} ^{87})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problems exist:
» Alcoholism, active
» Congestive heart failure ^{34} ^{60} ^{61} ^{64} ^{65} ^{114} ^{115}
» Hepatic function impairment, severe ^{60} ^{62} ^{63} ^{64} ^{65} ^{113} ^{114}^{125}    (hepatic precoma may be precipitated in patients with cirrhosis, who are extremely sensitive to effects of MAO inhibitors)

» Pheochromocytoma ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{113} ^{114} ^{115}^{125}    (pressor substances secreted by such tumors may alter blood pressure during therapy with MAO inhibitors)

» Renal function impairment, severe ^{60} ^{61} ^{63} ^{64} ^{114} ^{115}^{125}    (cumulative effects of MAO inhibitors may occur because of reduced renal excretion)

Sensitivity to any MAO inhibitor, including furazolidone, procarbazine, or selegiline ^{60} ^{61} ^{64} ^{65} ^{114} ^{115}^{125}
Risk-benefit should be considered when the following medical problems exist
Asthma ^{66} or bronchitis    (medications used in the treatment of these conditions may interact with MAO inhibitors)

Bipolar disorder ^{60} ^{61} ^{63} ^{64} ^{65} ^{102} ^{114} ^{115}    (switch from depressive to manic phase may occur)

» Cardiac arrhythmias
» Cardiovascular disease ^{60} ^{62} ^{63} ^{64} ^{65} ^{113} ^{114} or coronary insufficiency ^{04} or
Cerebrovascular disease ^{60} ^{62} ^{63} ^{64} ^{65} ^{113} ^{114}^{125}    (ischemia may be aggravated as a result of reduced blood pressure ^{62} ^{63} ^{113}; however, in patients with serious heart block or a conduction disturbance, an MAO inhibitor may be preferred to a tricyclic antidepressant because of significant slowing of resting pulse [heart rate] ^{38} or shortening of the PR and ^{13} ^{20} ^{31} QT intervals, and a significant decrease in blood pressure)

Diabetes mellitus ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{113} ^{114} ^{115}    (insulin or oral hypoglycemic requirements may be altered)

Epilepsy ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{113} ^{114} ^{115}    (pattern of epileptiform seizures may be changed)

» Headaches, severe or frequent ^{60} ^{61} ^{62} ^{65} ^{113} ^{114} ^{115}    (headache as a first sign of hypertensive reaction during therapy may be masked)

» Hepatic function impairment ^{60} ^{62} ^{63} ^{64} ^{65} ^{113} ^{114}^{125}    (hepatic precoma may be precipitated in patients with cirrhosis, who are extremely sensitive to effects of MAO inhibitors)

» Hypertension ^{60} ^{62} ^{63} ^{64} ^{65} ^{113} ^{114}^{125}    (use of MAO inhibitors is not recommended in patients on multiple-drug therapy since hypotensive effects may be potentiated; hypertensive crises resulting from dietary lapses may be more severe in hypertensive patients ^{13} ^{14})

Hyperthyroidism ^{62} ^{63} ^{113}^{125}    (sensitivity to pressor amines may be increased)

Parkinson"s disease ^{62} ^{113}    (may be aggravated)

» Renal function impairment ^{60} ^{61} ^{62} ^{63} ^{64} ^{113} ^{114} ^{115}    (cumulative effects may occur)

» Schizophrenia ^{60} ^{61} ^{63} ^{64} ^{65} ^{102} ^{114} ^{115}    (MAO inhibitors may aggravate psychosis and/or cause excessive stimulation in schizophrenic patients)

» Suicidal tendencies ^{60} ^{61} ^{62} ^{63} ^{65} ^{113} ^{114} ^{115}^{125}    (patients may continue to exhibit suicidal tendencies because significant improvement may not occur for several weeks after initiation of therapy with MAO inhibitors)

» Caution is required also in patients who have undergone sympathectomy; these patients may be more sensitive to the hypotensive effects of MAO inhibitors ^{04} .

