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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(eye soe kar BOKS a zid)
Generic Available (U.S.)
No
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088633.pdf, must be dispensed with this medication.
U.S. Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of depression
Pregnancy Risk Factor
C
Lactation
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to isocarboxazid or any component of the formulation; cardiovascular disease (including CHF, or HTN); cerebrovascular disease; history of hepatic disease or abnormal liver function tests; pheochromocytoma; renal disease or severe renal impairment
Concurrent use of sympathomimetics (including amphetamines, cocaine, dopamine, epinephrine, methylphenidate, norepinephrine, or phenylephrine) and related compounds (methyldopa, levodopa, phenylalanine, tryptophan, or tyrosine), as well as ophthalmic alpha2-agonists (apraclonidine, brimonidine); may result in behavioral and neurologic symptoms
CNS depressants, cyclobenzaprine, dextromethorphan, ethanol, meperidine, bupropion, buspirone; may result in delirium, excitation, hyper-/hypotension, hyperpyrexia, seizures, and coma
Isocarboxazid initiation: At least 2 weeks should elapse between the discontinuation of serotoninergic agents (including SSRIs and tricyclics) and the initiation of isocarboxazid; at least 5 weeks should elapse between the discontinuation of fluoxetine and the initiation of isocarboxazid; at least 1 week should elapse between the discontinuation of other monoamine oxidase (MAO) inhibitors and the initiation of isocarboxazid (using half the normal starting dose). In all cases, a sufficient amount of time must be allowed for the clearance of the serotoninergic agent and any active metabolites prior to the initiation of isocarboxazid.
Isocarboxazid discontinuation: At least 2 weeks should elapse between the discontinuation of isocarboxazid and the initiation of the following agents: Serotoninergic agents (including SSRIs, fluoxetine, and tricyclics), bupropion, and other antidepressants. Two to 3 weeks should elapse between the discontinuation of isocarboxazid and the initiation of meperidine. At least 10 days should elapse between the discontinuation of isocarboxazid and initiation of buspirone. At least 1 week should elapse between the discontinuation of isocarboxazid and the initiation of other MAO inhibitors (see specific agent for details).
Antihypertensive agents (including thiazide diuretics): may result in potentiation of antihypertensive effects.
General anesthesia, spinal anesthesia (hypotension may be exaggerated). Use caution with local anesthetics containing sympathomimetic agents. Discontinue drug 10 days prior to elective surgery.
Foods high in tyramine or dopamine content; foods and/or supplements containing tyrosine, phenylalanine, tryptophan, or caffeine; may result in hypertensive reactions.
Warnings/Precautions
Boxed warnings:
• Suicidal thinking/behavior: See “Major psychiatric warnings” below.
Major psychiatric warnings:
• [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1-2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Isocarboxazid is FDA approved for the treatment of depression in children ≥16 years of age.
The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Patients treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.
Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur.
May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. Isocarboxazid is not FDA approved for the treatment of bipolar depression.
Concerns related to adverse effects:
• Hypertensive crisis: May occur with foods/supplements high in tyramine, tryptophan, phenylalanine, or tyrosine content. Treatment with phentolamine is recommended for hypertensive crises.
• Orthostatic hypotension: May cause orthostatic hypotension (especially at dosages >30 mg/day); use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).
Disease-related concerns:
• Diabetes: Use with caution in patients with diabetes mellitus; sensitization to the effects of insulin may occur, monitor blood glucose closely.
• Glaucoma: Use with caution in patients with glaucoma.
• Hepatic impairment: Should not be used in patients with a history of liver disease or with abnormal liver function tests.
• Renal impairment: Use with caution in patients with renal impairment. Should not be used in patients with severe impairment.
• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold.
• Thyroid dysfunction: Use with caution in patients with hyperthyroidism.
Concurrent drug therapy issues:
• High potential for interactions: Do not use with other MAO inhibitors or antidepressants. Avoid products containing sympathomimetic stimulants, dextromethorphan, disulfiram, and meperidine. Concurrent use with antihypertensive agents may lead to exaggeration of hypotensive effects.
Special populations:
• Elderly: The MAO inhibitors are effective and generally well tolerated by older patients. It is the potential interactions with tyramine-containing foods and other drugs, and their effects on blood pressure that have limited their use.
• Pediatrics: Safety and efficacy have not been established in patients <16 years of age. Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents and young adults. (See major psychiatric warnings).
• Hyperactive or agitated patients: Use with caution in patients who are hyperactive and/or hyperexcitable.
Other warnings/precautions:
• Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.
• Isocarboxazid is not indicated for initial therapy, but should be reserved for patients who have not responded to other antidepressants.
• Myelography: Discontinue at least 48 hours prior to myelography.
