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  • CLASSES

    Anti-Parkinson drugs, MAO type B Inhibitors
    MAOI Antidepressants

    BOXED WARNING

    Children, suicidal ideation

    Safety and efficacy of oral selegiline have not been established in children or adolescents. Transdermal selegiline is contraindicated in children less than 12 years due to the risk of hypertensive crisis; transdermal selegiline is not recommended for children and adolescents 12 to 17 years of age. Limited data suggest increased exposure to selegiline in children younger than 12 years of age compared to adolescents and adults with transdermal use, and children may not be able to reliably adhere to the required dietary restrictions. A flexible-dose controlled trial of transdermal selegiline failed to demonstrate efficacy, although the overall safety profile was similar to adults. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in pediatric patients. A causal role has been established for antidepressants in inducing suicidality in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants (SSRIs and others). The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment of SSRIs and other antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in children or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly during treatment initiation and at the time of a dose change. It is unknown if the suicidality risk in children and young adults extends beyond several months. The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another psychiatric disorder. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment are considered at an increased risk for suicidal ideation or attempts, and should be closely monitored during treatment with transdermal selegiline. In patients who exhibit changes in symptoms, worsening of depression or suicidality, a decision should be made to change or discontinue treatment. If discontinuing, the medication should be tapered as rapidly as possible, but with recognition that sudden discontinuation can also cause adverse symptoms.

    DEA CLASS

    Rx

    DESCRIPTION

    Selective type-B monoamine oxidase inhibitor (MAOI) available orally and as a transdermal patch
    Oral formulations used as an adjunct treatment in Parkinson's disease; transdermal patch approved for major depressive disorder in adults
    Tyramine reactions, such as hypertensive crisis, are unlikely but possible at therapeutic dosing; follow tyramine restrictions as recommended
    Close monitoring is required in pediatrics and young adults receiving antidepressant therapy due to an increased risk of suicidality during the initial stages of treatment; transdermal selegiline is contraindicated in children less than 12 years due to an increased risk of hypertensive crisis

    COMMON BRAND NAMES

    Carbex, Eldepryl, EMSAM, Zelapar

    HOW SUPPLIED

    Carbex/Selegiline/Selegiline Hydrochloride Oral Tab: 5mg
    Eldepryl/Selegiline/Selegiline Hydrochloride Oral Cap: 5mg
    EMSAM Topical Film ER: 6mg, 9mg, 12mg, 24h
    Zelapar Oral Tab Orally Dis: 1.25mg

    DOSAGE & INDICATIONS

    For the treatment of Parkinson's disease or parkinsonism in combination with levodopa or levodopa/carbidopa.
    Oral dosage (tablets and capsules, e.g., Eldepryl)
    Adults

    5 mg PO twice daily, administered with breakfast and lunch.

    Oral dosage (orally disintegrating tablets, e.g., Zelapar ODT)
    Adults

    1.25 mg PO once daily in the morning, before breakfast and without liquid. Give for at least 6 weeks. After 6 weeks if needed for efficacy and tolerated, the dose may be increased to 2.5 mg PO once daily in the morning, before breakfast and without liquid. ODT doses more than 2.5 mg daily have not been shown to confer additional benefit, and safe use of more than 2.5 mg/day without dietary tyramine restrictions has not been established. Dose reductions of levodopa may be needed if dopaminergic side effects, including dyskinesia and hallucinations emerge. In clinical trials with selegiline ODT, the mean reduction of 'off' time was 13.1% for selegiline ODT and 5.1% for placebo. Selegeline ODT-treated patients had an average of 2.2 hours per day less "off" time compared to baseline. Placebo-treated patients had 0.6 hours/day less "off" time compared to baseline. These differences were statistically significant.

    For the treatment of major depression.
    Transdermal dosage
    Adults

    The initial and target dose is 6 mg in 24 hours applied transdermally once daily. If clinically indicated, dose increases should occur in increments of 3 mg/24 hours at intervals of no less than 2 weeks. Effective dose range: 6 to 12 mg/24 hours. Max: 12 mg/24 hours. It is not known if the higher doses are more effective than the lowest dose. Inform patients to avoid tyramine-containing foods/beverages/dietary supplements beginning on the first day of selegiline 9 mg/24 hours or 12 mg/24 hours patch. Continue to avoid tyramine for 2 weeks after a dose reduction to selegiline 6 mg/24 hours or following the discontinuation of selegiline 9 mg/24 hours or 12 mg/24 hours.

    MAXIMUM DOSAGE

    Adults

    10 mg/day PO (oral tablets or capsules); 2.5 mg/day PO (orally-disintegrating tablet); Emsam 12 mg/24 hour transdermally.

    Geriatric

    10 mg/day PO (oral tablets or capsules); 2.5 mg/day PO (orally-disintegrating tablet); Emsam 12 mg/24 hour transdermally.

    Adolescents

    Safety and efficacy have not been established.

    Children

    12 years: Safety and efficacy have not been established.
    Less than 12 years: Transdermal patch is contraindicated.

    Infants

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild to Moderate hepatic impairment (Child-Pugh score 5 to 9): A dose reduction of selegiline orally disintegrating tablets (from 2.5 mg/day to 1.25 mg/day) may be required depending on clinical response. No adjustment of transdermal selegiline is needed. Specific guidelines for dosage adjustments for oral selegiline tablets and capsules are not available.
    Severe hepatic impairment (Child-Pugh score greater than 9): Selegiline orally disintegrating tablets are not recommended. Transdermal selegiline has not been studied. Specific guidelines for oral selegiline tablets or capsules in severe hepatic impairment are not available.

    Renal Impairment

    No dose adjustment of selegiline orally disintegrating tablets is required in patients with mild to moderate renal impairment (CrCl 30 to 89 mL/minute). Selegiline orally disintegrating tablets are not recommended in patients with severe renal impairment or end-stage renal disease (CrCl less than 30 mL/minute). No dosage adjustment of transdermal selegiline is needed in patients with mild, moderate, or severe renal impairment; transdermal selegiline has not been studied in patients with end-stage renal disease. Specific guidelines for dosage adjustment of oral selegiline tablets or caspules are not available.

    ADMINISTRATION

    Oral Administration

    Specific manufacturer recommendations for dietary tyramine intake must be followed to minimize the risk of a hypertensive crisis.

    Oral Solid Formulations

    Oral tablet or capsule (e.g., Eldepryl)
    Administer twice daily with breakfast and lunch.
    Do not administer doses greater than 10 mg/day because of the risk of hypertensive crisis.
     
    Orally-disintegrating tablets (e.g., Zelapar)
    Do not push selegiline ODT through the foil backing; peel back the backing of 1 or 2 blisters (as prescribed) with dry hands, and gently remove the tablet(s).
    Immediately place the tablet(s) on top of the patient's tongue where it will disintegrate in seconds. Do not swallow the ODT tablet.
    The patient should avoid ingesting food or liquids for 5 minutes before and after taking selegiline ODT.
    Do not administer doses greater than 2.5 mg/day because of the risk of hypertensive crisis.

    Topical Administration
    Transdermal Patch Formulations

    Specific manufacturer recommendations for dietary tyramine intake must be followed to minimize the risk of a hypertensive crisis when using the 9 mg/24 hour or 12 mg/24 hour transdermal patch strengths.
     
    Emsam transdermal selegiline patch Administration
    Remove the transdermal patch from the pouch by tearing at the notches on the pouch. Do not use scissors.
    The patch should be applied immediately after removal from the pouch. Do not store the patch outside of the sealed pouch.
    Do not cut or trim patch.
    Before application, wash the area with soap and warm water, and dry thoroughly.
    Apply the patch to dry, intact skin on the upper chest or back, upper thigh, or the outer surface of the upper arm. Apply to an area of skin that is not hairy, oily, irritated, broken, scarred, or calloused.
    After application, hands should be washed with soap and water.
    Usual activities, including exercise, bathing, and swimming can be maintained while wearing the patch.
    Avoid exposing the application site to external sources of direct heat, such as heating pads or electric blankets, heat lamps, saunas, hot tubs, heated water beds, and prolonged direct sunlight.
    If the patch falls off, apply a new patch to a new site and resume the previous dose schedule. In dermal adhesion studies, roughly 6% to 7% of patches applied to the upper torso became detached during a 10-day period.
    Advise patients to wear only 1 patch at a time.
    Rotate patch sites between the upper arm, upper chest, upper thigh, and upper back. New patches can be applied to sites near the previous site, but not to the same site.
    Once a patch is removed, a used patch should be folded to stick to itself and discarded in a waste receptacle out of the reach of children and pets.

    STORAGE

    Carbex:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Eldepryl:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    EMSAM:
    - Do not store outside of the sealed pouch
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Zelapar:
    - Product should be used within 3 months after opening
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Selegiline is contraindicated in patients with a hypersensitivity to selegiline or any inactive ingredients of the formulations.

    MAOI therapy

    Selegiline is an irreversible, selective monoamine oxidase (MAO) type B inhibitor. Therefore, selegiline is contraindicated in patients receiving any other MAOI therapy due to the risk for hypertensive crisis.. selegiline transdermal system is contraindicated with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), St. John's wort, the tricyclic antidepressants (TCAs), cyclobenzaprine, the opiate analgesics meperidine, tramadol, and other opiate agonists, and the antitussive agent dextromethorphan because of a risk of serotonin syndrome or bizarre behaviors when selegiline is used with these agents. Other drugs (e.g., carbamazepine) are contraindicated due to a risk of serious high blood pressure, including crisis. After stopping treatment with drugs contraindicated with selegiline, a time period equal to 4 to 5 half-lives (approximately 1 week) of the drug or any active metabolite should elapse before starting therapy with selegiline. At least 2 weeks should elapse after stopping selegiline before starting therapy with any drug that is contraindicated with selegiline.

    Alcoholism, ethanol ingestion, hypertension, hypertensive crisis

    The monoamine oxidase (MAO) enzyme system is important in the catabolism of dietary amines (e.g., tyramine), and selegiline acts as an irreversible MAO inhibitor. MAO exists as 2 isoenzymes, referred to as MAO-A and MAO-B. Selegiline shows greater affinity for MAO-B; however, as selegiline concentrations increase, this selectivity is lost with resulting dose-related inhibition of MAO-A. Intestinal MAO is predominantly type A, while in the brain both isoenzymes exist. Significant inhibition of intestinal MAO-A activity can impose a cardiovascular safety risk. MAOIs have been associated with hypertensive crisis caused by the ingestion of foods, beverages, or nutritional supplements with a high concentration of tyramine. Clinical data do not support the need for tyramine dietary modification at the selegiline transdermal dose of 6 mg/24 hour; however, unrestricted dietary tyramine data in clinical trials evaluating the 9 mg/24 hour or 12 mg/24 hour patch are limited and tyramine restrictions should be followed with these higher doses. Study results of selegiline orally disintegrating tablets (ODT) showed that an increase in tyramine sensitivity for blood pressure responses appears to begin at a dose of 5 mg/day; however, hypertensive crisis has also been reported with selegiline ODT use that was not above the recommended dosing. Patients receiving selegiline ODT should be advised to avoid certain foods containing a very large amount of tyramine (e.g., aged cheese) because of the potential for large increases in blood pressure. Oral selegiline tablets and capsules can ordinarily be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day); however, hypertensive reactions at recommended doses associated with dietary influences have been reported. Advise patients of dietary tyramine-restriction recommendations. Selegiline should not be used in patients with alcoholism. Tyramine-rich foods and beverages include: aged cheese; yeast extract; protein extract; soy sauce; fava bean or broad bean pods; smoked meats; pickled meats; chicken livers, smoked poultry; pickled poultry; smoked fish (lox, smoked salmon); pickled fish (pickled herring); fermented sausage (bologna, pepperoni, salami, summer sausage) or other fermented meat; bananas; avocados; any over-ripe fruit; and tap beer and beers that have not been pasteurized. The manufacturer of transdermal selegiline recommends avoiding ethanol ingestion and specifically recommends avoiding tyramine-rich alcoholic beverages such as all varieties of tap beer and beers that have not been pasteurized during use of the 9 mg/24 hour or 12 mg/24 hour patch and for 2 weeks after discontinuation or dose reduction to 6 mg/24 hour due to the risk for hypertensive crisis. Patients receiving any formulation of selegiline should be monitored for new onset hypertension or exacerbation of pre-existing hypertension. Hypertensive crisis, which can be fatal, may manifest as occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea, vomiting, sweating with possible fever and cold, clammy skin, dilated pupils, photophobia, tachycardia or bradycardia with possible constricting chest pain, or intracranial bleeding. A complete drug, food, and dietary supplement history should be obtained in all patients prior to prescribing selegiline. Patients should be instructed on the signs and symptoms of severe hypertension and advised to seek immediate medical attention if these signs or symptoms are present. If a hypertensive crisis occurs, selegiline should be discontinued immediately and the appropriate medical treatment should be initiated to lower blood pressure (e.g., phentolamine, labetalol, nitroprusside) and treat associated symptoms. Patients must be closely monitored until the symptoms have stabilized.

    Pheochromocytoma

    Transdermal selegiline is contraindicated in patients with pheochromocytoma. The associated tumor secretes pressor substances (e.g., norepinephrine) and the metabolism of these pressor substances may be reduced by MAOIs and potentially cause a hypertensive crisis. Oral forms of selegiline should generally also be avoided in these patients, due to similar reasons.

    Children, suicidal ideation

    Safety and efficacy of oral selegiline have not been established in children or adolescents. Transdermal selegiline is contraindicated in children less than 12 years due to the risk of hypertensive crisis; transdermal selegiline is not recommended for children and adolescents 12 to 17 years of age. Limited data suggest increased exposure to selegiline in children younger than 12 years of age compared to adolescents and adults with transdermal use, and children may not be able to reliably adhere to the required dietary restrictions. A flexible-dose controlled trial of transdermal selegiline failed to demonstrate efficacy, although the overall safety profile was similar to adults. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in pediatric patients. A causal role has been established for antidepressants in inducing suicidality in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants (SSRIs and others). The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment of SSRIs and other antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in children or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly during treatment initiation and at the time of a dose change. It is unknown if the suicidality risk in children and young adults extends beyond several months. The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another psychiatric disorder. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment are considered at an increased risk for suicidal ideation or attempts, and should be closely monitored during treatment with transdermal selegiline. In patients who exhibit changes in symptoms, worsening of depression or suicidality, a decision should be made to change or discontinue treatment. If discontinuing, the medication should be tapered as rapidly as possible, but with recognition that sudden discontinuation can also cause adverse symptoms.

    Bipolar disorder, mania

    The use of antidepressants, such as transdermal selegiline, has been associated with the precipitation of mania or hypomania in susceptible individuals. If a patient develops manic symptoms, transdermal selegiline should be withheld, and appropriate therapy initiated to treat the manic symptoms. Depression may also be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Patients with depression or comorbid depression in the setting of other psychiatric illness being treated with an antidepressant 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. Caregivers should be advised to closely observe the patient on a daily basis and to communicate immediately with the prescriber the emergence of agitation, irritability, unusual changes in behavior, or emergence of suicidality.

    Behavioral changes, psychosis, schizophrenia

    Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during oral selegiline treatment or after starting or increasing the dose. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of 1 or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Patients with a major psychotic disorder, such as schizophrenia, should generally not be treated with selegiline because the dopamine-enhancing properties of selegiline may cause or exacerbate hallucinations and psychosis. In addition, certain medications used to treat psychosis, such as dopamine antagonists, may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of selegiline. Behavioral changes have also 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. Families and caregivers of patients being treated with selegiline, for both psychiatric and nonpsychiatric indications, 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 healthcare providers. Such monitoring should include daily observation by families and caregivers.

    Impulse control symptoms

    Some patients receiving medications for Parkinson's disease that increase dopaminergic tone have reported intense and uncontrollable urges to gamble, increased sexual urges, or other intense urges. Causality due to dopaminergic agents has not been established; however, in some cases the urges stopped after the dose was reduced or the drug was discontinued. Practitioners should inquire periodically about new or worsening impulse control symptoms in Parkinson's patients receiving selegiline. Likewise, patients should be instructed to report such changes while receiving selegiline. Dose reduction or discontinuation should be considered in those who experience these effects.

    Hypotension, orthostatic hypotension

    Patients should be advised that they may develop symptomatic or asymptomatic hypotension while taking oral selegiline, particularly during treatment initiation. Caution patients against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially during treatment initiation. The incidence of orthostatic hypotension was higher in elderly adult patients than younger adult patients (3% vs. 0%). Orthostatic hypotension has also occurred with other oral dose forms. During clinical trial evaluation of transdermal selegiline, orthostatic hypotension occurred more frequently with the use of transdermal selegiline than placebo (10% vs. 7%). Patients with a pre-existing tendency towards changes in postural blood pressure should be observed closely for changes in blood pressure throughout treatment, and dose increases should be made carefully.