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood pressure measurements ^{61} ^{62} ^{63} ^{65} ^{113} ^{115}    (careful and frequent monitoring is recommended because of the variety of factors that may produce dangerous alterations in pressure during therapy )

Hepatic function determinations ^{60} ^{64} ^{114}    (although rare, drug-induced hepatitis has occurred with MAO inhibitor therapy )

Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent

Orthostatic hypotension ^{32} ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{70} ^{113} ^{114} ^{115}^{125} , severe (dizziness or lightheadedness, especially when getting up from a lying or sitting position)

Note: Falling or fainting may result. Orthostatic hypotension occurs in hypertensive as well as normal and hypotensive patients ^{62} ^{63} ^{113}. Reduction in the dosage of MAO inhibitor may be required to bring blood pressure up to pretreatment levels.

Incidence less frequent

Diarrhea ^{62} ^{63} ^{113}^{125}

peripheral edema ^{32} ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{70} ^{113} ^{114} ^{115} (swelling of feet and lower legs)

sympathetic stimulation (fast or pounding heartbeat; unusual excitement or nervousness)^{60}^{62}^{63}^{64}^{113}^{114}

Note: Edema may subside spontaneously within a week. However, if edema persists, electrolytes should be monitored to rule out syndrome of inappropriate antidiuretic hormone secretion (SIADH). ^{32}

Incidence rare

Hepatitis ^{60} ^{61} ^{62} ^{63} ^{65} ^{113} ^{114} ^{115} (dark urine; skin rash; yellow eyes or skin)

leukopenia ^{29} ^{61} ^{62} ^{63} ^{65} ^{113} ^{115} (fever; sore throat)

parkinsonian syndrome (slurred speech; staggering gait)^{22}^{23}

Note: A potentially lethal hyperserotonergic state known as the serotonin syndrome may occur, typically as the result of combining serotonergic agents (such as amitriptyline, clomipramine, doxepin, or imipramine; fluoxetine, paroxetine, or sertraline; or trazodone) with MAO inhibitors. The syndrome may be manifested by mental status changes (confusion, hypomania), restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, and fever. If recognized early, the syndrome usually resolves quickly upon withdrawal of the offending agents. ^{111}

Symptoms of hypertensive crisis

Severe chest pain

enlarged pupils

fast or slow heartbeat

severe headache

increased sensitivity of eyes to light

increased sweating, possibly with fever or cold, clammy skin

nausea or vomiting

stiff or sore neck
^{60}^{61}^{62}^{63}^{64}^{65}^{113}^{114}^{115}^{125}
Note: Intracranial bleeding (sometimes fatal in outcome) has occurred in association with hypertensive crisis ^{61} ^{62} ^{63} ^{65} ^{113} ^{115}.
Palpitation or frequent headaches may be prodromal signs of a hypertensive reaction ^{62} ^{63} ^{65} ^{113}.

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

Anticholinergic effect ^{32} or syndrome of inappropriate antidiuretic hormone secretion [SIADH] ^{60} ^{62} ^{64} ^{113} ^{114} (decreased urine output)

blurred vision ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{113} ^{114} ^{115}

CNS stimulation ^{32} ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{70} ^{113} ^{114} ^{115}^{125} (muscle twitching during sleep; restlessness or agitation; trouble in sleeping ^{42})—more likely with tranylcypromine

decreased sexual ability ^{32} ^{53} ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{70} ^{113} ^{114} ^{115}^{125}

drowsiness —more likely with isocarboxazid and phenelzine ^{62} ^{63} ^{65} ^{113}

mild headache without increase in blood pressure ^{60} ^{62} ^{63} ^{64} ^{113} ^{114}

increased appetite and weight gain, related to carbohydrate craving ^{04} ^{20} ^{43} ^{61} ^{115}

increased sweating ^{32} ^{36} ^{61} ^{64} ^{70} ^{115}

nausea^{125}

orthostatic hypotension ^{60} ^{62} ^{63} ^{65} ^{70} ^{113} ^{114}^{125} , mild (dizziness or lightheadedness; tiredness and weakness)

shakiness or trembling ^{60} ^{61} ^{114} ^{115}

weakness ^{62} ^{63} ^{64} ^{65} ^{113}

Note: Decreased sexual ability may include anorgasmia in males and females; ejaculatory disorders; and, less commonly, impotence in males ^{08} ^{15} ^{16} ^{61} ^{115}.