Adverse Reactions
>10%: Central nervous system: Dizziness (29%), headache (15%)
1% to 10%:
Cardiovascular: Orthostatic hypotension (4%), syncope (2%), palpitation (2%)
Central nervous system: Sleep disturbance (5%), drowsiness (4%), anxiety (2%), chills (2%), forgetfulness (2%), hyperactivity (2%), lethargy (2%), sedation (2%)
Gastrointestinal: Xerostomia (9%), constipation (7%), nausea (6%), diarrhea (2%)
Genitourinary: Urinary frequency (2%), impotence (2%), urinary hesitancy (1%)
Neuromuscular & skeletal: Tremor (4%), myoclonus (2%), paresthesia (2%)
Miscellaneous: Diaphoresis (2%), heavy feeling (2%)
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Ataxia, black tongue, coma, hallucination, hematologic changes, hepatitis, SIADH, Parkinsonian syndrome, sexual disturbances, toxic amblyopia
Drug Interactions
Acetylcholinesterase Inhibitors (Central): Anticholinergics may diminish the therapeutic effect of Acetylcholinesterase Inhibitors (Central). Acetylcholinesterase Inhibitors (Central) may diminish the therapeutic effect of Anticholinergics. If the anticholinergic action is a side effect of the agent, the result may be beneficial. Risk C: Monitor therapy
Alpha-/Beta-Agonists (Direct-Acting): MAO Inhibitors may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Primarily with oral administration of phenylephrine. Exceptions: Dipivefrin. Risk D: Consider therapy modification
Alpha-/Beta-Agonists (Indirect-Acting): MAO Inhibitors may enhance the hypertensive effect of Alpha-/Beta-Agonists (Indirect-Acting). Risk X: Avoid combination
Alpha1-Agonists: MAO Inhibitors may enhance the hypertensive effect of Alpha1-Agonists. Risk X: Avoid combination
Alpha2-Agonists (Ophthalmic): MAO Inhibitors may enhance the hypertensive effect of Alpha2-Agonists (Ophthalmic). Risk X: Avoid combination
Altretamine: May enhance the orthostatic hypotensive effect of MAO Inhibitors. Risk C: Monitor therapy
Amphetamines: MAO Inhibitors may enhance the hypertensive effect of Amphetamines. Risk X: Avoid combination
Anilidopiperidine Opioids: May enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Management: Avoid use of fentanyl (and other anilidopiperidine opioids when possible) in patients who have used a monoamine oxidase inhibitor within the past 14 days due to reports of unpredictable but severe adverse effects. Risk X: Avoid combination
Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Levocabastine (Nasal); Paliperidone. Risk C: Monitor therapy
Antihypertensives: MAO Inhibitors may enhance the hypotensive effect of Antihypertensives. MAO Inhibitors may enhance the orthostatic hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Atomoxetine: MAO Inhibitors may enhance the neurotoxic (central) effect of Atomoxetine. Risk X: Avoid combination
Beta2-Agonists: MAO Inhibitors may enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy
Bezafibrate: MAO Inhibitors may enhance the adverse/toxic effect of Bezafibrate. Risk X: Avoid combination
Buprenorphine: May enhance the adverse/toxic effect of MAO Inhibitors. Risk X: Avoid combination
BuPROPion: MAO Inhibitors may enhance the neurotoxic (central) effect of BuPROPion. Risk X: Avoid combination
BusPIRone: May enhance the adverse/toxic effect of MAO Inhibitors. Elevated blood pressure has been reported. Risk X: Avoid combination
CarBAMazepine: May enhance the adverse/toxic effect of MAO Inhibitors. Risk X: Avoid combination
COMT Inhibitors: May enhance the adverse/toxic effect of MAO Inhibitors. Risk D: Consider therapy modification
Cyclobenzaprine: May enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination
Dexmethylphenidate: MAO Inhibitors may enhance the hypertensive effect of Dexmethylphenidate. Risk X: Avoid combination
Dextromethorphan: MAO Inhibitors may enhance the serotonergic effect of Dextromethorphan. This may cause serotonin syndrome. Risk X: Avoid combination
Diethylpropion: MAO Inhibitors may enhance the hypertensive effect of Diethylpropion. Risk X: Avoid combination
Doxapram: MAO Inhibitors may enhance the hypertensive effect of Doxapram. Risk C: Monitor therapy
HYDROmorphone: MAO Inhibitors may enhance the adverse/toxic effect of HYDROmorphone. Risk X: Avoid combination
Levodopa: May enhance the adverse/toxic effect of MAO Inhibitors. Of particular concern is the development of hypertensive reactions when levodopa is used with nonselective MAOI. Risk D: Consider therapy modification
Linezolid: MAO Inhibitors may enhance the adverse/toxic effect of Linezolid. Risk X: Avoid combination
Lithium: MAO Inhibitors may enhance the adverse/toxic effect of Lithium. Risk C: Monitor therapy
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Maprotiline: May enhance the adverse/toxic effect of MAO Inhibitors. Risk X: Avoid combination