    Hepatic disease

    Caution is advisable in patients with hepatic disease; selegiline undergoes hepatic metabolism to active metabolites. Dosages of selegiline orally disintegrating tablets (ODT) in patients with mild to moderate hepatic impairment (Child-Pugh 5 to 9) are adjusted to clinical response. Selegiline ODT is not recommended in patients with severe hepatic impairment. No adjustment of transdermal selegiline is required in patients with mild or moderate liver impairment (Child-Pugh 5 to 9); transdermal selegiline has not been studied in patients with severe liver impairment (Child-Pugh score 10 to 15). Use oral selegiline tablets or capsules with caution in hepatically impaired patients; no specific recommendations are available.

    Renal failure, renal impairment

    Caution is advisable in patients with renal impairment; specific manufacturer recommendations should be followed. No dosage adjustment of transdermal selegiline is needed in patients with mild, moderate, or severe renal impairment; however, there are no data in patients with end-stage renal disease (ESRD). No dose adjustment of selegiline orally disintegrating tablets (ODT) is required in patients with mild to moderate renal impairment with a creatinine clearance (CrCl) 30 to 89 mL/minute). Selegiline ODT is not recommended in patients with severe renal impairment or end-stage renal disease (CrCl less than 30 mL/minute). No specific guidance is available for oral selegiline tablets or capsules in patients with renal impairment or renal failure.

    Melanoma

    Epidemiological studies have shown that patients with Parkinson's disease have a 2- to 6-fold higher risk of developing melanoma than the general population. It is unclear if this increased risk is disease-related or associated with other factors such as the medications used to treat Parkinson's disease. Therefore, it is recommended that a qualified practitioner (e.g., dermatologist) monitor for melanomas on a regular basis during selegiline use for any indication. Advise patients with Parkinson’s disease that they have a higher risk of developing melanoma. In addition, patients should be instructed to regularly monitor for skin changes that may indicate the presence of melanoma and to promptly report these changes to their provider.

    Driving or operating machinery

    Selegiline transdermal has not been shown to impair psychomotor performance; however, any psychoactive drug may potentially impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that selegiline transdermal therapy does not impair their ability to engage in such activities. Advise patients to avoid alcohol during treatment for depression. Oral selegiline may cause sedation; alcohol may enhance these effects. There have been reports of patients with Parkinson's disease who have fallen asleep while performing activities of daily living, including driving, while receiving drugs that increase dopaminergic tone, including oral selegiline products. Excessive drowsiness has, in some cases, occurred as late as one year after the initiation of treatment. In some cases excessive drowsiness has resulted in auto accidents or other harmful events in the course of daily living. Symptoms of excessive drowsiness may not be preceded by warning signs such as somnolence. Before initiating treatment with selegiline, patients should be advised about the potential to develop drowsiness and specifically asked about factors that may increase this risk, such as concomitant use of sedating medications and the presence of sleep disorders. Reassessment for oversedation is suggested throughout therapy. Patients should exercise caution while driving or operating machinery, working at heights, or performing other tasks that require alertness while receiving oral selegiline. Those who have experienced somnolence or a sudden episode of sleep with the drug should avoid these activities. Selegiline should generally be discontinued in those experiencing episodes of falling asleep while engaged in activities of daily living. It is not known if a reduction in dosage will subsequently reduce or eliminate excessive somnolence or sudden episodes of sleep.

    Abrupt discontinuation

    Although not reported with selegiline during clinical trials for Parkinson's disease, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy. Avoid abrupt discontinuation of therapy when possible.

    Pregnancy

    Because there are no adequate and well-controlled studies of selegiline use in pregnant women, the drug should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Selegiline has a low molecular weight and would be expected to cross the placenta. A case report of oral selegiline used in a pregnant woman who continued the drug throughout gestation noted no teratogenic defects or developmental delays in a healthy male infant over a 10-year period. However, animal studies suggest the potential for neurological changes. Decreases in fetal weight, delayed ossification, and embryo-fetal post-implantation lethality have been noted during the period of organogenesis in animal studies at doses up to 60 times the maximum recommended human dose (MRHD). Slight increases in visceral malformations have been seen during the period of embryo-fetal development in animal studies at doses up to 64 times the MRHD. An increase in stillborn pups and post-implantation loss has been seen in rat studies. Throughout lactation and post-weaning periods, decreases in pup weight, retarded pup physical development, and retarded pup neurobehavioral and sexual development were seen at all doses up to 60 times the MRHD. These findings suggest persistent effects on the offspring of treated dams. A no-effect dose was not established for developmental toxicity. It is not known how these animal findings relate to effects in pregnant women. Selegiline has not established use in labor and delivery.

    Breast-feeding

    It is unknown if selegiline is excreted into human breast milk, and a decision should be made whether to discontinue the drug or discontinue breast-feeding, taking into account the importance of the drug to the mother. Consideration should be given to discontinuing the use of all but absolutely essential drug treatments in nursing women. The manufacturer of transdermal selegiline advises caution if administering transdermal selegiline during breast-feeding. Selegiline has a low molecular weight (188 for the free base) and would be expected to cross into human breast milk. A case report describes maternal use of oral selegiline 10 mg/day, levodopa 400 mg, and benserazide 100 mg daily throughout pregnancy and for 3 days while breast-feeding; the child was followed for 10 years and no developmental abnormalities were found. An accurate prediction of the long-term adverse effects of selegiline in the nursing infant may not be possible because the drug affects central neurotransmitter function, and may alter the developing central nervous system. Although rasagiline may be considered as an alternative therapy to selegiline for the adjunct treatment of Parkinson's disease in breast-feeding women, safety data are lacking. In addition, both rasagiline and selegiline can inhibit prolactin secretion, and thus, interference with proper lactation is possible. Psychotropic medications affect neurotransmitter function in the developing central nervous system, and therefore, the accurate prediction of long-term adverse effects may not be possible. Due to individual variability in response to antidepressants, it may be prudent to continue the existing regimen if ongoing treatment is deemed necessary during breast-feeding. However, because a pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum, these agents may be preferable to transdermal selegiline when initiating antidepressant therapy in a breast-feeding mother. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    Geriatric patients should be advised that they may develop symptomatic or asymptomatic hypotension while taking selegiline, particularly during treatment initiation. Caution patients against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially during treatment initiation. The elderly population with Parkinson's disease, already at risk for falls, may be at greater risk with the use of selegiline; therefore, caution is warranted. During clinical trials of selegiline orally disintegrating tablets (ODT), the incidence of orthostatic hypotension was higher in geriatric patients than younger patients (3% vs. 0%). There were no overall differences in effectiveness between geriatric and younger adult patients who participated in clinical studies with transdermal selegiline; however, patients 50 years and older receiving transdermal selegiline appeared to be at higher risk for rash than younger adult patients receiving placebo (4.4% vs. 3.4%). The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, antiparkinson medications may cause significant confusion, restlessness, delirium, dyskinesia, nausea, dizziness, hallucinations, and agitation. In addition, there is an increased risk of postural hypotension and falls, particularly during concurrent use of antihypertensive medications. During use of transdermal selegiline as an antidepressant, the OBRA guidelines state that the duration of therapy should be in accordance with pertinent literature for the condition being treated, including clinical practice guidelines. All residents being treated for depression with any antidepressant should be monitored closely for worsening of depression and/or suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Antidepressants may cause dizziness, nausea, diarrhea, anxiety, nervousness, insomnia, somnolence, weight gain, anorexia, or increased appetite. Many of these effects can increase the risk for falls. Monoamine oxidase inhibitors (MAOIs) should not be administered to those with a confirmed or suspected cerebrovascular defect, confirmed cardiovascular disease or hypertension, or pheochromocytoma. MAOIs are rarely used due to their potential interactions (i.e., hypertensive crisis) with tyramine- or tryptophan-containing foods (e.g., cheese, wine) or other medications, and their profound effect on blood pressure. MAOIs should not be administered together or in rapid succession with other MAOIs, tricyclic antidepressants, bupropion, SSRIs, buspirone, sympathomimetics, meperidine, triptans, and other medications that affect serotonin or norepinephrine. Monitoring should consist of a review for continued need at least quarterly, and documentation of the rationale for continuation. When the drug is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the medication as outlined in the OBRA guidelines, unless a taper is clinically contraindicated.

    Phenylketonuria

    Selegiline orally disintegrating tablets should be used cautiously in patients with phenylketonuria. Each selegiline orally disintegrating tablet (Zelapar) contains 1.25 mg phenylalanine (a component of aspartame). Patients taking the 2.5 mg dose will receive 2.5 mg phenylalanine. Advise patients that selegiline orally disintegrating tablets contains aspartame which could cause problems in patients with phenylketonuria.

    Ambient temperature increase, heating pad, sunlight (UV) exposure

    The effect of direct heat applied to the selegiline transdermal patch on the bioavailability of selegiline has not been studied. However, in theory, heat may result in an increase in the amount of selegiline absorbed from the patch and produce elevated serum levels of selegiline. Patients should be advised to avoid exposing the patch application site to external sources of direct heat, such as a heating pad or electric blanket, or any external ambient temperature increase from heat lamps, saunas, hot tubs, heated water beds, and prolonged direct sunlight (UV) exposure.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / Incidence not known
    akinesia / Delayed / Incidence not known
    tardive dyskinesia / Delayed / Incidence not known
    esophageal ulceration / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    cholecystitis / Delayed / Incidence not known
    GI obstruction / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    atrial flutter / Early / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    AV block / Early / Incidence not known
    atrial fibrillation / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    hypertensive crisis / Early / Incidence not known
    prostatic hypertrophy / Delayed / Incidence not known
    epididymitis / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    ocular hemorrhage / Delayed / Incidence not known
    hearing loss / Delayed / Incidence not known
    retinal detachment / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    pneumothorax / Early / Incidence not known
    bronchospasm / Rapid / Incidence not known
    pleural effusion / Delayed / Incidence not known
    cyanosis / Early / Incidence not known
    hyperkalemia / Delayed / Incidence not known

    Moderate

    orthostatic hypotension / Delayed / 0-21.0
    confusion / Early / 6.1-6.1
    hallucinations / Early / 4.0-6.1
    dyskinesia / Delayed / 6.0-6.0
    stomatitis / Delayed / 5.0-5.0
    constipation / Delayed / 4.0-4.0
    ataxia / Delayed / 3.0-3.0
    hypertension / Early / 3.0-3.0
    erythema / Early / 0-3.0
    dyspnea / Early / 3.0-3.0
    dysphagia / Delayed / 2.0-2.0
    chest pain (unspecified) / Early / 2.0-2.0
    oral ulceration / Delayed / 2.0-2.0
    depression / Delayed / 0-2.0
    hypokalemia / Delayed / 2.0-2.0
    mania / Early / 0-1.0
    psychosis / Early / Incidence not known
    encephalopathy / Delayed / Incidence not known
    hypertonia / Delayed / Incidence not known
    involuntary movements / Delayed / Incidence not known
    subdural hematoma / Early / Incidence not known
    hypotonia / Delayed / Incidence not known
    myoclonia / Delayed / Incidence not known
    neuropathic pain / Delayed / Incidence not known
    aphasia / Delayed / Incidence not known
    migraine / Early / Incidence not known
    amnesia / Delayed / Incidence not known
    dystonic reaction / Delayed / Incidence not known
    memory impairment / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    esophagitis / Delayed / Incidence not known
    teeth grinding (bruxism) / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    cholelithiasis / Delayed / Incidence not known
    gastritis / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    angina / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    peripheral edema / Delayed / Incidence not known
    peripheral vasodilation / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    palpitations / Early / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    urinary retention / Early / Incidence not known
    ejaculation dysfunction / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known
    nephrolithiasis / Delayed / Incidence not known
    urinary incontinence / Early / Incidence not known
    glossitis / Early / Incidence not known
    impulse control symptoms / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    amblyopia / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    cataracts / Delayed / Incidence not known
    blepharospasm / Early / Incidence not known
    edema / Delayed / Incidence not known
    atopic dermatitis / Delayed / Incidence not known
    hematoma / Early / Incidence not known
    skin ulcer / Delayed / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    bone pain / Delayed / Incidence not known
    flank pain / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    gout / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    fluid retention / Delayed / Incidence not known
    hyperphosphatemia / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    hyponatremia / Delayed / Incidence not known
    dehydration / Delayed / Incidence not known
    hyperlipidemia / Delayed / Incidence not known
    secondary malignancy / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known