Incidence less frequent or rare

Anorexia ^{36} ^{60} ^{62} ^{63} ^{64} ^{113} ^{114} (decreased appetite)

chills ^{62} ^{63} ^{113}

constipation ^{32} ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{113} ^{114} ^{115}^{125}

dryness of mouth ^{32} ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{113} ^{114} ^{115}^{125} ——more frequent with isocarboxazid

Overdose
For specific information on the agents used in the management of monoamine oxidase (MAO) inhibitor antidepressant overdose, see:
   • Charcoal, Activated (Oral-Local) monograph;
   • Dantrolene (Systemic) monograph; and/or
   • Diazepam in Benzodiazepines (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Severe anxiety ^{04} ^{61} ^{62} ^{63} ^{65} ^{113} ^{115}

confusion ^{62} ^{63} ^{113}

convulsions ^{60} ^{61} ^{64} ^{65} ^{114} ^{115}^{125}

cool, clammy skin ^{61} ^{65} ^{115}

severe dizziness ^{61} ^{62} ^{63} ^{64} ^{65} ^{113} ^{115}

severe drowsiness ^{61} ^{62} ^{63} ^{65} ^{113} ^{114} ^{115}

fast and irregular pulse ^{60} ^{64} ^{65} ^{114}^{125}

fever ^{60} ^{61} ^{62} ^{63} ^{64} ^{113} ^{114} ^{115}^{125}

hallucinations ^{61} ^{115}

severe headache ^{61} ^{62} ^{63} ^{65} ^{113} ^{115}

high or low blood pressure ^{60} ^{61} ^{62} ^{63} ^{64} ^{113} ^{114} ^{115}^{125}

hyperactive reflexes ^{52} ^{61} ^{65} ^{115}

muscle stiffness ^{62} ^{63} ^{113}

respiratory depression or failure ^{60} ^{61} ^{64} ^{65} ^{114} ^{115}^{125} (troubled breathing)

slowed reflexes ^{36} ^{60} ^{64} ^{114}

sweating ^{60} ^{61} ^{64} ^{65} ^{114} ^{115}^{125}

severe trouble in sleeping ^{62} ^{113}

unusual irritability ^{61} ^{64} ^{65} ^{115}

Treatment of overdose

Note: Symptoms of overdose may be absent or minimal for nearly 12 hours after ingestion, and develop slowly thereafter, reaching a maximum in 24 to 48 hours. Immediate hospitalization with close monitoring of patient is essential during this period. ^{61} ^{115} Death has resulted.

To decrease absorption:
Induction of vomiting or gastric lavage ^{60} ^{62} ^{63} ^{64} ^{65} ^{113} ^{114}^{125} with protected airway followed by instillation of charcoal slurry in early overdose ^{61} ^{115}.

To enhance elimination:
In tranylcypromine overdose, acidification of urine to pH of 5 ^{20}.

Hemodialysis may be beneficial ^{32} but is of unproven value ^{38}.

Specific treatment:
Treatment of signs and symptoms of CNS stimulation with diazepam, administered intravenously and slowly ^{61} ^{115}. Phenothiazines should not be used because of additive hypotensive effects ^{61} ^{62} ^{113} ^{115}.

Treatment of hypotension and vascular collapse with intravenous fluids and a dilute pressor agent ^{60} ^{61} ^{62} ^{63} ^{113} ^{114} ^{115}^{125}.

Close monitoring of body temperature, and vigorous treatment of hyperpyrexia with antipyretics and a cooling blanket ^{61} ^{62} ^{63} ^{115}. Maintenance of fluid and electrolyte balance is essential ^{61} ^{115}.

Reduction of symptoms of hypermetabolic state (coma, respiratory failure, hyperpyrexia, tachycardia, muscular rigidity, tremor, and hyperreflexia) with intravenous dantrolene sodium at 2.5 mg per kg of body weight (mg/kg) a day in divided doses, with careful monitoring for signs of hepatotoxicity and pleural or pericardial effusions ^{28}.

Monitoring:
Close monitoring of body temperature.

Monitoring of liver function at the time of overdosage and during the 4 to 6 weeks after recovery^{125}.

Supportive care:
Support of respiration by management of the airway, and mechanical ventilation with the use of supplemental oxygen, as required ^{60} ^{61} ^{64} ^{114} ^{115}.

Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.

Note: Pathophysiologic effects of massive overdose may persist for several days; recovery from mild overdose may take 3 to 4 days ^{61} ^{115}.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Antidepressants, Monoamine Oxidase (MAO) Inhibitor (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to any MAO inhibitor, including furazolidone or procarbazine

Pregnancy—MAO inhibitors cross placenta; no appropriate human studies done; animal studies have shown hyperexcitability and reduced growth rate in neonates

Breast-feeding—Not known if distributed into human breast milk; animal studies have shown distribution into milk

Use in the elderly—Increased sensitivity to hypotensive effects
Other medications, especially CNS depressants, tricyclic antidepressants, oral antidiabetic agents, insulin, bupropion, buspirone, caffeine in high doses, carbamazepine, cyclobenzaprine, cocaine, maprotiline, dextromethorphan, fluoxetine, paroxetine, or sertraline, trazodone, guanadrel, guanethidine, rauwolfia alkaloids, levodopa, meperidine, methyldopa, methylphenidate, sympathomimetics, tryptophan, or foods and beverages containing tyramine
Other medical problems, especially alcoholism (active), congestive heart failure, hepatic function impairment, pheochromocytoma, renal function impairment, cardiac arrhythmias, cardiovascular disease, coronary insufficiency, severe or frequent headaches, hypertension, schizophrenia, or suicidal tendencies

Proper use of this medication
» May require up to 3 or 4 weeks of therapy to obtain signs of improvement; regular visits to physician, especially during first few months of therapy ^{04}, to check progress of therapy and to check for unwanted effects

» Taking exactly as directed by physician

» Importance of not taking more medication than the amount prescribed

» Proper dosing
Missed dose: Taking as soon as possible within 2 hours of next dose; going back to regular dosing schedule; not doubling doses

» Proper storage

Precautions while using this medication
» Avoiding tyramine-containing foods, alcoholic beverages, and large quantities of caffeine-containing beverages, over-the-counter cold and cough medicines, and other medications, unless prescribed; having list of such for reference

» Checking with hospital emergency room or physician if symptoms of hypertensive crisis develop

» Checking with physician before discontinuing medication; gradual reduction may be needed to prevent withdrawal effects

» Dizziness may occur; caution when getting up suddenly from a lying or sitting position

» Drowsiness and blurred vision may occur; caution when driving or doing things requiring alertness or clear vision

» Caution if any kind of surgery, dental treatment, or emergency treatment is required

Carrying medical identification card

» Patients with angina: Not increasing physical activities without consulting physician

Diabetic patients: Carefully checking urine or blood sugar; results may be lowered by this medication

» Obeying rules of caution for 14 days after discontinuing medication

Side/adverse effects
» Signs of potential side effects, especially symptoms of hypertensive crisis, severe orthostatic hypotension, diarrhea, peripheral edema, sympathetic stimulation, hepatitis, leukopenia, or parkinsonian syndrome

General Dosing Information
This medication is usually used for closely supervised patients who have not responded to other antidepressant therapy ^{62} ^{63} ^{113}.

Patient response to these agents is variable, and patients not responsive to one MAO inhibitor may be treated successfully with another.

Potentially suicidal patients should not have access to large quantities of this medication since depressed patients, particularly those who use alcohol excessively, may continue to exhibit suicidal tendencies until significant improvement occurs ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{113} ^{114} ^{115}^{125}.

It has been recommended that therapy with an MAO inhibitor be withdrawn gradually at least 10 to 14 days prior to surgery ^{32} ^{63} ^{64} ^{65} ^{71}^{125}; however, to avoid interruption of antidepressant therapy, patients receiving long-term MAO inhibition may undergo surgery without discontinuation of the MAO inhibitor ^{44} ^{45} ^{78} ^{79} ^{80}. Reduction of opioid (narcotic) analgesic or other premedication dosage to 1/4 of the usual dose is recommended, along with careful adjustment of anesthetic dosage ^{71}. Avoidance of meperidine or cocaine use within 2 to 3 weeks following MAO inhibition is recommended ^{25} ^{62} ^{113}^{125}.

Because insomnia or other sleep disturbances may be produced by their psychomotor-stimulating effect, these medications are usually not given in the evening ^{66}.