Meperidine: MAO Inhibitors may enhance the serotonergic effect of Meperidine. This may cause serotonin syndrome. Risk X: Avoid combination
Methadone: MAO Inhibitors may enhance the adverse/toxic effect of Methadone. Management: Initial safety testing, where small incremental doses of methadone are given with the patient closely monitored (including vitals, etc.), is recommended if methadone is to be used with (or within 14 days of) an MAO inhibitor. Avoid transdermal selegiline. Risk D: Consider therapy modification
Methyldopa: MAO Inhibitors may enhance the adverse/toxic effect of Methyldopa. Risk X: Avoid combination
Methylphenidate: MAO Inhibitors may enhance the hypertensive effect of Methylphenidate. Risk X: Avoid combination
Mirtazapine: MAO Inhibitors may enhance the neurotoxic (central) effect of Mirtazapine. Risk X: Avoid combination
Orthostatic Hypotension Producing Agents: MAO Inhibitors may enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Oxymorphone: May enhance the adverse/toxic effect of MAO Inhibitors. Risk X: Avoid combination
Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification
Propoxyphene: May enhance the adverse/toxic effect of MAO Inhibitors. Specifically, the risk of serotonin syndrome or other serotonergic adverse events may be increased. Risk X: Avoid combination
Reserpine: MAO Inhibitors may enhance the adverse/toxic effect of Reserpine. Existing MAOI therapy can result in paradoxical effects of added reserpine (e.g., excitation, hypertension). Management: Monoamine oxidase inhibitors (MAOIs) should be avoided or used with great caution in patients who are also receiving reserpine. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: MAO Inhibitors may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk X: Avoid combination
Serotonin 5-HT1D Receptor Agonists: MAO Inhibitors may decrease the metabolism of Serotonin 5-HT1D Receptor Agonists. Management: If MAO inhibitor therapy is required, naratriptan, eletriptan or frovatriptan may be a suitable 5-HT1D agonist to employ. Exceptions: Eletriptan; Frovatriptan; Naratriptan. Risk X: Avoid combination
Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification
Serotonin/Norepinephrine Reuptake Inhibitors: MAO Inhibitors may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This may cause serotonin syndrome. Risk X: Avoid combination
Sibutramine: May enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Risk X: Avoid combination
Tapentadol: May enhance the adverse/toxic effect of MAO Inhibitors. Risk X: Avoid combination
Tetrabenazine: May enhance the adverse/toxic effect of MAO Inhibitors. Risk X: Avoid combination
Tetrahydrozoline: MAO Inhibitors may enhance the hypertensive effect of Tetrahydrozoline. Risk X: Avoid combination
Tetrahydrozoline (Nasal): MAO Inhibitors may enhance the hypertensive effect of Tetrahydrozoline (Nasal). Risk X: Avoid combination
TraMADol: May enhance the neuroexcitatory and/or seizure-potentiating effect of MAO Inhibitors. TraMADol may enhance the serotonergic effect of MAO Inhibitors. Management: Consider alternatives to combined treatment with tramadol and monoamine oxidase inhibitors due to an increased risk of serotonin syndrome and seizures. Avoid transdermal selegiline. Risk D: Consider therapy modification
Tricyclic Antidepressants: MAO Inhibitors may enhance the serotonergic effect of Tricyclic Antidepressants. This may cause serotonin syndrome. Risk X: Avoid combination
Tryptophan: May enhance the adverse/toxic effect of MAO Inhibitors. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects. Avoid beverages containing tyramine (hearty red wine and beer).
Food: Concurrent ingestion of foods rich in tyramine may cause sudden and severe high blood pressure (hypertensive crisis). Avoid tyramine-containing foods with MAO-Is.
Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, kava kava (may increase risk of serotonin syndrome and/or excessive sedation); Avoid supplements containing caffeine, tyrosine, tryptophan, or phenylalanine. Ingestion of large quantities may increase the risk of severe side effects (eg, hypertensive reactions, serotonin syndrome).
Mechanism of Action
Thought to act by increasing endogenous concentrations of epinephrine, norepinephrine, dopamine, and serotonin through inhibition of the enzyme (monoamine oxidase) responsible for the breakdown of these neurotransmitters
Dosage
Oral: Adults: Initial: 10 mg 2-4 times/day; may increase by 10 mg/day every 2-4 days to 40 mg/day by the end of the first week (divided into 2-4 doses). After first week, may increase by up to 20 mg/week to a maximum of 60 mg/day. May take 3-6 weeks to see effects. Dose should be reduced once maximum clinical effect is seen. If no response obtained within 6 weeks, additional titration is unlikely to be beneficial. Note: Use caution in patients on >40 mg/day; experience is limited.