    Mild

    nausea / Early / 11.0-20.4
    headache / Early / 4.1-18.0
    dizziness / Early / 11.0-14.3
    insomnia / Early / 7.0-12.0
    diarrhea / Early / 2.0-9.0
    abdominal pain / Early / 8.2-8.2
    xerostomia / Early / 4.0-8.0
    rhinitis / Early / 7.0-7.0
    dyspepsia / Early / 4.0-5.0
    back pain / Delayed / 5.0-5.0
    pharyngitis / Delayed / 3.0-4.0
    rash (unspecified) / Early / 4.0-4.0
    drowsiness / Early / 3.0-3.0
    tremor / Early / 3.0-3.0
    vomiting / Early / 3.0-3.0
    muscle cramps / Delayed / 3.0-3.0
    flatulence / Early / 2.0-2.0
    ecchymosis / Delayed / 2.0-2.0
    irritability / Delayed / Incidence not known
    hyporeflexia / Delayed / Incidence not known
    agitation / Early / Incidence not known
    emotional lability / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    lethargy / Early / Incidence not known
    malaise / Early / Incidence not known
    fatigue / Early / Incidence not known
    hyperkinesis / Delayed / Incidence not known
    vertigo / Early / Incidence not known
    hypersalivation / Early / Incidence not known
    nightmares / Early / Incidence not known
    weakness / Early / Incidence not known
    paranoia / Early / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    restlessness / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    gingivitis / Delayed / Incidence not known
    pyrosis (heartburn) / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    syncope / Early / Incidence not known
    increased urinary frequency / Early / Incidence not known
    orgasm dysfunction / Delayed / Incidence not known
    urinary urgency / Early / Incidence not known
    nocturia / Early / Incidence not known
    libido decrease / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    skin irritation / Early / Incidence not known
    dysgeusia / Early / Incidence not known
    diplopia / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    xerophthalmia / Early / Incidence not known
    epistaxis / Delayed / Incidence not known
    sinusitis / Delayed / Incidence not known
    fever / Early / Incidence not known
    infection / Delayed / Incidence not known
    hiccups / Early / Incidence not known
    diaphoresis / Early / Incidence not known
    alopecia / Delayed / Incidence not known
    pallor / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    skin discoloration / Delayed / Incidence not known
    xerosis / Delayed / Incidence not known
    seborrhea / Delayed / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    arthropathy / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    chills / Rapid / Incidence not known
    myalgia / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    hypovitaminosis / Delayed / Incidence not known
    leukocytosis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Acetaminophen; Aspirin, ASA; Caffeine: (Major) Excessive use of caffeine in any form should be avoided in patients receiving Monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive. Ordinarily, selegiline may be an exception, it can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet.
    Acetaminophen; Butalbital: (Major) Additive CNS depression may occur if butalbital is used concomitantly with monoamine oxidase inhibitors.
    Acetaminophen; Butalbital; Caffeine: (Major) Additive CNS depression may occur if butalbital is used concomitantly with monoamine oxidase inhibitors. (Major) Excessive use of caffeine in any form should be avoided in patients receiving Monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive. Ordinarily, selegiline may be an exception, it can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine. (Major) Additive CNS depression may occur if butalbital is used concomitantly with monoamine oxidase inhibitors. (Major) Excessive use of caffeine in any form should be avoided in patients receiving Monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive. Ordinarily, selegiline may be an exception, it can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet.
    Acetaminophen; Caffeine; Dihydrocodeine: (Severe) Dihydrocodeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of dihydrocodeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as dihydrocodeine. (Major) Excessive use of caffeine in any form should be avoided in patients receiving Monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive. Ordinarily, selegiline may be an exception, it can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Major) Excessive use of caffeine in any form should be avoided in patients receiving Monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive. Ordinarily, selegiline may be an exception, it can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Major) Excessive use of caffeine in any form should be avoided in patients receiving Monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive. Ordinarily, selegiline may be an exception, it can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Acetaminophen; Codeine: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine.
    Acetaminophen; Dextromethorphan: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Acetaminophen; Dextromethorphan; Doxylamine: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Acetaminophen; Hydrocodone: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Acetaminophen; Oxycodone: (Major) Concomitant use of oxycodone with other CNS depressants, such as MAOIs, can lead to additive respiratory or CNS depression, hypotension, profound sedation, or coma. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Advise patients against driving or performing other tasks requiring alertness until they know how the combination affects them.
    Acetaminophen; Pentazocine: (Major) Patients receiving concurrent pentazocine and MAOIs are at increased risk for developing serotonin syndrome; pentazocine should be used cautiously, if at all, in these patients.
    Acetaminophen; Propoxyphene: (Severe) Concurrent use of selegiline or selegiline, transdermal and propoxyphene is contraindicated. Severe reactions such as excitation, sweating, rigidity, hypertension, severe respiratory depression, coma, and peripheral vascular collapse, possibly resulting in death, can occur. At least 2 weeks should elapse between stopping selegiline and starting propoxyphene.
    Acetaminophen; Tramadol: (Severe) Tramadol use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol.
    Alfentanil: (Major) Alfentanil belongs to the phenylpiperidine group of opioids. Meperidine, also a phenylpiperidine agent, has been reported to produce a life-threatening serotonin syndrome when coadministered with monoamine oxidase inhibitors. In addition to the potential for serotonin syndrome, opioids also potentiate the respiratory and CNS depression and hypotension caused by MAOIs. Severe and unpredictable potentiation of MAOIs has been reported rarely with alfentanil. Appropriate monitoring and immediate availability of vasodilators and beta blockers for the treatment of hypertension is recommended if alfentanil is used within 14 days of MAOI administration. Advise patients against driving or performing other hazardous activities after receiving alfentanil.
    Aliskiren: (Moderate) Orthostatic hypotension has been reported during administration of selegiline. Therefore, caution is advised during concurrent use with antihypertensive agents.
    Aliskiren; Amlodipine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Orthostatic hypotension has been reported during administration of selegiline. Therefore, caution is advised during concurrent use with antihypertensive agents.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Orthostatic hypotension has been reported during administration of selegiline. Therefore, caution is advised during concurrent use with antihypertensive agents.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Orthostatic hypotension has been reported during administration of selegiline. Therefore, caution is advised during concurrent use with antihypertensive agents.
    Aliskiren; Valsartan: (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Orthostatic hypotension has been reported during administration of selegiline. Therefore, caution is advised during concurrent use with antihypertensive agents.
    Almotriptan: (Major) Serotonin syndrome has been reported during co-administration of serotonin-receptor agonists and monoamine oxidase inhibitors (MAOIs). Since oral selegiline selectively inhibits MAO-B at recommended doses, no interaction with almotriptan would be expected with normal prescription use. However, there is a decline in MAO-B selectivity with increasing doses. Therefore, high dose treatment with oral selegiline may increase central serotonin levels through MAO-A inhibition. In addition, selegiline, transdermal inhibits both MAO-A and MAO-B at the usual antidepressant doses. However, whether or not 5-HT1B/1D agonists such as almotriptan can cause serious cases of serotonin syndrome when used with serotonergic drugs has been debated since serotonin syndrome is thought to result primarily from 5-HT2A activation. Approximately 27% of a dose of almotriptan is metabolized by MAO-A. Theoretically, use of high dose selegiline could increase systemic exposure to almotriptan through MAO-A inhibition, although a significant interaction appears remote based on results of an interaction study between almotriptan and the selective MAO-A inhibitor moclobemide.
    Alogliptin: (Moderate) Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and other antidiabetic agents. Animal data indicate that tranylcypromine stimulates insulin secretion. It has also been proposed that MAOIs may interfere with the adrenergic response to hypoglycemia but it is uncertain how significant this action may be. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Alogliptin; Metformin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents. Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost. (Moderate) Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and other antidiabetic agents. Animal data indicate that tranylcypromine stimulates insulin secretion. It has also been proposed that MAOIs may interfere with the adrenergic response to hypoglycemia but it is uncertain how significant this action may be. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Alogliptin; Pioglitazone: (Moderate) Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and other antidiabetic agents. Animal data indicate that tranylcypromine stimulates insulin secretion. It has also been proposed that MAOIs may interfere with the adrenergic response to hypoglycemia but it is uncertain how significant this action may be. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Alpha-blockers: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy with antihypertensives such as alpha-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Alpha-glucosidase Inhibitors: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents. Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Alprazolam: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Altretamine: (Severe) Avoid concomitant use of antidepressant MAOIs during altretamine therapy whenever possible. Concurrent administration of altretamine and antidepressants of the monoamine oxidase (MAO) inhibitor class may cause severe orthostatic hypotension. Four patients, all over 60 years of age, were reported to have experienced symptomatic hypotension after 4 to 7 days of concomitant therapy with altretamine and MAO inhibitors (MAOIs). The mechanism of the interaction is not clear. While clinical reports of this interaction do not exist for selegiline transdermal, orthostatic hypotension has been reported as an uncommon but potentially significant adverse event in the elderly utilizing selegiline transdermal. The cautious use of altretamine and selegiline transdermal in this at-risk population should be observed to avoid pharmacodynamic interactions.
    Ambrisentan: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties suah as ambrisentan. Careful monitoring of blood pressure is suggested during concurrent therapy.
    Amide local anesthetics: (Severe) Patients receiving local anesthetics may have an increased risk of hypotension. Combined hypotensive effects are possible with use of MAOIs and spinal anesthetics. Use of epinephrine added to etidocaine with monoamine oxidase inhibitors (MAOIs) or drugs with MAOI activity (e.g., furazolidone, linezolid, or procarbazine) is not recommended. When local anesthetics containing sympathomimetic vasoconstrictors are coadministered with MAOIs, severe and prolonged hypertension may occur. MAOIs and agents with MAOI activity can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient. Administration of a phenothiazine or a butyrophenone may reduce or reverse the pressor effect of epinephrine. Phenelzine, tranylcypromine, and transdermal selegiline are contraindicated for use for at least 10 days prior to elective surgery.
    Amiloride: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Amitriptyline: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with tricyclic antidepressants (TCAs) or within 14 days of discontinuing treatment with a TCA. Conversely, TCAs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Amitriptyline; Chlordiazepoxide: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with tricyclic antidepressants (TCAs) or within 14 days of discontinuing treatment with a TCA. Conversely, TCAs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Amlodipine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Amlodipine; Atorvastatin: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Amlodipine; Benazepril: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Amlodipine; Olmesartan: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Amlodipine; Telmisartan: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Amlodipine; Valsartan: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Amobarbital: (Major) MAOIs may prolong the effect of some barbiturates. Additionally, patients receiving MAOIs may have an increased risk of hypotension after administration of barbiturates used for sedation induction.
    Amoxapine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with heterocyclic antidepressants (e.g., trazodone, mirtazapine, amoxapine, maptrotiline) or within 14 days of discontinuing treatment with a heterocyclic antidepressant. Conversely, heterocyclic antidepressants should not be initiated within 14 days of stopping an MAOI. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Anagrelide: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including selegiline, could lead to increases in the serum concentration of selegiline and thus, adverse effects. Monitor for increased toxicity of selegiline.
    Angiotensin II receptor antagonists: (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Angiotensin-converting enzyme inhibitors: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Anxiolytics; Sedatives; and Hypnotics: (Moderate) The manufacturers of MAOIs contraindicate the use of MAOIs with some CNS depressant drugs due to additive CNS depressant effects. If combination therapy is necessary, use caution; warn patients to avoid driving or performing other hazardous activities until they know how the combination affects them. A dose reduction of one or both medications may be required.
    Apraclonidine: (Severe) Apraclonidine is contraindicated for use in patients receiving MAOIs. Apraclonidine should not be administered to patients who have received MAOIs within the previous 14 days.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if selegiline and aprepitant, fosaprepitant are used concurrently, and monitor for an increase in selegiline-related adverse effects for several days after administration of a multi-day aprepitant regimen. Selegiline is a CYP3A4 substrate in vitro. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of selegiline. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Aprepitant is also a CYP2C9 inducer and selegiline is a CYP2C9 substrate in vitro. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.
    Armodafinil: (Major) Armodafinil has not been evaluated for drug interactions with monoamine oxidase inhibitors (MAOIs). It is known that many other CNS stimulants may induce severe cardiovascular and cerebrovascular responses if administered in combination with drugs with non-selective MAO inhibitor activity. Until more is known regarding the pharmacology of armodafinil, it is prudent avoid the use of armodafinil in the presence of an MAO inhibitor. Due to the prolonged duration of action of MAOIs, a period of at least 14 days between the last dose of the MAOI and the first dose of armodafinil should elapse.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Additive CNS depression may occur if butalbital is used concomitantly with monoamine oxidase inhibitors. (Major) Excessive use of caffeine in any form should be avoided in patients receiving Monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive. Ordinarily, selegiline may be an exception, it can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine. (Major) Additive CNS depression may occur if butalbital is used concomitantly with monoamine oxidase inhibitors. (Major) Excessive use of caffeine in any form should be avoided in patients receiving Monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive. Ordinarily, selegiline may be an exception, it can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Severe) Dihydrocodeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of dihydrocodeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as dihydrocodeine. (Major) Excessive use of caffeine in any form should be avoided in patients receiving Monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive. Ordinarily, selegiline may be an exception, it can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet.
    Aspirin, ASA; Carisoprodol; Codeine: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of oxycodone with other CNS depressants, such as MAOIs, can lead to additive respiratory or CNS depression, hypotension, profound sedation, or coma. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Advise patients against driving or performing other tasks requiring alertness until they know how the combination affects them.
    Atazanavir: (Moderate) Caution is warranted when atazanavir is administered with selegiline as there is a potential for elevated selegiline concentrations. Selegiline is a substrate of CYP3A4; atazanavir is an inhibitor of CYP3A4.
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when atazanavir is administered with selegiline as there is a potential for elevated selegiline concentrations. Selegiline is a substrate of CYP3A4; atazanavir is an inhibitor of CYP3A4. (Moderate) Caution is warranted when cobicistat is administered with selegiline as there is a potential for elevated selegiline concentrations. Selegiline is a substrate of CYP3A4 and cobicistat is an inhibitor of CYP3A4.
    Atenolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Atenolol; Chlorthalidone: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) Concurrent use of methylene blue and MAOIs (e.g., tranylcypromine, isocarboxazid, phenelzine, and including selective MAOIs such as selegiline, rasagiline) should generally be avoided due to the potential for serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and traditional MAOIs similarly increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonergic agents. It is not known if patients receiving intravenous methylene blue with MAO-inhibiting agents or linezolid are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If emergent treatment with methylene blue is required in a patient receiving an MAOI, the MAOI should be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the MAOI should be stopped at least 2 weeks prior to methylene blue treatment. Because rasagiline is a selective monoamine oxidase-B (MAO-B) inhibitor at manufacturer recommended doses, an interaction with serotonin-enhancing medications may be less likely to occur than with other traditional MAO inhibitors.
    Atropine; Difenoxin: (Severe) The concomitant administration of diphenoxylate or difenoxin and monoamine oxidase inhibitors can cause hypertensive crisis. Avoid concurrent use.
    Atropine; Diphenoxylate: (Severe) The concomitant administration of diphenoxylate or difenoxin and monoamine oxidase inhibitors can cause hypertensive crisis. Avoid concurrent use.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Monoamine oxidase inhibitors (MAOIs) can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. MAOIs may prolong the effect of phenobarbital and cause additive CNS depression.
    atypical antipsychotic: (Moderate) Due to the potential for additive CNS and cardiovascular effects, MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.
    Azilsartan: (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Azilsartan; Chlorthalidone: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Monoamine oxidase inhibitors (MAOIs) can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. MAOIs may prolong the effect of phenobarbital and cause additive CNS depression.
    Belladonna; Opium: (Major) Concomitant use of central nervous system depressants, such as MAOIs, can potentiate the effects of opium, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Benazepril: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Bendroflumethiazide; Nadolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Benzodiazepines: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) Concurrent use of methylene blue and MAOIs (e.g., tranylcypromine, isocarboxazid, phenelzine, and including selective MAOIs such as selegiline, rasagiline) should generally be avoided due to the potential for serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and traditional MAOIs similarly increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonergic agents. It is not known if patients receiving intravenous methylene blue with MAO-inhibiting agents or linezolid are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If emergent treatment with methylene blue is required in a patient receiving an MAOI, the MAOI should be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the MAOI should be stopped at least 2 weeks prior to methylene blue treatment. Because rasagiline is a selective monoamine oxidase-B (MAO-B) inhibitor at manufacturer recommended doses, an interaction with serotonin-enhancing medications may be less likely to occur than with other traditional MAO inhibitors.
    Benzonatate: (Major) These drugs should be prescribed with caution. It may be advisable to avoid the use of benzonatate, which is structurally similar to local anesthetic agents, in patients receiving a monoamine oxidase inhibitor (MAOI). Consider alternatives to benzonatate. Patients receiving a MAOI concurrently with local anesthetics may have an increased risk of hypotension or CNS-related effects. If co-use is medically necessary, observe the patient for additive effects such as low blood pressure, sedation, dizziness, mental confusion, or other side effects.
    Beta-adrenergic blockers: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Beta-agonists: (Major) Beta-agonists should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors (MAOIs) due to their sympathomimetic effects. Weigh the risks of co-use, and where possible, allow a washout period after discontinuation of the MAOI before instituring beta-agonist treatment or vice-versa. The cardiovascular effects of beta-agonists may be potentiated by concomitant use of MAOIs. At least one case of hypertension occurred in a patient with previous episodes of high blood pressure who was receiving albuterol and selegiline concurrently. Close observation for such effects is prudent, particularly if beta-agonists are administered within 2 weeks of stopping the MAOI. Monitor blood pressure and heart rate.
    Betaxolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Bisoprolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering selegiline with boceprevir due to an increased potential for selegiline-related adverse events. If selegiline dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of selegiline. Selegiline is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated selegiline plasma concentrations.
    Brigatinib: (Moderate) Monitor for decreased efficacy of selegiline if coadministration with brigatinib is necessary. Selegiline is a CYP3A substrate and brigatinib induces CYP3A in vitro. Adequate studies have not been done investigating the effect of CYP3A4-inducers on selegiline; plasma concentrations may decrease.
    Brimonidine: (Moderate) Use caution during concurrent administration of brimonidine and monoamine oxidase inhibitors (MAOIs). MAOIs can affect the metabolism and uptake of circulating amines. MAOIs may theoretically interfere with the metabolism of brimonidine resulting in increased systemic side effects like hypotension.
    Brimonidine; Brinzolamide: (Moderate) Use caution during concurrent administration of brimonidine and monoamine oxidase inhibitors (MAOIs). MAOIs can affect the metabolism and uptake of circulating amines. MAOIs may theoretically interfere with the metabolism of brimonidine resulting in increased systemic side effects like hypotension.
    Brimonidine; Timolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Use caution during concurrent administration of brimonidine and monoamine oxidase inhibitors (MAOIs). MAOIs can affect the metabolism and uptake of circulating amines. MAOIs may theoretically interfere with the metabolism of brimonidine resulting in increased systemic side effects like hypotension.
    Brompheniramine; Carbetapentane; Phenylephrine: (Major) Carbetapentane should be avoided in patients receiving MAOIs, and should not be used within 14 days of discontinuation of an MAOI. Carbetapentane has similar pharmacologic properties to dextromethorphan, and can block neuronal uptake of serotonin. Excessive concentrations of serotonin in the CNS may occur if carbetapentane is combined with MAOIs. A serotonin syndrome, consisting of nausea, hypotension, excitation, hyperpyrexia, and coma is possible.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Bumetanide: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Buprenorphine: (Major) Concurrent use of opioids with other drugs that modulate serotonergic function, such as monoamine oxidase inhibitors (MAOIs), has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. In addition, both MAOIs and buprenorphine have CNS depressant effects which may be additive during combination therapy. Patients should be advised to avoid driving or other tasks requiring mental alertness until the effects of the combination are known.
    Buprenorphine; Naloxone: (Major) Concurrent use of opioids with other drugs that modulate serotonergic function, such as monoamine oxidase inhibitors (MAOIs), has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. In addition, both MAOIs and buprenorphine have CNS depressant effects which may be additive during combination therapy. Patients should be advised to avoid driving or other tasks requiring mental alertness until the effects of the combination are known.