After dosage is stopped, the effects of these medications may persist for up to 2 weeks (time required for regeneration of monoamine oxidase). During this period, food and drug contraindications must be observed. ^{61} ^{64} ^{70} ^{115}

Diet/Nutrition
Foods and beverages containing tyramine or other high pressor amines, such as aged cheese ^{51} ^{83} ^{84} ^{85} ^{86} ^{87}^{125}; fava or broad bean pods ^{51} ^{83} ^{85} ^{86} ^{87}; yeast/protein extracts ^{51} ^{83} ^{84} ^{85} ^{86} ^{87}; smoked or pickled meats, poultry, or fish ^{32} ^{51} ^{83} ^{86} ^{87}; fermented sausage (bologna, pepperoni, salami, summer sausage) or other fermented meat ^{51} ^{83} ^{85} ^{86}; sauerkraut ^{82} ^{85}; any overripe fruit ^{51} ^{86}; beer ^{27} ^{51}; reduced-alcohol and alcohol-free beer and wine ^{36} ^{37} ^{88}; red and white wines ^{36} ^{37} ^{38} ^{39} ^{51}; sherry ^{51}; and liqueurs ^{51}, when used concurrently with MAO inhibitors, may cause sudden and severe hypertensive reactions. The reactions are usually limited to a few hours and are easily treated with rapidly acting hypotensive agents (such as labetalol, nifedipine, or if necessary in severe cases refractory to other agents, phentolamine). The severity depends on the amount of tyramine ingested, rate of gastric emptying, and length of the interval between the dose of MAO inhibitor and ingestion of tyramine ^{24}. When MAO inhibitors are discontinued, dietary restrictions must continue for at least 2 weeks ^{61} ^{64} ^{70}. Other foods, such as yogurt, sour cream, cream cheese, cottage cheese, chocolate, and soy sauce, if eaten when fresh and in moderation, are considered unlikely to cause serious problems ^{51}.

For treatment of hypertensive crisis
Recommended treatment includes:

   • Discontinuing MAO inhibitor ^{60} ^{61} ^{62} ^{63} ^{65} ^{113} ^{114} ^{115}.
   • Lowering blood pressure immediately with intravenous administration of 5 mg of phentolamine, with care being taken to inject slowly, to prevent excessive hypotensive effect ^{32} ^{60} ^{61} ^{62} ^{63} ^{65} ^{69} ^{70} ^{113} ^{114} ^{115}. Alternatively, some clinicians prefer to use labetalol (intravenously or orally), reserving phentolamine for severe or non-responding cases ^{74} ^{75} ^{76}.
   • Reducing fever by external cooling ^{60} ^{61} ^{62} ^{63} ^{65} ^{69} ^{113} ^{114} ^{115}.

ISOCARBOXAZID

Oral dosage form

ISOCARBOXAZID TABLETS USP

Usual adult dose
Antidepressant
Initial: Oral, 10 milligrams (mg) twice daily. If tolerated, dose may be increased by 10 mg every 2 to 4 days to achieve a dose of 40 mg daily by the end of the first week of treatment^{125}. If needed and tolerated, dose may be increased to 60 mg daily^{125}.

Maintenance: Oral, the lowest effective dose should be used. After maximum clinical effect is achieved, an attempt should be made to reduce the dose over several weeks without jeopardizing the therapeutic response^{125}.

Usual adult prescribing limits
60 mg per day ^{125}.

Usual pediatric dose
Children younger than 16 years of age—Safety and efficacy have not been established ^{125}.

Usual geriatric dose
See Usual adult dose

Strength(s) usually available
U.S.—

10 mg (Rx) [Marplan (scored) (corn starch) ( gelatin ) ( lactose ) (magnesium stearate ) ( talc ) (FD&C Red No. 3 ) ( FD&C Yellow No. 6)]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F). Store in a tight container. Protect from heat and light.

Auxiliary labeling:
• Avoid alcoholic beverages.
• May cause drowsiness.

Note: Depressed patients with suicidal tendencies, particularly those who use alcohol excessively, should not have access to large quantities of MAO inhibitors ^{125}.

PHENELZINE

Additional Dosing Information
See also General Dosing Information.