Monitoring Parameters
Blood pressure, heart rate; mood, suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased)
Dietary Considerations
Avoid tyramine-containing foods/beverages. Some examples include aged or matured cheese, air-dried or cured meats (including sausages and salamis), fava or broad bean pods, tap/draft beers, Marmite concentrate, sauerkraut, soy sauce and other soybean condiments. Food's freshness is also an important concern; improperly stored or spoiled food can create an environment where tyramine concentrations may increase.
Geriatric Considerations
The MAO inhibitors are effective and generally well tolerated by elderly patients. It is their potential interactions with tyramine-containing foods and other drugs and their effects on blood pressure that have limited their use. The MAO inhibitors are usually reserved for patients who do not tolerate or respond to the traditional “cyclic” or “second generation” antidepressants. The brain activity of monoamine oxidase increases with age and even more so in patients with Alzheimer's disease. Therefore, the MAO inhibitor may have an increased role in patients with Alzheimer's disease who are depressed. Information on the use of isocarboxazid in the elderly is limited.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: Patients receiving MAO inhibitors who undergo surgery may be at risk of developing significant hypertension when used with direct-acting adrenergic agents (eg, norepinephrine) and of lethal hypertension when administered with indirect-acting adrenergic agents (eg, ephedrine). The use of meperidine in these patients may also precipitate serotonin syndrome and is contraindicated. Years ago, it was advised that patients receiving MAO inhibitors have this drug discontinued for at least 10 days before elective surgery. However, the decision to continue or withhold MAO inhibitors must be done in collaboration with the patient's psychiatrist. Currently, an MAO-safe anesthetic technique which excludes the use of meperidine and indirect-acting adrenergic agonists is recommended for patients requiring continuing MAO therapy (Huyse, 2006).
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Orthostatic hypotension, xerostomia (normal salivary flow resumes upon discontinuation).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Attempts should be made to avoid use of vasoconstrictor due to possibility of hypertensive episodes with monoamine oxidase inhibitors
Mental Health: Comment
Not commonly used due to a required low tyramine diet and drug-drug interactions. It is estimated that 20 mg of tranylcypromine = 40 mg of isocarboxazid = 45 mg phenelzine. Phenelzine and isocarboxazid are hydrazine MAO inhibitors and tranylcypromine is a nonhydrazine. These drugs produce irreversible inhibition of MAO inhibitors. The half-life for regeneration is 2-3 days. Therefore, a 2-week period is required when switching from an MAO inhibitor to another antidepressant.
While hypertension and hypertensive crisis are risks associated with MAO inhibitor therapy, orthostatic hypotension may also occur. Orthostasis associated with MAO inhibitor therapy is not related to alpha1-adrenergic receptor blockade. The “false transmitter” concept is used to explain this side effect. This concept states that MAO inhibitors promote gradual accumulation in sympathetic nerve ending of amines lacking direct sympathomimetic activity (octopamine) at the expense of the normal synaptic transmitter, norepinephrine. Since octopamine has little ability to activate either alpha- or beta-adrenergic receptors, a functional impairment of sympathetic neurotransmission occurs.
The MAO inhibitors are usually reserved for patients who do not tolerate or respond to other antidepressants. The brain activity of monoamine oxidase increases with age and even more so in patients with Alzheimer's disease. Therefore, the MAO inhibitors may have an increased role in patients with Alzheimer's disease who are depressed. Phenelzine is less stimulating than tranylcypromine.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral:
Marplan®: 10 mg [scored]
Pricing: U.S. (www.drugstore.com)
Tablets (Marplan)
10 mg (30): $107.69
References
Huyse FJ, Touw DJ, van Schijndel RS, et al, “Psychotropic Drugs and the Perioperative Period: A Proposal for a Guideline in Elective Surgery,” Psychosomatics, 2006, 47(1):8-22.
Pass SE and Simpson RW, “Discontinuation and Reinstitution of Medications During the Perioperative Period,” Am J Health Syst Pharm, 2004, 61(9):899-912.
Shulman KI and Walker SE, “A Reevaluation of Dietary Restrictions for Irreversible Monoamine Oxidase Inhibitors,” Psychiatr Ann, 2001, 31(6):378-84.
Shulman KI and Walker SE, “Refining the MAOI Diet: Tyramine Content of Pizzas and Soy Products,” J Clin Psychiatry, 1999, 60(3):191-3.
Walker SE, Shulman KI, Tailor SA, et al, “Tyramine Content of Previously Restricted Foods in Monoamine Oxidase Inhibitor Diets,” J Clin Psychopharmacol, 1996, 16(5):383-8.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
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