    Bupropion: (Severe) Monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with bupropion or within 14 days of discontinuing treatment with bupropion. Conversely, bupropion should not be initiated within 14 days of stopping an MAOI. There is an increased risk of hypertensive reactions when bupropion is used concurrently with other drugs that inhibit the reuptake of dopamine or norepinephrine or inhibit their metabolism, such as MAOIs.
    Bupropion; Naltrexone: (Severe) Monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with bupropion or within 14 days of discontinuing treatment with bupropion. Conversely, bupropion should not be initiated within 14 days of stopping an MAOI. There is an increased risk of hypertensive reactions when bupropion is used concurrently with other drugs that inhibit the reuptake of dopamine or norepinephrine or inhibit their metabolism, such as MAOIs.
    Buspirone: (Severe) Concomitant use of MAOIs and buspirone is contraindicated because several cases of elevated blood pressure have been reported in patients taking MAO inhibitors who were then given buspirone HCL. A 10-day interval after discontinuing isocarboxazid is recommended before initiating buspirone treatment.
    Butabarbital: (Major) Monoamine oxidase inhibitors may prolong the effect of some barbiturates. Barbiturates should be used cautiously in patients receiving MAOIs.
    Butorphanol: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including butorphanol.
    Caffeine: (Major) Excessive use of caffeine in any form should be avoided in patients receiving Monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive. Ordinarily, selegiline may be an exception, it can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet. (Major) Excessive use of caffeine in any form should be avoided in patients receiving monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive.Selegiline can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet.
    Caffeine; Ergotamine: (Major) Excessive use of caffeine in any form should be avoided in patients receiving Monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive. Ordinarily, selegiline may be an exception, it can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet.
    Calcium-channel blockers: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Canagliflozin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Canagliflozin; Metformin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents. Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost. (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Candesartan: (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Capecitabine: (Moderate) Use caution if coadministration of capecitabine with selegiline is necessary, and monitor for an increase in selegiline-related adverse reactions. Selegiline is a CYP2C9 substrate in vitro; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    Captopril: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Carbamazepine: (Severe) MAOIs should not be coadministered at the same time with carbamazepine, a dibenzazepine-related drug. Hypertensive crises, seizures, coma, or circulatory collapse may occur in patients receiving this combination. At least 7 days should elapse between discontinuation of carbamazepine and initiation of an MAOI. MAOIs should be discontinued for a minimum of 14 days or longer if the clinical situation permits, before administering carbamazepine. When starting MAOI therapy after discontinuing carbamazepine, it is advised to begin the MAOI at one-half the normal starting dosage for at least the first week of therapy. Carefully monitor the patient. Watch carefully for other effects besides effects on blood pressure, such as sedation, confusion, and increased CNS depression. If carbamazepine is used for the treatment of epilepsy, be aware that MAOI effects can include lowering of seizure threshold in some patients. Carbamazepine has also been shown to significantly elevate the levels of the MAOI selegiline, which may further increase the risk of a hypertensive crisis.
    Carbetapentane; Chlorpheniramine: (Major) Carbetapentane should be avoided in patients receiving MAOIs, and should not be used within 14 days of discontinuation of an MAOI. Carbetapentane has similar pharmacologic properties to dextromethorphan, and can block neuronal uptake of serotonin. Excessive concentrations of serotonin in the CNS may occur if carbetapentane is combined with MAOIs. A serotonin syndrome, consisting of nausea, hypotension, excitation, hyperpyrexia, and coma is possible.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Major) Carbetapentane should be avoided in patients receiving MAOIs, and should not be used within 14 days of discontinuation of an MAOI. Carbetapentane has similar pharmacologic properties to dextromethorphan, and can block neuronal uptake of serotonin. Excessive concentrations of serotonin in the CNS may occur if carbetapentane is combined with MAOIs. A serotonin syndrome, consisting of nausea, hypotension, excitation, hyperpyrexia, and coma is possible.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Major) Carbetapentane should be avoided in patients receiving MAOIs, and should not be used within 14 days of discontinuation of an MAOI. Carbetapentane has similar pharmacologic properties to dextromethorphan, and can block neuronal uptake of serotonin. Excessive concentrations of serotonin in the CNS may occur if carbetapentane is combined with MAOIs. A serotonin syndrome, consisting of nausea, hypotension, excitation, hyperpyrexia, and coma is possible.
    Carbetapentane; Guaifenesin: (Major) Carbetapentane should be avoided in patients receiving MAOIs, and should not be used within 14 days of discontinuation of an MAOI. Carbetapentane has similar pharmacologic properties to dextromethorphan, and can block neuronal uptake of serotonin. Excessive concentrations of serotonin in the CNS may occur if carbetapentane is combined with MAOIs. A serotonin syndrome, consisting of nausea, hypotension, excitation, hyperpyrexia, and coma is possible.
    Carbetapentane; Guaifenesin; Phenylephrine: (Major) Carbetapentane should be avoided in patients receiving MAOIs, and should not be used within 14 days of discontinuation of an MAOI. Carbetapentane has similar pharmacologic properties to dextromethorphan, and can block neuronal uptake of serotonin. Excessive concentrations of serotonin in the CNS may occur if carbetapentane is combined with MAOIs. A serotonin syndrome, consisting of nausea, hypotension, excitation, hyperpyrexia, and coma is possible.
    Carbetapentane; Phenylephrine: (Major) Carbetapentane should be avoided in patients receiving MAOIs, and should not be used within 14 days of discontinuation of an MAOI. Carbetapentane has similar pharmacologic properties to dextromethorphan, and can block neuronal uptake of serotonin. Excessive concentrations of serotonin in the CNS may occur if carbetapentane is combined with MAOIs. A serotonin syndrome, consisting of nausea, hypotension, excitation, hyperpyrexia, and coma is possible.
    Carbetapentane; Phenylephrine; Pyrilamine: (Major) Carbetapentane should be avoided in patients receiving MAOIs, and should not be used within 14 days of discontinuation of an MAOI. Carbetapentane has similar pharmacologic properties to dextromethorphan, and can block neuronal uptake of serotonin. Excessive concentrations of serotonin in the CNS may occur if carbetapentane is combined with MAOIs. A serotonin syndrome, consisting of nausea, hypotension, excitation, hyperpyrexia, and coma is possible.
    Carbetapentane; Pseudoephedrine: (Major) Carbetapentane should be avoided in patients receiving MAOIs, and should not be used within 14 days of discontinuation of an MAOI. Carbetapentane has similar pharmacologic properties to dextromethorphan, and can block neuronal uptake of serotonin. Excessive concentrations of serotonin in the CNS may occur if carbetapentane is combined with MAOIs. A serotonin syndrome, consisting of nausea, hypotension, excitation, hyperpyrexia, and coma is possible.
    Carbetapentane; Pyrilamine: (Major) Carbetapentane should be avoided in patients receiving MAOIs, and should not be used within 14 days of discontinuation of an MAOI. Carbetapentane has similar pharmacologic properties to dextromethorphan, and can block neuronal uptake of serotonin. Excessive concentrations of serotonin in the CNS may occur if carbetapentane is combined with MAOIs. A serotonin syndrome, consisting of nausea, hypotension, excitation, hyperpyrexia, and coma is possible.
    Carbidopa; Levodopa: (Moderate) Concurrent therapy with MAO-B inhibitors and levodopa may be associated with severe orthostatic hypotension not attributable to levodopa alone. Dosages of levodopa should be reduced 2 to 3 days after beginning selegiline therapy.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concurrent therapy with MAO-B inhibitors and levodopa may be associated with severe orthostatic hypotension not attributable to levodopa alone. Dosages of levodopa should be reduced 2 to 3 days after beginning selegiline therapy.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Carteolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Carvedilol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Cetirizine: (Major) The anticholinergic activity of MAOIs is minimal; however, anticholinergic effects sometimes occur. Most manufacturers recommend that cetirizine/levocetirizine not be used within two weeks of therapy with a MAOI.
    Cetirizine; Pseudoephedrine: (Major) The anticholinergic activity of MAOIs is minimal; however, anticholinergic effects sometimes occur. Most manufacturers recommend that cetirizine/levocetirizine not be used within two weeks of therapy with a MAOI.
    Chlordiazepoxide: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Chlordiazepoxide; Clidinium: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Chloroprocaine: (Severe) Combined hypotensive effects are possible with use of MAOIs and spinal anesthetics. Use of epinephrine added to chloroprocaine with monoamine oxidase inhibitors (MAOIs) or drugs with MAOI activity (e.g., furazolidone, linezolid, or procarbazine) is not recommended. When local anesthetics containing sympathomimetic vasoconstrictors are coadministered with MAOIs, severe and prolonged hypertension may occur. MAOIs and agents with MAOI activity can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient. Phenelzine, tranylcypromine, and transdermal selegiline are contraindicated for use for at least 10 days prior to elective surgery.
    Chlorothiazide: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Chlorpheniramine; Codeine: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine.
    Chlorpheniramine; Dextromethorphan: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Severe) Dihydrocodeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of dihydrocodeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Severe) Dihydrocodeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of dihydrocodeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Chlorpheniramine; Hydrocodone: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Chlorpromazine: (Major) Concurrent use of MAOIs and phenothiazines may prolong or intensify the hypotensive, anticholinergic, or sedative effects of either agent. Due to the potential for additive CNS and cardiovascular effects, MAOIs and phenothiazines should be used together cautiously.
    Chlorthalidone: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Chlorthalidone; Clonidine: (Severe) Monoamine oxidase inhibitors (MAOIs) may interact with antihypertensive medications. If a patient receiving an MAOI is started on clonidine, severe hypertension may occur, and this reaction may be followed by hypotension, which may be severe. Additionally, if a patient is withdrawn from clonidine, an excess of circulating catecholamines may occur. The clinician should use these agents together with caution; blood pressure should be monitored frequently. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Clevidipine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Clomipramine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with tricyclic antidepressants (TCAs) or within 14 days of discontinuing treatment with a TCA. Conversely, TCAs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Clonazepam: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Clonidine: (Severe) Monoamine oxidase inhibitors (MAOIs) may interact with antihypertensive medications. If a patient receiving an MAOI is started on clonidine, severe hypertension may occur, and this reaction may be followed by hypotension, which may be severe. Additionally, if a patient is withdrawn from clonidine, an excess of circulating catecholamines may occur. The clinician should use these agents together with caution; blood pressure should be monitored frequently.
    Clopidogrel: (Moderate) At high concentrations in vitro, clopidogrel inhibits the activity of CYP2C9.Thus, clopidogrel could increase plasma concentrations of drugs metabolized by this isoenzyme, such as selegiline. Although there are no in vivo data with which to predict the magnitude or clinical significance of this potential interaction, caution should be used when selegiline is coadministered with clopidogrel.
    Clorazepate: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with selegiline as there is a potential for elevated selegiline concentrations. Selegiline is a substrate of CYP3A4 and cobicistat is an inhibitor of CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with selegiline as there is a potential for elevated selegiline concentrations. Selegiline is a substrate of CYP3A4 and cobicistat is an inhibitor of CYP3A4. (Moderate) Caution is warranted when elvitegravir is administered with selegiline as there is a potential for decreased selegiline concentrations. Selegiline is a substrate of CYP2C9, while elvitegravir is a CYP2C9 inducer.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with selegiline as there is a potential for elevated selegiline concentrations. Selegiline is a substrate of CYP3A4 and cobicistat is an inhibitor of CYP3A4. (Moderate) Caution is warranted when elvitegravir is administered with selegiline as there is a potential for decreased selegiline concentrations. Selegiline is a substrate of CYP2C9, while elvitegravir is a CYP2C9 inducer.
    Codeine: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine.
    Codeine; Guaifenesin: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine.
    Codeine; Phenylephrine; Promethazine: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine. (Severe) The concurrent use of MAOIs with sedating H1-blockers is not recommended because of an increase in the intensity and prolongation of CNS-depressant and anticholinergic effects. Most manufacturers recommend that H1-antagonists not be used within two weeks of therapy with a MAOI.
    Codeine; Promethazine: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine. (Severe) The concurrent use of MAOIs with sedating H1-blockers is not recommended because of an increase in the intensity and prolongation of CNS-depressant and anticholinergic effects. Most manufacturers recommend that H1-antagonists not be used within two weeks of therapy with a MAOI.
    COMT inhibitors: (Moderate) These drugs may be taken together in the treatment of Parkinson's disease. No specific drug-drug pharmacokinetic interactions have been noted. However, when adding additional therapies for this disease, the practitioner should be alert to adverse effects related to dopaminergic and serotonergic activities, and the potential need for dosage titrations based on drug tolerance and effectiveness.
    Cyclobenzaprine: (Severe) Concurrent use of cyclobenzaprine and MAOIs is contraindicated. Further, use of cyclobenzaprine within 14 days of MAOI discontinuation is contraindicated. Hyperpyretic crisis, seizures and deaths have occurred in patients receiving cyclobenzaprine or structurally similar tricyclic antidepressants concomitantly with MAO inhibitor drugs. A patient taking phenelzine developed symptoms of serotonin syndrome including confusion, agitation, tremors, tachycardia, diaphoresis, hallucinations, delusions, and fever after the third oral dose of cyclobenzaprine 10 mg, which was prescribed every 8 hours. The patient remained symptomatic despite drug discontinuation. All of her symptoms progressively resolved over the next 3 days. Reinitiation of phenelzine was without consequences.
    Dapagliflozin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Dapagliflozin; Metformin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents. Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost. (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Dapagliflozin; Saxagliptin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents.Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost. (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Darunavir: (Moderate) Caution is warranted when darunavir is administered with selegiline as there is a potential for elevated selegiline concentrations. Selegiline is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with selegiline as there is a potential for elevated selegiline concentrations. Selegiline is a substrate of CYP3A4 and cobicistat is an inhibitor of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with selegiline as there is a potential for elevated selegiline concentrations. Selegiline is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of selegiline with ritonavir may result in elevated selegiline plasma concentrations. Selegiline is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Desflurane: (Moderate) Use of monoamine oxidase inhibitors (MAOIs) with inhaled anesthetics, such as desflurane, may increase the risk of hemodynamic instability during surgery. Caution is advised if these drugs are administered together.
    Desipramine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with tricyclic antidepressants (TCAs) or within 14 days of discontinuing treatment with a TCA. Conversely, TCAs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Desmopressin: (Major) Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with SIADH including MAOIs. Use combination with caution, and monitor patients for signs and symptoms of hyponatremia.
    Desvenlafaxine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with serotonin norepinephrine reuptake inhibitors (SNRIs). MAOIs should not be used within 5 days of discontinuing treatment with duloxetine or within 7 days of discontinuing treatment with other SNRIs. Conversely, SNRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Deutetrabenazine: (Severe) Deutetrabenazine use is contraindicated in patients who are receiving or have received MAOI therapy within the past 14 days. The major metabolites of deutetrabenazine (alpha-dihydrotetrabenazine [HTBZ] and beta-HTBZ) are reversible inhibitors of vesicular monoamine transporter 2 (VMAT2). Inhibition of VMAT2 results in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Dextromethorphan: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Dextromethorphan; Guaifenesin: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Dextromethorphan; Promethazine: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan. (Severe) The concurrent use of MAOIs with sedating H1-blockers is not recommended because of an increase in the intensity and prolongation of CNS-depressant and anticholinergic effects. Most manufacturers recommend that H1-antagonists not be used within two weeks of therapy with a MAOI.
    Dextromethorphan; Quinidine: (Severe) Dextromethorphan should be used cautiously, if at all, in patients receiving MAOIs; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranylcypromine, phenelzine). Dextromethorphan can block neuronal uptake of serotonin and may produce excessive concentrations of serotonin in the CNS if combined with monoamine oxidase inhibitors (MAOIs), with the potential for severe reactions. The interaction may cause symptoms similar to those seen with meperidine and MAOIs. A single case report is noted of an acute, fatal drug reaction immediately following the ingestion of a cough mixture containing dextromethorphan in a patient who had been taking phenelzine; the 26-year old female felt nauseated and dizzy, then collapsed. Her temperature rose to 42 degrees C and 4 hours later she died of a cardiac arrest. Similar cases of interactions between phenelzine or isocarboxazid and dextromethorphan have been reported in the medical literature. There has also been a report of an interaction in which drowsiness and bizarre behavior appeared following the ingestion of a dextromethorphan lozenge with phenelzine. Patients should avoid the use of dextromethorphan-containing medications during MAOI use and for 2 weeks following MAOI discontinuation. Selective inhibitors of MAO-B (e.g., selegiline) also contain warnings regarding avoiding use of dextromethorphan concurrently when possible; the manufacturer of selegiline transdermal specifically contraindicates the combined use with dextromethorphan.
    Diazepam: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Diazoxide: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with vasodilators. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Dienogest; Estradiol valerate: (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. In one pharmacokinetic study, it was reported that both peak and total selegiline concentrations were increased 10- and 20-fold, respectively, in users of oral contraceptives versus non-users. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Severe) Dihydrocodeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of dihydrocodeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as dihydrocodeine.
    Diltiazem: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Dolasetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering dolasetron with other drugs that have serotonergic properties such as Monoamine oxidase inhibitors. If serotonin syndrome is suspected, discontinue dolasetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Dorzolamide; Timolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Doxazosin: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy with antihypertensives such as alpha-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Doxepin: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with tricyclic antidepressants (TCAs) or within 14 days of discontinuing treatment with a TCA. Conversely, TCAs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Dronabinol, THC: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including dronabinol.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Selegiline is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Droperidol: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including droperidol. Following administration of droperidol, lower doses of the other CNS depressant should be used.
    Drospirenone; Ethinyl Estradiol: (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Duloxetine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with serotonin norepinephrine reuptake inhibitors (SNRIs). MAOIs should not be used within 5 days of discontinuing treatment with duloxetine or within 7 days of discontinuing treatment with other SNRIs. Conversely, SNRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Elbasvir; Grazoprevir: (Moderate) Administering selegiline with elbasvir; grazoprevir may result in elevated selegiline plasma concentrations. Selegiline is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eletriptan: (Major) Serotonin syndrome has been reported during co-administration of serotonin-receptor agonists and monoamine oxidase inhibitors (MAOIs). Since oral selegiline selectively inhibits MAO-B at recommended doses, no interaction with eletriptan would be expected with normal prescription use. However, there is a decline in MAO-B selectivity with increasing doses. Therefore, high dose treatment with oral selegiline may increase central serotonin levels through MAO-A inhibition. In addition, selegiline, transdermal inhibits both MAO-A and MAO-B at the usual antidepressant doses. However, whether or not 5-HT1B/1D agonists such as eletriptan can cause serious cases of serotonin syndrome when used with serotonergic drugs has been debated since serotonin syndrome is thought to result primarily from 5-HT2A activation. Unlike some serotonin-receptor agonists, eletriptan is not a substrate for monoamine oxidase; therefore, its metabolism is not affected by MAOIs.
    Elvitegravir: (Moderate) Caution is warranted when elvitegravir is administered with selegiline as there is a potential for decreased selegiline concentrations. Selegiline is a substrate of CYP2C9, while elvitegravir is a CYP2C9 inducer.
    Empagliflozin: (Moderate) Selected monoamine oxidase inhibitors (MAOIs) have potentiated hypoglycemia in animal models; there are conflicting data regarding hypoglycemic reactions in humans. These effects do not appear to be due to MAO activity, but rather, a change in gluconeogenesis or insulin sensitivity related to a hydrazine chemical structure. It is not clear if all MAOIs affect blood glucose control or potentiate antidiabetic medications. When initiating MAOIs in a patient receiving antidiabetic agents, the patient should monitor their blood glucose and report any changes in blood sugar control.
    Empagliflozin; Linagliptin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents, such as linagliptin. (Moderate) Selected monoamine oxidase inhibitors (MAOIs) have potentiated hypoglycemia in animal models; there are conflicting data regarding hypoglycemic reactions in humans. These effects do not appear to be due to MAO activity, but rather, a change in gluconeogenesis or insulin sensitivity related to a hydrazine chemical structure. It is not clear if all MAOIs affect blood glucose control or potentiate antidiabetic medications. When initiating MAOIs in a patient receiving antidiabetic agents, the patient should monitor their blood glucose and report any changes in blood sugar control.
    Empagliflozin; Metformin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents. Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost. (Moderate) Selected monoamine oxidase inhibitors (MAOIs) have potentiated hypoglycemia in animal models; there are conflicting data regarding hypoglycemic reactions in humans. These effects do not appear to be due to MAO activity, but rather, a change in gluconeogenesis or insulin sensitivity related to a hydrazine chemical structure. It is not clear if all MAOIs affect blood glucose control or potentiate antidiabetic medications. When initiating MAOIs in a patient receiving antidiabetic agents, the patient should monitor their blood glucose and report any changes in blood sugar control.
    Enalapril, Enalaprilat: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Enalapril; Felodipine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Enflurane: (Severe) Patients taking MAOIs should not undergo elective surgery, including dental procedures, that require the use of general anesthetics due to the potential for CNS and cardiovascular reactions. Combined hypotensive effects are possible with the combined use of MAOIs and spinal anesthetics. MAOIs should be discontinued for at least 10 days prior to elective surgery.