The initial dosage should be increased gradually, depending on patient tolerance. Rapid dosage increases can cause early hypotensive effects and may result in patient noncompliance. A more conservative increase usually avoids this. ^{04} ^{93} At least 4 weeks at a given dosage may be necessary for some patients to achieve improvement and significant MAO inhibition ^{61} ^{115}.

Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

PHENELZINE SULFATE TABLETS USP

Usual adult dose
Antidepressant
Initial: Oral, 1 mg per kg of body weight a day ^{57} ^{77} ^{108}.

Maintenance: Oral, 45 mg a day ^{57} ^{77} ^{104}.

[Antipanic agent]¹
Oral, initially 15 mg every morning for the first four days, the dosage being increased gradually over two weeks as needed and tolerated, up to 15 mg three or four times a day ^{91} ^{93} ^{94} ^{102} ^{106}.

Usual adult prescribing limits
90 mg per day ^{61} ^{69} ^{70} ^{115}.

Usual pediatric dose
Children younger than 16 years of age—Safety and efficacy have not been established ^{61} ^{65} ^{115}.

Usual geriatric dose
Antidepressant
Oral, initially 0.8 to 1 mg per kg of body weight a day in divided doses, the dosage being gradually increased as needed and tolerated ^{20} ^{100} ^{102} ^{107}, up to a maximum of 60 mg a day ^{20} ^{102}.

Note: Elderly patients are often started on 15 mg in the morning and require a more gradual titration of dose than other adults, to minimize the adverse effects, especially hypotension ^{20} ^{93} ^{106}.

Strength(s) usually available
U.S.—

15 mg (Rx) [Nardil (acacia) (calcium carbonate) (carnauba wax) ( corn starch) (FD&C Yellow No. 6) (gelatin) (kaolin) ( magnesium stearate) (mannitol) ( pharmaceutical glaze) (povidone) ( sucrose) (talc) (white wax) (white wheat flour)^{61}]

Canada—

15 mg (Rx) [Nardil]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F). Store in a tight container. Protect from heat and light.

Auxiliary labeling:
• Avoid alcoholic beverages.
• May cause drowsiness.

Note: Depressed patients with suicidal tendencies, particularly those who use alcohol excessively, should not have access to large quantities of MAO inhibitors ^{61} ^{115}.

TRANYLCYPROMINE

Summary of Differences
Side/adverse effects: May produce more CNS stimulation than other MAO inhibitors ^{70}.

Additional Dosing Information
See also General Dosing Information.

Dosage should be individualized. If there are no signs of improvement after up to 2 weeks on the usual effective dosage of 30 mg a day, the dosage may be increased by 10 mg a day at intervals of 1 to 3 weeks, up to a maximum of 60 mg a day. ^{62} ^{113}

When electroconvulsive therapy is being administered concurrently, 10 mg twice a day can usually be given during the series, the dose being reduced to 10 mg a day for maintenance therapy ^{63}.

Gradual withdrawal from tranylcypromine is recommended ^{62}, to avoid recurrence of original symptoms, which may reappear if medication is withdrawn prematurely ^{20}.

Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

TRANYLCYPROMINE SULFATE TABLETS

Usual adult dose
Antidepressant
Initial: Oral, 30 mg a day in divided doses. If there are no signs of improvement after two weeks, the dosage may be increased by 10 mg a day at intervals of one to three weeks, up to a maximum of 60 mg a day. ^{62} ^{113}

Maintenance: Oral, 10 to 40 mg a day ^{93} ^{102}.

[Antipanic agent]¹
Oral, initially 10 mg in the morning for the first four days, the dosage being increased gradually over two weeks as needed and tolerated, up to 20 to 30 mg a day ^{91} ^{102} ^{106}.

Usual adult prescribing limits
60 mg per day ^{62} ^{100}.

Usual pediatric dose
Children younger than 16 years of age—Safety and efficacy have not been established ^{62} ^{63} ^{113}.

Usual geriatric dose
Antidepressant
Oral, initially 2.5 to 5 mg a day, the dosage being increased gradually in increments of 2.5 to 5 mg every three to four days, up to a maximum of 45 mg a day ^{27}.