    Enzalutamide: (Minor) Monitor for decreased efficacy of selegiline if coadministration with enzalutamide is necessary. Selegiline is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Adequate studies have not been done to assess the effect of CYP3A4 inducers on selegiline.
    Eplerenone: (Moderate) Additive hypotensive effects may be seen when MAOIs are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with vasodilators.
    Epoprostenol: (Moderate) Additive hypotensive effects may be seen when MAOIs are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with vasodilators.
    Eprosartan: (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Eslicarbazepine: (Severe) MAOIs should not be coadministered at the same time with eslicarbazepine, a dibenzazepine-related drug. Hypertensive crises, seizures, coma, or circulatory collapse may occur in patients receiving this combination. At least 7 days should elapse between discontinuation of eslicarbazepine and initiation of an MAOI. MAOIs should be discontinued for a minimum of 14 days or longer if the clinical situation permits, before administering eslicarbazepine. When starting MAOI therapy after discontinuing eslicarbazepine, it is advised to begin the MAOI at one-half the normal starting dosage for at least the first week of therapy. Carefully monitor the patient. Watch carefully for other effects besides effects on blood pressure, such as sedation, confusion, and increased CNS depression. If eslicarbazepine is used for the treatment of epilepsy, be aware that MAOI effects can include lowering of seizure threshold in some patients.
    Esmolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Estazolam: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Ester local anesthetics: (Severe) Combined hypotensive effects are possible with use of MAOIs and spinal anesthetics. Use of epinephrine added to chloroprocaine with monoamine oxidase inhibitors (MAOIs) or drugs with MAOI activity (e.g., furazolidone, linezolid, or procarbazine) is not recommended. When local anesthetics containing sympathomimetic vasoconstrictors are coadministered with MAOIs, severe and prolonged hypertension may occur. MAOIs and agents with MAOI activity can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient. Phenelzine, tranylcypromine, and transdermal selegiline are contraindicated for use for at least 10 days prior to elective surgery.
    Estradiol Cypionate; Medroxyprogesterone: (Moderate) Selegiline concentrations may be increased by the co-administration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Estradiol: (Moderate) Selegiline concentrations may be increased by the co-administration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on combined contraceptive agents in order to limit the risk of increased MAO type B inhibition. (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. In one pharmacokinetic study, it was reported that both peak and total selegiline concentrations were increased 10- and 20-fold, respectively, in users of oral contraceptives versus non-users. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Ethacrynic Acid: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Ethanol: (Major) Ethanol may cause additive CNS depression and some ethanol-containing products may also contain tyramine. Many manufacturers contraindicate the use of ethanol (alcohol) during traditional MAOI therapy such as treatment with isocarboxazid, phenelzine, or tranylcypromine. Certain alchoholic beverages thatare tyramine-rich can precipitate a hypertensive reaction if consumed by patients during therapy with these MAOIs. These include some beers; wines; sherry; hard liquor; or liqueurs. Selegeline can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages containing high concentrations of pressor amines such as tyramine. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Rare cases of hypertensive reactions associated with ingestion of tyramine-containing products have been reported in patients receiving the normal daily doses of selegiline.
    Ethinyl Estradiol: (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Ethinyl Estradiol; Desogestrel: (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Ethinyl Estradiol; Norethindrone: (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Ethinyl Estradiol; Norgestimate: (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Ethinyl Estradiol; Norgestrel: (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Etomidate: (Severe) Patients taking MAOIs should not undergo elective surgery, including dental procedures, that require the use of general anesthetics due to the potential for CNS and cardiovascular reactions. Combined hypotensive effects are possible with the combined use of MAOIs and spinal anesthetics. MAOIs should be discontinued for at least 10 days prior to elective surgery.
    Felbamate: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Felodipine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Fenoldopam: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with vasodilators. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Fentanyl: (Major) The use of fentanyl is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within 14 days. Concomitant use of fentanyl with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. Serotonin syndrome and death occurred in1 patient previously stable on the MAOI tranylcypromine following an uneventful CABG surgery in which fentanyl was administered. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as fentanyl.
    Fluphenazine: (Major) Concurrent use of MAOIs and phenothiazines may prolong or intensify the hypotensive, anticholinergic, or sedative effects of either agent. Due to the potential for additive CNS and cardiovascular effects, MAOIs and phenothiazines should be used together cautiously.
    Flurazepam: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Food: (Severe) Food interactions with MAOIs can be serious. Beverages containing caffeine or ethanol may also be hazardous. Excessive caffeine consumption can produce severe hypertensive crises or dangerous cardiac arrhythmias if administered to patients taking an MAOI. Preparations containing caffeine should be used sparingly such as tea, coffee, chocolate, cola, guarana, or 'stay awake' products. Some non-prescription medicines also contain caffeine and should not be taken without health care professional advice. According to product labeling, a variety of tyramine-containing foods can precipitate severe hypertensive episodes if consumed with MAOIs: aged cheese; yeast extract; protein extract; soy sauce; fava bean or broad bean pods; smoked meats; pickled meats; smoked poultry; pickled poultry; smoked fish (lox, smoked salmon); pickled fish (pickled herring); fermented sausage (bologna, pepperoni, salami, summer sausage) or other fermented meat; liver; anchovies; sauerkraut; bananas; overripe avocados; canned figs; raisins; raspberries; any over-ripe fruit; yogurt; and sour cream. Modifications to established guidelines are available through independent sources, supported by updated analytical methods for determining tyramine content of foods, and using a safety threshold of < 6 mg of tyramine/serving. Certain foods that are prohibited in product labeling have been found to contain little or no tyramine. Milk products including sour cream, yogurt, and processed cheese slices do not contain tyramine. The tyramine content of brewer's yeast, baker's yeast, raspberries, and avocados is low. In some analyses, avocados have been shown to contain 0 to 2.3 mg of tyramine/100 g serving. Other allowable foods according to independent sources include cottage cheese, cream cheese, freshly packaged meat or fish, beef/chicken bouillon, bananas, chocolate, peanuts, properly stored pickled or smoked fish, and soy milk. Improper storage and handling of foods, or spoilage may increase tyramine content and present a risk of hypertensive crisis. Some alcohol-containing products may also contain tyramine. Beverages that contain tyramine can precipitate a hypertensive reaction if consumed during therapy with an MAOI. These include some beers (including reduced-ethanol and ethanol-free beer); wines (red and white varieties); sherry; hard liquor; or liqueurs. Following discontinuation of any MAOI, dietary restrictions should continue for at least 2 weeks due to the slow recovery from the enzyme-inhibiting effects of these drugs. Selegeline may be an exception. However, rare cases of hypertensive reactions associated with ingestion of tyramine-containing foods have been reported in patients receiving the normal daily doses of selegiline. Selegiline can ordinarily only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages containing high concentrations of pressor amines such as tyramine. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Transdermal selegiline has specific dietary guidelines for each strength of patch. Tyramine-rich foods and beverages should be avoided beginning on the first day of selegiline transdermal 9 mg/24 hour or 12 mg/24 hour treatment. Avoidance should be continued for 2 weeks after a dose reduction to selegiline transdermal 6 mg/24 hours or following the discontinuation of selegiline transdermal 9 mg/24 hours or 12 mg/24 hours. At the 6 mg/24 hour transdermal dose, selegiline is selective for MAO type B and food/beverage/dietary supplement restrictions are not required. At transdermal doses of 9 or 12 mg/24 hour, the interaction of selegiline transdermal with foods and beverages containing high concentrations of pressor amines such as tyramine cannot be ruled out.
    Fosinopril: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Fospropofol: (Severe) Patients taking MAOIs should not undergo elective surgery, including dental procedures, that require the use of general anesthetics due to the potential for CNS and cardiovascular reactions. Combined hypotensive effects are possible with the combined use of MAOIs and spinal anesthetics. MAOIs should be discontinued for at least 10 days prior to elective surgery.
    Frovatriptan: (Major) Serotonin syndrome has been reported during co-administration of serotonin-receptor agonists and monoamine oxidase inhibitors (MAOIs). Since oral selegiline selectively inhibits MAO-B at recommended doses, no interaction with frovatriptan would be expected with normal prescription use. However, there is a decline in MAO-B selectivity with increasing doses. Therefore, high dose treatment with oral selegiline may increase central serotonin levels through MAO-A inhibition. In addition, selegiline, transdermal inhibits both MAO-A and MAO-B at the usual antidepressant doses. However, whether or not 5-HT1B/1D agonists such as frovatriptan can cause serious cases of serotonin syndrome when used with serotonergic drugs has been debated since serotonin syndrome is thought to result primarily from 5-HT2A activation. Unlike some serotonin-receptor agonists, frovatriptan is not a substrate for monoamine oxidase; therefore, its metabolism is not affected by MAOIs.
    Furosemide: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Gabapentin: (Moderate) Monoamine oxidase inhibitors (MAOIs) can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Gallium Ga 68 Dotatate: (Moderate) Exaggerated hypotensive effects may result when MAOIs are used in combination with other antihypertensive drugs, including diuretics; patients should be observed for symptoms of orthostatic hypotension
    General anesthetics: (Severe) Patients taking MAOIs should not undergo elective surgery, including dental procedures, that require the use of general anesthetics due to the potential for CNS and cardiovascular reactions. Combined hypotensive effects are possible with the combined use of MAOIs and spinal anesthetics. MAOIs should be discontinued for at least 10 days prior to elective surgery.
    Ginseng, Panax ginseng: (Severe) There have been two reports in the literature describing a possible, but not definitive, interaction between ginseng and phenelzine; it is not clear if other MAOIs would interact, but caution is warranted. In one case, headache and tremulousness were reported in a 64-year old when ginseng was added to phenelzine. A second patient suffered from irritability, headache, and vague visual hallucinations during combined use of ginseng and phenelzine. Some of these effects have been reported with the use of phenelzine alone.
    Glipizide; Metformin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents. Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Glyburide; Metformin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents. Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Granisetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering granisetron with other drugs that have serotonergic properties such as selegiline. If serotonin syndrome is suspected, discontinue granisetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Green Tea: (Severe) Green tea catechins inhibit Catechol O methyltransferase, COMT in animals. Monoamine oxidase, MAO and COMT are the two major enzymes involved in the metabolism of catecholamines. It may be prudent to avoid the combination of green tea and monoamine oxidase inhibitors. As is recommended with other COMT inhibitors, 14 days should lapse between the discontinuation of nonselective MAOIs and the use of green tea. In addition, some, but not all, green tea products contain caffeine; caffeine interacts with MAOIs. Dangerous cardiac arrhythmias or severe hypertension can occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs. Caffeine use should be minimized or avoided during and for 12 weeks after discontinuation of any MAOI. Rasagiline is a selective MAO-B inhibitor at manufacturer recommended doses; therefore, serious reactions with green tea are expected to be less likely to occur than with non-selective MAOIs such as phenelzine or tranylcypromine.
    Guaifenesin; Hydrocodone: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Guanabenz: (Severe) Guanabenz withdrawal can result in an increase in serum catecholamine levels. Thus, drugs that alter the metabolism or uptake of catecholamines, such as monoamine oxidase inhibitors (MAOIs) should be used cautiously in patients who are undergoing guanabenz withdrawal.
    Guanfacine: (Severe) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Certain antihypertensive-MAOI combinations warrant particular caution. If a patient receiving an MAOI is started on clonidine, severe hypertension may occur, and this reaction may be followed by hypotension, which may be severe. Additionally, if a patient is withdrawn from clonidine, an excess of circulating catecholamines may occur. A similar reaction with MAOIs may be anticipated with concurrent administration of guanfacine since both guanfacine and clonidine are centrally-acting alpha-2 adrenergic agonists. Concurrent administration of guanfacine and MAOIs should be avoided if possible.
    Guarana: (Severe) Caffeine, an active constituent of guarana, interacts with MAOIs (including drugs with MAOI activity such as furazolidone, isoniazid, INH, linezolid, procarbazine, and high doses of yohimbine). Dangerous cardiac arrhythmias or severe hypertension can occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs. Guarana should be avoided during and for 1 to 2 weeks after discontinuation of any MAOI. Rasagiline is a selective MAO-B inhibitor at manufacturer recommended doses; therefore, serious reactions with guarana are expected to be less likely to occur with rasagiline.
    Halothane: (Severe) Patients taking MAOIs should not undergo elective surgery, including dental procedures, that require the use of general anesthetics due to the potential for CNS and cardiovascular reactions. Combined hypotensive effects are possible with the combined use of MAOIs and spinal anesthetics. MAOIs should be discontinued for at least 10 days prior to elective surgery.
    Homatropine; Hydrocodone: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Hydantoins: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Hydralazine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with vasodilators. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with vasodilators. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with vasodilators. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydrochlorothiazide, HCTZ: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Severe) The manufacturer of methyldopa contraindicates its use with monoamine oxidase inhibitors (MAOIs). Administration of MAOIs with methyldopa has resulted in headaches, severe hypertension, and hallucinations. Data describing this interaction are limited. In addition, other reports describe safe use of these agents in combination. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Hydrocodone: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Hydrocodone; Ibuprofen: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Hydrocodone; Phenylephrine: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Hydrocodone; Pseudoephedrine: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Hydromorphone: (Major) Concomitant use of hydromorphone with monoamine oxidase inhibitors (MAOIs) can potentiate the effects of hydromorphone and may lead to additive respiratory or CNS depression. If concurrent use of hydromorphone and a MAOI is required, carefully monitor the patient for hypotension, excessive sedation, respiratory depression, and CNS depression. The manufacturer of hydromorphone extended-release tablets (Palladone) recommends discontinuation of the MAOI for at least 14 days before starting Palladone. Advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Severe) Concurrent use of methylene blue and MAOIs (e.g., tranylcypromine, isocarboxazid, phenelzine, and including selective MAOIs such as selegiline, rasagiline) should generally be avoided due to the potential for serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and traditional MAOIs similarly increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonergic agents. It is not known if patients receiving intravenous methylene blue with MAO-inhibiting agents or linezolid are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If emergent treatment with methylene blue is required in a patient receiving an MAOI, the MAOI should be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the MAOI should be stopped at least 2 weeks prior to methylene blue treatment. Because rasagiline is a selective monoamine oxidase-B (MAO-B) inhibitor at manufacturer recommended doses, an interaction with serotonin-enhancing medications may be less likely to occur than with other traditional MAO inhibitors.
    Ibuprofen; Oxycodone: (Major) Concomitant use of oxycodone with other CNS depressants, such as MAOIs, can lead to additive respiratory or CNS depression, hypotension, profound sedation, or coma. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Advise patients against driving or performing other tasks requiring alertness until they know how the combination affects them.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with selegiline, a CYP3A substrate, as selegiline toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloprost: (Moderate) Additive hypotensive effects may be seen when MAOIs are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with vasodilators.
    Imipramine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with tricyclic antidepressants (TCAs) or within 14 days of discontinuing treatment with a TCA. Conversely, TCAs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Incretin Mimetics: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Indapamide: (Moderate) Additive hypotensive effects may be seen when MAOIs are combined with antihypertensives. Monitor blood pressure during concurrent therapy of MAOIs with diuretics.
    Insulins: (Moderate) Monitor patients receiving monoamine oxidase inhibitors (MAOIs) concomitantly with insulin for changes in glycemic control. Animal data indicate that MAOIs may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas.
    Iohexol: (Major) Use of medications that lower the seizure threshold, such as monoamine oxidase inhibitors, should be carefully evaluated when considering intrathecal radiopaque contrast agents. While the contributory role of such medications has not been established, some physicians discontinue these drugs at least 48 hours before and for at least 24 hours after intrathecal use.
    Iopamidol: (Major) Use of medications that lower the seizure threshold, such as monoamine oxidase inhibitors, should be carefully evaluated when considering intrathecal radiopaque contrast agents. While the contributory role of such medications has not been established, some physicians discontinue these drugs at least 48 hours before and for at least 24 hours after intrathecal use.
    Iopromide: (Major) Use of medications that lower the seizure threshold, such as monoamine oxidase inhibitors, should be carefully evaluated when considering intrathecal radiopaque contrast agents. While the contributory role of such medications has not been established, some physicians discontinue these drugs at least 48 hours before and for at least 24 hours after intrathecal use.
    Ioversol: (Major) Use of medications that lower the seizure threshold, such as monoamine oxidase inhibitors, should be carefully evaluated when considering intrathecal radiopaque contrast agents. While the contributory role of such medications has not been established, some physicians discontinue these drugs at least 48 hours before and for at least 24 hours after intrathecal use.
    Irbesartan: (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with selegiline may result in increased serum concentrations of selegiline. Selegiline is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoflurane: (Severe) Patients taking MAOIs should not undergo elective surgery, including dental procedures, that require the use of general anesthetics due to the potential for CNS and cardiovascular reactions. Combined hypotensive effects are possible with the combined use of MAOIs and spinal anesthetics. MAOIs should be discontinued for at least 10 days prior to elective surgery.
    Isoniazid, INH: (Major) Concurrent use of selegiline and isoniazid may increase the risk of a hypertensive crisis. Isoniazid has monoamine oxidase inhibiting activity and selegiline is a monoamine oxidase inhibitor (MAOI) type B. Monoamine oxidase type A is the primary enzyme in the gastrointestinal tract, and is responsible for the breakdown of dietary amines such as tyramine. When monoamine oxidase is inhibited by an MAOI, tyramine is absorbed systemically and may result in a hypertensive crisis. Although selegiline is a selective monoamine oxidase inhibitor type B, there is a risk of hypertension during ingestion of substances high in tyramine or during concurrent use of other drugs with MAOI activity such as isoniazid, since the MAOI-B selectivity of selegiline decreases with increasing dosages.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Concurrent use of selegiline and isoniazid may increase the risk of a hypertensive crisis. Isoniazid has monoamine oxidase inhibiting activity and selegiline is a monoamine oxidase inhibitor (MAOI) type B. Monoamine oxidase type A is the primary enzyme in the gastrointestinal tract, and is responsible for the breakdown of dietary amines such as tyramine. When monoamine oxidase is inhibited by an MAOI, tyramine is absorbed systemically and may result in a hypertensive crisis. Although selegiline is a selective monoamine oxidase inhibitor type B, there is a risk of hypertension during ingestion of substances high in tyramine or during concurrent use of other drugs with MAOI activity such as isoniazid, since the MAOI-B selectivity of selegiline decreases with increasing dosages.
    Isoniazid, INH; Rifampin: (Major) Concurrent use of selegiline and isoniazid may increase the risk of a hypertensive crisis. Isoniazid has monoamine oxidase inhibiting activity and selegiline is a monoamine oxidase inhibitor (MAOI) type B. Monoamine oxidase type A is the primary enzyme in the gastrointestinal tract, and is responsible for the breakdown of dietary amines such as tyramine. When monoamine oxidase is inhibited by an MAOI, tyramine is absorbed systemically and may result in a hypertensive crisis. Although selegiline is a selective monoamine oxidase inhibitor type B, there is a risk of hypertension during ingestion of substances high in tyramine or during concurrent use of other drugs with MAOI activity such as isoniazid, since the MAOI-B selectivity of selegiline decreases with increasing dosages.
    Isosulfan Blue: (Major) Use of medications that lower the seizure threshold, such as monoamine oxidase inhibitors, should be carefully evaluated when considering intrathecal radiopaque contrast agents. While the contributory role of such medications has not been established, some physicians discontinue these drugs at least 48 hours before and for at least 24 hours after intrathecal use.
    Isradipine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Kava Kava, Piper methysticum: (Major) Avoid the concomitant use of psycho-active herbs, such as kava kava, with MAOIs whenever possible. The German Commission E and other groups warn that any substances that act on the CNS, including MAOIs, may interact with the phytomedicinal kava kava, Piper methysticum. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action.
    Ketamine: (Severe) Patients taking MAOIs should not undergo elective surgery, including dental procedures, that require the use of general anesthetics due to the potential for CNS and cardiovascular reactions. Combined hypotensive effects are possible with the combined use of MAOIs and spinal anesthetics. MAOIs should be discontinued for at least 10 days prior to elective surgery.
    Labetalol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Lamotrigine: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Levetiracetam: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Levobetaxolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Levobunolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Levocetirizine: (Major) The anticholinergic activity of MAOIs is minimal; however, anticholinergic effects sometimes occur. Most manufacturers recommend that cetirizine/levocetirizine not be used within two weeks of therapy with a MAOI.
    Levodopa: (Moderate) Concurrent therapy with MAO-B inhibitors and levodopa may be associated with severe orthostatic hypotension not attributable to levodopa alone. Dosages of levodopa should be reduced 2 to 3 days after beginning selegiline therapy.
    Levomethadyl: (Major) Concomitant use of central nervous system depressants, such as MAOIs, can potentiate the effects of levomethadyl, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Levomilnacipran: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with serotonin norepinephrine reuptake inhibitors (SNRIs). MAOIs should not be used within 5 days of discontinuing treatment with duloxetine or within 7 days of discontinuing treatment with other SNRIs. Conversely, SNRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Levorphanol: (Major) Levorphanol is specifically not recommended for use with monoamine oxidase inhibitors (MAOIs) due to possible additive CNS depressant effects.
    Linagliptin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents, such as linagliptin.
    Linagliptin; Metformin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents. Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost. (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents, such as linagliptin.
    Lisinopril: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Lithium: (Major) There is an increased risk of serotonin syndrome during concurrent use of drugs with central serotonergic properties such as lithium and monoamine oxidase inhibitors. Signs and symptoms of serotonin syndrome include autonomic instability (e.g., labile blood pressure, tachycardia, diaphoresis, dizziness, hyperthermia), mental status changes (e.g., delirium, confusion, coma), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), gastrointestinal effects (e.g., nausea, vomiting, diarrhea), seizures, and in rare cases, death. If concurrent use is necessary, monitor for the emergence of serotonin syndrome and inform patients of the increased risk. If serotonin syndrome is suspected, serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Loop diuretics: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of selegiline with ritonavir may result in elevated selegiline plasma concentrations. Selegiline is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Lorazepam: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Lorcaserin: (Major) Avoid use together if possible. The MAOIs are not recommended to be taken with serotonergic medications due to the risk for serotonin syndrome. Lorcaserin affects serotonergic neurotransmitter systems. Patients receiving this combination should be monitored for the emergence of serotonin syndrome.
    Losartan: (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Loxapine: (Moderate) Due to the potential for additive CNS and cardiovascular effects, MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of selegiline by decreasing its systemic exposure. If used together, monitor patients closely for loss of selegiline efficacy; a selegiline dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the maximum recommended dose. Selegiline is a substrate of CYP3A4, CYP2B6, and CYP2C9. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce CYP2B6 and induce and/or inhibit CYP2C9.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of selegiline by decreasing its systemic exposure. If used together, monitor patients closely for loss of selegiline efficacy; a selegiline dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the maximum recommended dose. Selegiline is a substrate of CYP3A4, CYP2B6, and CYP2C9. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce CYP2B6 and induce and/or inhibit CYP2C9.
    Magnesium Salts: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with antidepressants.
    Mannitol: (Moderate) Exaggerated hypotensive effects may result when MAOIs are used in combination with other antihypertensive drugs, including diuretics; patients should be observed for symptoms of orthostatic hypotension
    Maprotiline: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with heterocyclic antidepressants (e.g., trazodone, mirtazapine, amoxapine, maptrotiline) or within 14 days of discontinuing treatment with a heterocyclic antidepressant. Conversely, heterocyclic antidepressants should not be initiated within 14 days of stopping an MAOI. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Meglitinides: (Moderate) Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to antidiabetic agents. It has also been proposed that MAOIs may interfere with the adrenergic response to hypoglycemia but it is uncertain how significant this action may be. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Meperidine: (Severe) Meperidine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Severe reactions including coma, severe respiratory depression, cyanosis, and hypotension have occurred; some reactions have been fatal. The mechanism of these reactions is unclear; however, it may be related to a preexisting hyperphenylalaninemia. Concomitant use of meperidine with other serotonergic drugs such as MAOIs may result in serotonin syndrome with excitation; sweating; rigidity; hypertension; severe respiratory depression; coma; and circulatory collapse, possibly resulting in death. Intravenous hydrocortisone or prednisolone has been used to treat severe reactions, with the addition of intravenous chlorpromazine in cases exhibiting hypertension and hyperpyrexia. The usefulness and safety of opiate antagonists in the treatment of these reactions is unknown.
    Meperidine; Promethazine: (Severe) Meperidine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Severe reactions including coma, severe respiratory depression, cyanosis, and hypotension have occurred; some reactions have been fatal. The mechanism of these reactions is unclear; however, it may be related to a preexisting hyperphenylalaninemia. Concomitant use of meperidine with other serotonergic drugs such as MAOIs may result in serotonin syndrome with excitation; sweating; rigidity; hypertension; severe respiratory depression; coma; and circulatory collapse, possibly resulting in death. Intravenous hydrocortisone or prednisolone has been used to treat severe reactions, with the addition of intravenous chlorpromazine in cases exhibiting hypertension and hyperpyrexia. The usefulness and safety of opiate antagonists in the treatment of these reactions is unknown. (Severe) The concurrent use of MAOIs with sedating H1-blockers is not recommended because of an increase in the intensity and prolongation of CNS-depressant and anticholinergic effects. Most manufacturers recommend that H1-antagonists not be used within two weeks of therapy with a MAOI.
    Mephobarbital: (Major) MAOIs may prolong the effect of mephobarbital and cause additive CNS depression. MAOIs can also cause a change in seizure patterns, so an adjustment in the dose of any anticonvulsant may be necessary.
    Mesoridazine: (Major) Concurrent use of MAOIs and phenothiazines may prolong or intensify the hypotensive, anticholinergic, or sedative effects of either agent. Due to the potential for additive CNS and cardiovascular effects, MAOIs and phenothiazines should be used together cautiously.
    Mestranol; Norethindrone: (Moderate) Selegiline concentrations may be increased by the co-administration of oral contraceptives containing estrogens and progestins. Dose reductions in selegiline may be necessary in patients on hormonal combined contraceptive agents.
    Metformin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents. Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Metformin; Pioglitazone: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents. Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Metformin; Repaglinide: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents. Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost. (Moderate) Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to antidiabetic agents. It has also been proposed that MAOIs may interfere with the adrenergic response to hypoglycemia but it is uncertain how significant this action may be. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Metformin; Rosiglitazone: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents. Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Metformin; Saxagliptin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents. Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost. (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents.Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Metformin; Sitagliptin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents. Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost. (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents.Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Methadone: (Severe) Concurrent use of methadone and selegiline is contraindicated. Although at low doses selegiline is selective for MAO type B, in doses above 30-40 mg/day, this selectivity is lost. Severe reactions such as excitation, sweating, rigidity, hypertension, severe respiratory depression, coma, and peripheral vascular collapse, possibly resulting in death, can occur. At least 2 weeks should elapse between stopping selegiline and starting methadone.
    Methazolamide: (Moderate) Exaggerated hypotensive effects may result when MAOIs are used in combination with other antihypertensive drugs, including diuretics; patients should be observed for symptoms of orthostatic hypotension; hypotension usually responds to phenelzine dosage reduction or to discontinuation, if needed.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Severe) Concurrent use of methylene blue and MAOIs (e.g., tranylcypromine, isocarboxazid, phenelzine, and including selective MAOIs such as selegiline, rasagiline) should generally be avoided due to the potential for serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and traditional MAOIs similarly increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonergic agents. It is not known if patients receiving intravenous methylene blue with MAO-inhibiting agents or linezolid are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If emergent treatment with methylene blue is required in a patient receiving an MAOI, the MAOI should be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the MAOI should be stopped at least 2 weeks prior to methylene blue treatment. Because rasagiline is a selective monoamine oxidase-B (MAO-B) inhibitor at manufacturer recommended doses, an interaction with serotonin-enhancing medications may be less likely to occur than with other traditional MAO inhibitors.
    Methohexital: (Severe) Patients receiving monoamine oxidase inhibitors (MAOIs) may have an increased risk of hypotension after administration of general anesthetics, although specific studies are not available. Combined hypotensive effects are also possible with the combined use of MAOIs and spinal anesthetics. In general, MAOIs should be discontinued for at least 10 days prior to elective surgery.
    Methyclothiazide: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Methyldopa: (Severe) The manufacturer of methyldopa contraindicates its use with monoamine oxidase inhibitors (MAOIs). Administration of MAOIs with methyldopa has resulted in headaches, severe hypertension, and hallucinations. Data describing this interaction are limited. In addition, other reports describe safe use of these agents in combination.
    Methylene Blue: (Severe) Concurrent use of methylene blue and MAOIs (e.g., tranylcypromine, isocarboxazid, phenelzine, and including selective MAOIs such as selegiline, rasagiline) should generally be avoided due to the potential for serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and traditional MAOIs similarly increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonergic agents. It is not known if patients receiving intravenous methylene blue with MAO-inhibiting agents or linezolid are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If emergent treatment with methylene blue is required in a patient receiving an MAOI, the MAOI should be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the MAOI should be stopped at least 2 weeks prior to methylene blue treatment. Because rasagiline is a selective monoamine oxidase-B (MAO-B) inhibitor at manufacturer recommended doses, an interaction with serotonin-enhancing medications may be less likely to occur than with other traditional MAO inhibitors.
    Metoclopramide: (Major) Close monitoring is advisable if combination therapy is necessary. Metoclopramide is a central dopamine antagonist and may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, or tardive dyskinesia), and rarely, neuroleptic malignant syndrome. The risk of extrapyramidal effects may be increased during concurrent use of metoclopramide and selegiline, and the therapeutic benefits of selegiline in treating Parkinson's disease may be diminished during use of a central dopamine antagonist such as metoclopramide. In addition, because metoclopramide causes release of catecholamines in patients with essential hypertension, it should be administered cautiously to patients receiving MAOIs.
    Metolazone: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Metoprolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Midazolam: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Milnacipran: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with serotonin norepinephrine reuptake inhibitors (SNRIs). MAOIs should not be used within 5 days of discontinuing treatment with duloxetine or within 7 days of discontinuing treatment with other SNRIs. Conversely, SNRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Minoxidil: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with vasodilators. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Mirabegron: (Major) While the manufacturer does not discuss the use of mirabegron in patients on MAOI therapy, it may be best to use this combination cautiously. Mirabegron is a selective beta-3 adrenergic agonist that may elevate blood pressure slightly at clinically used doses, and it is possible that this sympathomimetic activity could raise the risk of hypertensive crisis in patients receiving monoamine oxidase inhibitors (MAOIs), similar to other adrenergic medications. Beta-3 selectivity is usually lost at doses above those used clinically for overactive bladder (i.e., at mirabegron doses of 200 mg/day PO). Sympathomimetic adrenergic agonists are typically contraindicated in patients receiving MAOIs. When administering a MAOI in close proximity to such a drug, at least 2 weeks should usually elapse between discontinuation of one agent and initiation of therapy with the other; consult the specific product literature for precise recommendations.
    Mirtazapine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with heterocyclic antidepressants (e.g., trazodone, mirtazapine, amoxapine, maptrotiline) or within 14 days of discontinuing treatment with a heterocyclic antidepressant. Conversely, heterocyclic antidepressants should not be initiated within 14 days of stopping an MAOI. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Mitotane: (Moderate) Use caution if mitotane and selegiline are used concomitantly, and monitor for decreased efficacy of selegiline and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and selegiline is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of selegiline.
    Modafinil: (Major) Modafinil has not been evaluated for drug interactions with monoamine oxidase inhibitors (MAOIs). It is known that many other CNS stimulants may induce severe cardiovascular and cerebrovascular responses if administered in combination with drugs with non-selective MAO inhibitor activity. Until more is known regarding the pharmacology of modafinil, it is prudent avoid the use of modafinil in the presence of an MAO inhibitor. Due to the prolonged duration of action of MAOIs, a period of at least 14 days between the last dose of the MAOI and the first dose of modafinil should elapse.
    Moexipril: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Morphine: (Severe) Morphine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of morphine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as morphine.
    Morphine; Naltrexone: (Severe) Morphine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of morphine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as morphine.
    Nabilone: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including nabilone.
    Nadolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Nalbuphine: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including nalbuphine. Use nalbuphine cautiously with MAOIs; warn patients to not drive or perform other hazardous activities until they know how a particular drug combination affects them. In some cases, the dosages of the CNS depressants may need reduced.
    Naproxen; Sumatriptan: (Major) Serotonin syndrome has been reported during co-administration of serotonin-receptor agonists and monoamine oxidase inhibitors (MAOIs). Since oral selegiline selectively inhibits MAO-B at recommended doses, no interaction with sumatriptan would be expected with normal prescription use. However, there is a decline in MAO-B selectivity with increasing doses. Therefore, high dose treatment with oral selegiline may increase central serotonin levels through MAO-A inhibition. In addition, selegiline, transdermal inhibits both MAO-A and MAO-B at the usual antidepressant doses. However, whether or not 5-HT1B/1D agonists such as sumatriptan can cause serious cases of serotonin syndrome when used with serotonergic drugs has been debated since serotonin syndrome is thought to result primarily from 5-HT2A activation. Some serotonin-receptor agonists, such as sumatriptan are partially metabolized by MAO-A. Theoretically, use of high dose selegiline could increase systemic exposure to sumatriptan through MAO-A inhibition.
    Naratriptan: (Major) Serotonin syndrome has been reported during co-administration of serotonin-receptor agonists and monoamine oxidase inhibitors (MAOIs). Since oral selegiline selectively inhibits MAO-B at recommended doses, no interaction with naratriptan would be expected with normal prescription use. However, there is a decline in MAO-B selectivity with increasing doses. Therefore, high dose treatment with oral selegiline may increase central serotonin levels through MAO-A inhibition. In addition, selegiline, transdermal inhibits both MAO-A and MAO-B at the usual antidepressant doses. However, whether or not 5-HT1B/1D agonists such as naratriptan can cause serious cases of serotonin syndrome when used with serotonergic drugs has been debated since serotonin syndrome is thought to result primarily from 5-HT2A activation. Unlike some serotonin-receptor agonists, naratriptan is not a substrate for monoamine oxidase; therefore, its metabolism is not affected by MAOIs.
    Nateglinide: (Moderate) Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to antidiabetic agents. It has also been proposed that MAOIs may interfere with the adrenergic response to hypoglycemia but it is uncertain how significant this action may be. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Nebivolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Nebivolol; Valsartan: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Nefazodone: (Severe) Nefazodone is considered contraindicated for concurrent use with MAOIs. Because nefazodone inhibits the reuptake of serotonin and, to a lesser extent, norepinephrine, combination with a MAOI could possibly produce confusion, delirium, coma, seizures, hyperthermia, or other, less severe, symptoms. Although severe reactions have been seen when drugs with a pharmacological profile similar to nefazodone were used with MAOI therapy, no controlled trials have been done with nefazodone. At least 2 weeks should elapse between the discontinuation of MAOI therapy and the start of nefazodone therapy, or at least 1 week should elapse between the discontinuation of nefazodone and the initiation of a MAOI.
    Netupitant; Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as Monoamine oxidase inhibitors. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Nicardipine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Nifedipine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Nimodipine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Nisoldipine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antidepressants. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with antidepressants.
    Nitroprusside: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with vasodilators. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Non-Ionic Contrast Media: (Major) Use of medications that lower the seizure threshold, such as monoamine oxidase inhibitors, should be carefully evaluated when considering intrathecal radiopaque contrast agents. While the contributory role of such medications has not been established, some physicians discontinue these drugs at least 48 hours before and for at least 24 hours after intrathecal use.
    Nortriptyline: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with tricyclic antidepressants (TCAs) or within 14 days of discontinuing treatment with a TCA. Conversely, TCAs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Olmesartan: (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of selegiline with ritonavir may result in elevated selegiline plasma concentrations. Selegiline is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Ondansetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as Monoamine oxidase inhibitors. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Oritavancin: (Moderate) Coadministration of oritavancin and selegiline may result in increases or decreases in selegiline exposure and may increase side effects or decrease efficacy of selegiline. Selegiline is metabolized by CYP3A4 and CYP2C9. Oritavancin weakly induces CYP3A4, while weakly inhibiting CYP2C9. If these drugs are administered concurrently, monitor the patient for signs of toxicity or lack of efficacy.
    Oxazepam: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Oxcarbazepine: (Severe) MAOIs should not be coadministered at the same time with oxcarbazepine, a dibenzazepine-related drug. Hypertensive crises, seizures, coma, or circulatory collapse may occur in patients receiving this combination. At least 7 days should elapse between discontinuation of oxcarbazepine and initiation of an MAOI. MAOIs should be discontinued for a minimum of 14 days or longer if the clinical situation permits, before administering oxcarbazepine. When starting MAOI therapy after discontinuing oxcarbazepine, it is advised to begin the MAOI at one-half the normal starting dosage for at least the first week of therapy. Carefully monitor the patient. Watch carefully for other effects besides effects on blood pressure, such as sedation, confusion, and increased CNS depression. If oxcarbazepine is used for the treatment of epilepsy, be aware that MAOI effects can include lowering of seizure threshold in some patients.
    Oxycodone: (Major) Concomitant use of oxycodone with other CNS depressants, such as MAOIs, can lead to additive respiratory or CNS depression, hypotension, profound sedation, or coma. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Advise patients against driving or performing other tasks requiring alertness until they know how the combination affects them.
    Oxymetazoline: (Major) Oxymetazoline should not be used in patients taking non-selective monoamine oxidase inhibitors (MAOIs); also avoid use in patients taking selegiline. The combination of an MAOI and a sympathomimetic drug, including decongestants given via topical, nasal, or ophthalmic routes, may rarely result in high blood pressure or in more serious cases, hypertensive crisis. Avoid use during and up to 2 weeks following discontinuation of the MAOI.
    Oxymorphone: (Major) Some manufacturers of oxymorphone recommend against use within 14 days of treatment with a monoamine oxidase inhibitor (MAOI) because severe and unpredictable potentiation by MAO inhibitors has been reported with opiates. During concurrent use of other CNS depressants, additive respiratory or CNS depressant effects, hypotension, profound sedation, coma, or death may occur. If concurrent use is necessary, assess the level of tolerance to CNS depression that has developed, the duration of use, the patient's overall response to treatment, and the patient's use of alcohol or illicit drugs. Initiate oxymorphone at one-third to one-half the usual dosage in patients concurrently receiving another CNS depressant and slowly titrate the dose based on efficacy and tolerability. Consider a lower dose of the CNS depressant. Advise patients against driving or performing other activities requiring mental alertness until they know how the combination affects them.
    Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as Monoamine oxidase inhibitors. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and selegiline, a CYP3A4 substrate, may cause an increase in systemic concentrations of selegiline. Use caution when administering these drugs concomitantly.
    Penbutolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Pentazocine: (Major) Patients receiving concurrent pentazocine and MAOIs are at increased risk for developing serotonin syndrome; pentazocine should be used cautiously, if at all, in these patients.
    Pentazocine; Naloxone: (Major) Patients receiving concurrent pentazocine and MAOIs are at increased risk for developing serotonin syndrome; pentazocine should be used cautiously, if at all, in these patients.
    Pentobarbital: (Major) Monoamine oxidase inhibitors (MAOIs) can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. MAOIs may prolong the effect of pentobarbital and cause additive CNS depression.
    Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as MAOIs.
    Perindopril: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Perindopril; Amlodipine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Perphenazine: (Major) Concurrent use of MAOIs and phenothiazines may prolong or intensify the hypotensive, anticholinergic, or sedative effects of either agent. Due to the potential for additive CNS and cardiovascular effects, MAOIs and phenothiazines should be used together cautiously.
    Perphenazine; Amitriptyline: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with tricyclic antidepressants (TCAs) or within 14 days of discontinuing treatment with a TCA. Conversely, TCAs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Major) Concurrent use of MAOIs and phenothiazines may prolong or intensify the hypotensive, anticholinergic, or sedative effects of either agent. Due to the potential for additive CNS and cardiovascular effects, MAOIs and phenothiazines should be used together cautiously.
    Phenobarbital: (Major) Monoamine oxidase inhibitors (MAOIs) can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. MAOIs may prolong the effect of phenobarbital and cause additive CNS depression.
    Phenoxybenzamine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy with antihypertensives such as alpha-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Phentolamine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy with antihypertensives such as alpha-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Phenylephrine; Promethazine: (Severe) The concurrent use of MAOIs with sedating H1-blockers is not recommended because of an increase in the intensity and prolongation of CNS-depressant and anticholinergic effects. Most manufacturers recommend that H1-antagonists not be used within two weeks of therapy with a MAOI.
    Pindolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Posaconazole: (Major) Posaconazole and selegiline should be coadministered with caution due to an increased potential for selegiline-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of selegiline. These drugs used in combination may result in elevated selegiline plasma concentrations, causing an increased risk for selegiline-related adverse events.