Strength(s) usually available
U.S.—

10 mg (Rx) [Parnate (acacia) (calcium sulfate) (cellulose) ( ethylcellulose) (FD&C Red No. 3) (FD&C Yellow No. 6) (gelatin) (iron oxide) (magnesium stearate) (starch) (sucrose)^{62}]

Canada—

10 mg (Rx) [Parnate (gluten) (sodium <1 mmol [0.003 mg]) (sucrose)^{63}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.

Auxiliary labeling:
• Avoid alcoholic beverages ^{62} ^{113}.
• May cause drowsiness.

Note: Depressed patients with suicidal tendencies, particularly those who use alcohol excessively, should not have access to large quantities of MAO inhibitors ^{62} ^{113}.

Revised: 6/16/2000

References

PDR Physicians" desk reference. 40th ed. 1986. Oradell, NJ: Medical Economics Company, 1986.

Stockley. Drug Interactions, 1981: 367.

Conrad, Bressler, editors. Drug Therapy for the Elderly. St Louis: C.V. Mosby: 1982.

Panelist comment.

Salzman C. Clinical guidelines for the use of antidepressant drugs in geriatric patients. J Clin Psychiatry 46: 10(Sec 2): 38-44.

Pharmaceutical Journal. 1986 Apr 5: 418-9.

PDR Physicians" desk reference. 41st ed. 1987. Oradell, NJ: Medical Economics Company, 1987.

McDaniel K. Review: Clinical pharmacology of monoamine oxidase inhibitors. Clin Neuropharmacol 1986; 9(3): 207-34.

Quitkin F, editor. MAO inhibitors—Their use in atypical depression: Highlights of a Roundtable Conference, January 4, 1985. Excerpta medica. New York, NY.

Tranylcypromine and tryptophan: Toxic reactions. Clin-Alert 13; 1985 Jul 12: 121.

L-Tryptophan and monoamine oxidase inhibitors: Hypomania. Clin Alert 5; 1988 Mar 14: 47.

Opioid (Narcotic) Analgesics (Systemic) monograph, USP DI 1986.

Robinson DS. Cardiovascular effects of phenelzine and amitriptyline in depressed outpatients. J Clin Psychiatry 1982; 43(5)(Sec 2): 8-15.

Rabkin JG, et al. Adverse reactions to monoamine oxidase inhibitors. Part II. Treatment correlates and clinical management. J Clin Psychopharmacol 1985; 5(1): 2-9.

Antidepressants: Sexual dysfunction. Reactions 1984 May 12.

Harrison WM, et al. Effects of antidepressant medication on sexual function: A controlled study. J Clin Psychopharmacol 1986; 8(3): 144-9.

Liskin B. Acute psychosis following phenelzine discontinuation. J Clin Psychopharmacol 1985; 5(1): 46-7.

Tyrer P. Clinical effects of abrupt withdrawal from tricyclic antidepressants and monoamine oxidase inhibitors after long-term treatment. J Affect Disord 1984; 6: 1-7.

Antidepressants and withdrawal phenomena. [In: Drugs and Therapeutics Bulletin 1986; 24: 29-30.] Reactions 1986 May 10.

Panelist comment.

Mallinger AG, et al. Pharmacokinetics of tranylcypromine in patients who are depressed: Relationship to cardiovascular effects. Clin Pharmacol Ther 1986; 40: 444-50.

Teusink JP, et al. Parkinsonian side effects induced by a monoamine oxidase inhibitor. Am J Psychiatry 1984; 141(1): 118-9.

Gilman MA, Sandyk R. Parkinsonism induced by a monoamine oxidase inhibitor. Postgrad Med J 62: 235-6, 1986.

Walker JJ. How to improve patient compliance with MAOIs. [In: J Clin Psychiatry 1984; 45: 78.] Reactions 1984 Aug 25.

Cocaine (Mucosal-Local) monograph. USP DI 1989, from NIDA Research Monograph Series 50 (Cocaine), 1984, and N Engl J Med 1986; 315: 1495.

Clary C, Schweizer E. Treatment of hypertensive crisis with sublingual nifedipine. [In: J Clin Psychiatry 1987; 48: 249-50.] Drug Newsletter 1987 Aug; 6(8): 62.

Monoamine oxidase inhibitors: Treatment of the depressed elderly patient. Drug Therapy for the elderly 1987; 2(11)

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