    Potassium-sparing diuretics: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Pramlintide: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents.Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Prazosin: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy with antihypertensives such as alpha-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Primidone: (Major) Monoamine oxidase inhibitors (MAOIs) can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. MAOIs may prolong the effect of barbiturates like primidone and cause additive CNS depression.
    Procaine: (Severe) Combined hypotensive effects are possible with use of MAOIs and spinal anesthetics. Use of epinephrine added to chloroprocaine with monoamine oxidase inhibitors (MAOIs) or drugs with MAOI activity (e.g., furazolidone, linezolid, or procarbazine) is not recommended. When local anesthetics containing sympathomimetic vasoconstrictors are coadministered with MAOIs, severe and prolonged hypertension may occur. MAOIs and agents with MAOI activity can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient. Phenelzine, tranylcypromine, and transdermal selegiline are contraindicated for use for at least 10 days prior to elective surgery.
    Procarbazine: (Severe) Procarbazine is a weak monoamine oxidase inhibitor. Avoid concomitant administration with other monoamine oxidase inhibitors because of the possibility of severe hyperpyretic or hypertensive crises, convulsions, or death. In general, at least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other.
    Prochlorperazine: (Major) Concurrent use of MAOIs and phenothiazines may prolong or intensify the hypotensive, anticholinergic, or sedative effects of either agent. Due to the potential for additive CNS and cardiovascular effects, MAOIs and phenothiazines should be used together cautiously.
    Promethazine: (Severe) The concurrent use of MAOIs with sedating H1-blockers is not recommended because of an increase in the intensity and prolongation of CNS-depressant and anticholinergic effects. Most manufacturers recommend that H1-antagonists not be used within two weeks of therapy with a MAOI.
    Propofol: (Severe) Patients taking MAOIs should not undergo elective surgery, including dental procedures, that require the use of general anesthetics due to the potential for CNS and cardiovascular reactions. Combined hypotensive effects are possible with the combined use of MAOIs and spinal anesthetics. MAOIs should be discontinued for at least 10 days prior to elective surgery.
    Propoxyphene: (Severe) Concurrent use of selegiline or selegiline, transdermal and propoxyphene is contraindicated. Severe reactions such as excitation, sweating, rigidity, hypertension, severe respiratory depression, coma, and peripheral vascular collapse, possibly resulting in death, can occur. At least 2 weeks should elapse between stopping selegiline and starting propoxyphene.
    Propranolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Protriptyline: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with tricyclic antidepressants (TCAs) or within 14 days of discontinuing treatment with a TCA. Conversely, TCAs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Quazepam: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Quinapril: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Ramelteon: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including ramelteon.
    Ramipril: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Rasagiline: (Severe) Rasagiline should not be used concurrently with or in rapid succession to other monoamine oxidase inhibitors (MAOIs) (e.g., isocarboxazid, pargyline, phenelzine, tranylcypromine, selegiline, or transdermal selegiline). The combination or rapid succession of MAOI treatment could result in severe CNS or cardiovascular reactions, including hypertensive crises, hyperpyrexia, CNS excitation, delirium, tremor, convulsions, coma, circulatory collapse or death. At least 14 days should elapse between the discontinuation of rasagiline and the initiation of another MAOI or the discontinuation of another MAOI and the initiation of rasagiline.
    Remifentanil: (Major) Remifentanil use is not recommended in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of remifentanil with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as remifentanil. If urgent use is necessary, use test doses of remifentanil with frequent titration of small doses and close monitoring. If serotonin syndrome is suspected, discontinue remifentanil and/or the MAOI.
    Repaglinide: (Moderate) Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to antidiabetic agents. It has also been proposed that MAOIs may interfere with the adrenergic response to hypoglycemia but it is uncertain how significant this action may be. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Reserpine: (Severe) The concomitant use of reserpine and monoamine oxidase inhibitors (MAOIs) is contraindicated. Acutely, reserpine can increase the risk of hypertensive crisis by causing an initial release of catecholamines from bound stores. During chronic administration, additive CNS depressant effects and hypotension are possible.
    Ritonavir: (Moderate) Concurrent administration of selegiline with ritonavir may result in elevated selegiline plasma concentrations. Selegiline is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Rizatriptan: (Severe) Rizatriptan is partially metabolized by MAO-A, and is contraindicated for use with non-selective MAOIs, including selegiline in its transdermal form, which inhibits both MAO-A and MAO-B at antidepressant doses. Serotonin syndrome has been reported during co-administration of serotonin-receptor agonists and monoamine oxidase inhibitors (MAOIs), due to the inhibitory effects of MAOIs on MAO-A, which decreases central serotonin degradation. Since oral selegiline selectively inhibits MAO-B at recommended doses, no interaction with serotonin-receptor agonists is expected with usual prescription use. However, there is a decline in MAO-B selectivity with increasing doses. Therefore, when recommended oral doses are exceeded (i.e., > 10 mg/day), there is the potential for selegiline to increase central serotonin levels through MAO-A inhibition. However, whether or not 5-HT1B/1D agonists such as serotonin-receptor agonists can cause serious cases of serotonin syndrome when used with serotonergic drugs has been debated since serotonin syndrome is thought to result primarily from 5-HT2A activation.
    Sacubitril; Valsartan: (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    S-adenosyl-L-methionine, SAM-e: (Major) Pharmacologic studies suggest that S-adenosyl-L-methionine, SAM-e may have additive pharmacodynamic effects with traditional antidepressant therapies such as the tricyclic antidepressants or MAOIs, but the pharmacology is poorly understood. Pharmacology studies indicate that SAM-e augments dopaminergic and serotonergic systems, and may have a weak inhibitory effect on MAO-B within the CNS. The routine addition of SAM-e to other conventional antidepressant medications, especially MAOIs, should be approached with caution until the mechanism of action of SAM-e with regard to neurotransmitter function or receptor activity is clarified. This dietary supplement is probably best avoided in combination with prescription antidepressants unless closely monitored by a health care professional.
    Safinamide: (Severe) Concurrent use of safinamide with other monoamine oxidase inhibitors (MAOIs) or use of other MAOIs within 2 weeks of taking safinamide is contraindicated due to the risk of increased blood pressure, including hypertensive crisis. Serotonin syndrome has also been reported during coadministration of MAOIs, presumably due to additive effects on central serotonin levels. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Saxagliptin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents.Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Secobarbital: (Major) MAOIs may prolong the effect of primidone and cause additive CNS depression.
    Sedating H1-blockers: (Major) Concurrent use of monoamine oxidase inhibitors (MAOIs) and sedating H1-blockers (sedating antihistamines) may result in additive sedation, anticholinergic effects, or hypotensive reactions. Consider alternative therapy to antihistamines where possible. If alternative combinations are not available, these medications may be used together with close monitoring. Many non-prescription products for coughs, colds, allergy, hay fever or insomnia contain sedating antihistamines. Patients receiving an MAOI should be counseled that it is essential to consult their healthcare provider or pharmacist prior to the use of any non-prescription products. Patients should also be advised against driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
    Selective norepinephrine reuptake inhibitors: (Severe) The use of selective norepinephrine reuptake inhibitors with monoamine oxidase inhibitors is contraindicated. At least 2 weeks should elapse between the discontinuation of a drug with MAO inhibiting activity and the start of selective norepinephrine reuptake inhibitors, or vice-versa. Selective norepinephrine reuptake inhibitors potentiate certain catecholamines by inhibiting neuronal reuptake. Since some of these catecholamines are deaminated by monoamine oxidase, the administration of drugs that inhibit this enzyme concurrently with an atomoxetine can lead to serious reactions, such as those seen with other reuptake inhibitors. These reactions may include confusion, seizures, and severe hypertension as well as less severe symptoms.
    Selective serotonin reuptake inhibitors: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Serotonin norepinephrine reuptake inhibitors: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with serotonin norepinephrine reuptake inhibitors (SNRIs). MAOIs should not be used within 5 days of discontinuing treatment with duloxetine or within 7 days of discontinuing treatment with other SNRIs. Conversely, SNRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Sevoflurane: (Severe) Patients taking MAOIs should not undergo elective surgery, including dental procedures, that require the use of general anesthetics due to the potential for CNS and cardiovascular reactions. Combined hypotensive effects are possible with the combined use of MAOIs and spinal anesthetics. MAOIs should be discontinued for at least 10 days prior to elective surgery.
    Sibutramine: (Severe) The concomitant use of sibutramine with MAOIs is contraindicated. Sibutramine is a serotonin reuptake inhibitor. Since serotonin is deaminated by monoamine oxidase-A, concurrent administration of sibutramine with drugs that inhibit this enzyme such as MAOIs can lead to serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. There should be at least a 2-week interval between discontinuation of MAOI therapy and initiation of sibutramine therapy. Similarly, there should be at least a 2-week interval after stopping sibutramine therapy and the start of MAOI therapy.
    Sildenafil: (Moderate) Additive hypotensive effects may be seen when Monoamine oxidase inhibitors (MAOIs) are combined with sildenafil. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with sildenafil.
    Simvastatin; Sitagliptin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents.Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Sitagliptin: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents.Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Sodium Oxybate: (Severe) Sympathomimetics and psychostimulants are contraindicated in patients receiving MAOIs. When administeringan MAOI in close proximity to a sympathomimetic or psychostimulant, at least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other. MAOIs can increase the amount of norepinephrine in neuronal storage sites. Administration of an indirect-acting sympathomimetic (e.g., those that cause release of norepinephrine) to patients receiving a MAOI may invoke a severe hypertensive reaction. Data describing an interaction between some psychostimulants (e.g., modafinil or sodium oxybate) and MAOIs are less readily available, but, in general, all psychostimulants should be avoided in patients receiving a MAOI.
    Sotalol: (Moderate) Limited data suggest that bradycardia is worsened when monoamine oxidase inhibitors (MAOIs) are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers.
    Spironolactone: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    St. John's Wort, Hypericum perforatum: (Severe) St. John's wort, Hypericum perforatum should not be used concurrently with MAOIs or drugs that possess MAOI-like activity because of the possibility of severe hyperpyretic or hypertensive crises, convulsions, or death. Since serotonin is deaminated by monoamine oxidase type A, administration of non-selective MAOIs concurrently with St. John's wort could potentially lead to a serious reaction known as 'serotonin syndrome'. At least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other.
    Succinimides: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Succinylcholine: (Major) Limited data suggest that the neuromuscular blocking effect of succinylcholine may be enhanced by drugs that reduce plasma pseudocholinesterase, such as monoamine oxidase inhibitors (MAOIs). These drugs should be used together with caution.
    Sufentanil: (Major) Concomitant use of sufentanil with other central nervous system (CNS) depressants, such as monoamine oxidase inhibitors (MAOIs), can potentiate sufentanil-induced CNS or respiratory depression and cardiovascular effects and the duration of these effects. Dose reduction of sufentanil and/or the concurrent CNS depressant is recommended. Advise patients against driving or performing other hazardous activities after receiving sufentanil.
    Sulfonylureas: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents.Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Sumatriptan: (Major) Serotonin syndrome has been reported during co-administration of serotonin-receptor agonists and monoamine oxidase inhibitors (MAOIs). Since oral selegiline selectively inhibits MAO-B at recommended doses, no interaction with sumatriptan would be expected with normal prescription use. However, there is a decline in MAO-B selectivity with increasing doses. Therefore, high dose treatment with oral selegiline may increase central serotonin levels through MAO-A inhibition. In addition, selegiline, transdermal inhibits both MAO-A and MAO-B at the usual antidepressant doses. However, whether or not 5-HT1B/1D agonists such as sumatriptan can cause serious cases of serotonin syndrome when used with serotonergic drugs has been debated since serotonin syndrome is thought to result primarily from 5-HT2A activation. Some serotonin-receptor agonists, such as sumatriptan are partially metabolized by MAO-A. Theoretically, use of high dose selegiline could increase systemic exposure to sumatriptan through MAO-A inhibition.
    Sympathomimetics: (Severe) In general, all types of sympathomimetics and psychostimulants should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and even respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use.
    Tapentadol: (Severe) Tapentadol use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of tapentadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tapentadol.
    Tedizolid: (Major) Although interactions with monamine oxidase inhibitors (MAOIs) were not evaluated in clinical trials, caution is warranted with the concurrent use of tedizolid and MAOIs due to the potential risk of severe hypertensive crisis and possibly serotonin syndrome, particularly with non-selective MAOIs (e.g., phenelzine, tranylcypromine, isocarboxazid). However, caution is also warranted with selective agents, such as selegiline and rasagiline. Although rasagiline differs from other MAOIs because it is MAO-B selective at recommended doses, it may be advisable to avoid co-administration with tedizolid until specific information becomes available about the safety of this combination. Tedizolid is an antibiotic that is also a weak reversible, non-selective MAO inhibitor, similar to linezolid, which is structurally related. Serotonin syndrome has been reported when linezolid has been administerd with certain serotonergic agents. In theory, serotonin syndome could occur with the concomitant use of MAOIs; however, the FDA states that it is unclear if concomitant use of linezolid and agents with lesser degrees of serotonergic activity would pose a comparable risk. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering selegiline with telaprevir due to an increased potential for selegiline-related adverse events. If selegiline dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of selegiline. Selegiline is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated selegiline plasma concentrations.
    Telmisartan: (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and selegiline is necessary, as the systemic exposure of selegiline may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of selegiline; consider increasing the dose of selegiline if necessary. Selegiline is a CYP3A4 substrate in vitro. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temazepam: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Terazosin: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy with antihypertensives such as alpha-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Teriflunomide: (Moderate) Use caution when administering teriflunomide with selegiline. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as selegiline, may decrease selegiline exposure and lead to efficacy reduction. If teriflunomide is discontinued in a patient taking selegiline, serum concentrations may increase. Monitor patients for increases in adverse effects, such as dyskinesia, hallucinations, or nausea. Dose adjustments may be required.
    Tetrabenazine: (Severe) Tetrabenazine use is contraindicated in patients who are receiving or have received MAOI therapy within the past 14 days. The major metabolites of tetrabenazine (alpha-dihydrotetrabenazine [HTBZ] and beta-HTBZ) are reversible inhibitors of vesicular monoamine transporter 2 (VMAT2). Inhibition of VMAT2 results in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores.
    Tetracaine: (Severe) Combined hypotensive effects are possible with use of MAOIs and spinal anesthetics. Use of epinephrine added to chloroprocaine with monoamine oxidase inhibitors (MAOIs) or drugs with MAOI activity (e.g., furazolidone, linezolid, or procarbazine) is not recommended. When local anesthetics containing sympathomimetic vasoconstrictors are coadministered with MAOIs, severe and prolonged hypertension may occur. MAOIs and agents with MAOI activity can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient. Phenelzine, tranylcypromine, and transdermal selegiline are contraindicated for use for at least 10 days prior to elective surgery.
    Tetrahydrozoline: (Severe) In general, tetrahydrozoline should not be combined with monoamine oxidase inhibitors (MAOIs). The combination of an MAOI and a sympathomimetic drug, including those given via nasal or ophthalmic routes, may result in hypertensive crisis. Avoid use during and up to 2 weeks following discontinuation of the MAOI.
    Thiazide diuretics: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Thiazolidinediones: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents.Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Thiopental: (Severe) Patients receiving MAOIs may have an increased risk of hypotension after administration of general anesthetics. In general, MAOIs should be discontinued for at least 10 days prior to elective surgery.
    Thioridazine: (Major) Concurrent use of MAOIs and phenothiazines may prolong or intensify the hypotensive, anticholinergic, or sedative effects of either agent. Due to the potential for additive CNS and cardiovascular effects, MAOIs and phenothiazines should be used together cautiously.
    Thiothixene: (Major) Concurrent use of monoamine oxidase inhibitors (MAOIs) and thiothixene may prolong or intensify the hypotensive, anticholinergic, or sedative effects of either agent. Due to the potential for additive CNS and cardiovascular effects, MAOIs and thiothixene should be used together cautiously.
    Tiagabine: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Timolol: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Torsemide: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Tramadol: (Severe) Tramadol use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol.
    Trandolapril: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Trandolapril; Verapamil: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Trazodone: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with heterocyclic antidepressants (e.g., trazodone, mirtazapine, amoxapine, maptrotiline) or within 14 days of discontinuing treatment with a heterocyclic antidepressant. Conversely, heterocyclic antidepressants should not be initiated within 14 days of stopping an MAOI. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Treprostinil: (Moderate) Additive hypotensive effects may be seen when MAOIs are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with vasodilators.
    Triamterene: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Triazolam: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Tricyclic antidepressants: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with tricyclic antidepressants (TCAs) or within 14 days of discontinuing treatment with a TCA. Conversely, TCAs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Trifluoperazine: (Major) Concurrent use of MAOIs and phenothiazines may prolong or intensify the hypotensive, anticholinergic, or sedative effects of either agent. Due to the potential for additive CNS and cardiovascular effects, MAOIs and phenothiazines should be used together cautiously.
    Trimipramine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with tricyclic antidepressants (TCAs) or within 14 days of discontinuing treatment with a TCA. Conversely, TCAs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Trospium: (Moderate) MAOIs exhibit secondary anticholinergic actions. Additive anticholinergic effects may be seen when MAOIs are used concomitantly with antimuscarinics such as trospium. Additive CNS effects are also possible when antimuscarinic drugs are combined with MAOIs.
    Valbenazine: (Major) Avoid the use of valbenazine with monoamine oxidase inhibitors (MAOIs). Concomitant use of valbenazine with MAOIs may increase the concentration of monoamine neurotransmitters in synapses, potentially leading to an increased risk of adverse reactions such as serotonin syndrome, or an attenuated treatment effect of valbenazine.
    Valerian, Valeriana officinalis: (Major) Any substances that act on the CNS may theoretically interact with valerian, Valeriana officinalis. The valerian derivative, dihydrovaltrate, binds at barbiturate binding sites; valerenic acid has been shown to inhibit enzyme-induced breakdown of GABA in the brain; the non-volatile monoterpenes (valepotriates) have sedative activity. Patients taking MAOIs should discuss the use of herbal supplements with their health care professional prior to consuming valerian; combinations should be approached with caution in the absence of clinical data.
    Valproic Acid, Divalproex Sodium: (Moderate) Concomitant use of CNS depressants with valproic acid can cause additive CNS depression. MAOIs, used concomitantly with valproic acid, can increase CNS depression and also can lower the seizure threshold,
    Valsartan: (Moderate) Additive hypotensive effects may be seen when selegiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Vasodilators: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with vasodilators. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Venlafaxine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with serotonin norepinephrine reuptake inhibitors (SNRIs). MAOIs should not be used within 5 days of discontinuing treatment with duloxetine or within 7 days of discontinuing treatment with other SNRIs. Conversely, SNRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Verapamil: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Vilazodone: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with vilazodone or within 14 days of discontinuing treatment with vilazodone. Conversely, vilazodone should not be initiated within 14 days of stopping an MAOI. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Vortioxetine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with vortioxetine or within 21 days of discontinuing treatment with vortioxetine. Conversely, vortioxetine should not be initiated within 14 days of stopping an MAOI. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Yohimbine: (Severe) Monoamine oxidase inhibitors (MAOIs) should not be used concurrently with or in rapid succession drugs that possess MAO-inhibiting activity, such as yohimbine. The combination or rapid succession of MAOI treatment could result in severe CNS or cardiovascular reactions, including hypertensive crises. At high doses, yohimbine may nonselectively inhibit monoamine oxidase (MAO) and also, at normal doses, activates the sympathetic nervous system via selective central alpha 2-adrenoceptor antagonism. It is best to avoid use of yohimbine with non-selective monoamine oxidase inhibitors (MAOIs), such as phenelzine, isocarboxazid, tranylcypromine, and even drugs with selective MAOI activity, such as selegiline and selegiline, transdermal, or rasagiline. The activity of yohimbine might result in increased blood pressure or other serious side effects. It would be prudent to avoid yohimbine during MAOI therapy and for 2 weeks after the discontinuation of a MAOI.
    Zolmitriptan: (Major) Serotonin syndrome has been reported during co-administration of serotonin-receptor agonists and monoamine oxidase inhibitors (MAOIs). Since oral selegiline selectively inhibits MAO-B at recommended doses, no interaction with zolmitriptan would be expected with normal prescription use. However, there is a decline in MAO-B selectivity with increasing doses. Therefore, high dose treatment with oral selegiline may increase central serotonin levels through MAO-A inhibition. In addition, selegiline, transdermal inhibits both MAO-A and MAO-B at the usual antidepressant doses. However, whether or not 5-HT1B/1D agonists such as zolmitriptan can cause serious cases of serotonin syndrome when used with serotonergic drugs has been debated since serotonin syndrome is thought to result primarily from 5-HT2A activation. In vitro data indicate that zolmitriptan is partially metabolized by MAO-A. In one drug interaction study, selegiline 10 mg/day for 1 week had no effect on the pharmacokinetics of zolmitriptan or its metabolite. Theoretically, use of higher doses of selegiline could increase systemic exposure to zolmitriptan through MAO-A inhibition.
    Zonisamide: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.

    PREGNANCY AND LACTATION

    Pregnancy

    Because there are no adequate and well-controlled studies of selegiline use in pregnant women, the drug should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Selegiline has a low molecular weight and would be expected to cross the placenta. A case report of oral selegiline used in a pregnant woman who continued the drug throughout gestation noted no teratogenic defects or developmental delays in a healthy male infant over a 10-year period. However, animal studies suggest the potential for neurological changes. Decreases in fetal weight, delayed ossification, and embryo-fetal post-implantation lethality have been noted during the period of organogenesis in animal studies at doses up to 60 times the maximum recommended human dose (MRHD). Slight increases in visceral malformations have been seen during the period of embryo-fetal development in animal studies at doses up to 64 times the MRHD. An increase in stillborn pups and post-implantation loss has been seen in rat studies. Throughout lactation and post-weaning periods, decreases in pup weight, retarded pup physical development, and retarded pup neurobehavioral and sexual development were seen at all doses up to 60 times the MRHD. These findings suggest persistent effects on the offspring of treated dams. A no-effect dose was not established for developmental toxicity. It is not known how these animal findings relate to effects in pregnant women. Selegiline has not established use in labor and delivery.

    It is unknown if selegiline is excreted into human breast milk, and a decision should be made whether to discontinue the drug or discontinue breast-feeding, taking into account the importance of the drug to the mother. Consideration should be given to discontinuing the use of all but absolutely essential drug treatments in nursing women. The manufacturer of transdermal selegiline advises caution if administering transdermal selegiline during breast-feeding. Selegiline has a low molecular weight (188 for the free base) and would be expected to cross into human breast milk. A case report describes maternal use of oral selegiline 10 mg/day, levodopa 400 mg, and benserazide 100 mg daily throughout pregnancy and for 3 days while breast-feeding; the child was followed for 10 years and no developmental abnormalities were found. An accurate prediction of the long-term adverse effects of selegiline in the nursing infant may not be possible because the drug affects central neurotransmitter function, and may alter the developing central nervous system. Although rasagiline may be considered as an alternative therapy to selegiline for the adjunct treatment of Parkinson's disease in breast-feeding women, safety data are lacking. In addition, both rasagiline and selegiline can inhibit prolactin secretion, and thus, interference with proper lactation is possible. Psychotropic medications affect neurotransmitter function in the developing central nervous system, and therefore, the accurate prediction of long-term adverse effects may not be possible. Due to individual variability in response to antidepressants, it may be prudent to continue the existing regimen if ongoing treatment is deemed necessary during breast-feeding. However, because a pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum, these agents may be preferable to transdermal selegiline when initiating antidepressant therapy in a breast-feeding mother. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Selegiline is an irreversible inhibitor of the monoamine oxidase (MAO) enzyme system. MAO exists as 2 catabolic isoenzymes, MAO-A and MAO-B. The neurotransmitters serotonin and norepinephrine are primarily catabolized by MAO-A and dopamine is primarily catabolized by MAO-B. In addition to their role in the catabolism of monoamines in the CNS, MAOs are also important in the catabolism of exogenous amines found in a variety of foods and drugs. MAO in the gastrointestinal tract is primarily type A, and provides protection from systemic absorption of exogenous amines with vasopressor actions, such as tyramine, which can cause hypertensive crisis if absorbed intact. Selegiline is considered a selective MAO-B inhibitor, although selectivity decreases as the dose increases. Restrictions on intake of dietary tyramine during selegiline administration vary according to formulation and dose. Two of the metabolites, amphetamine and methamphetamine, may interfere with neuronal uptake and enhance the release of some neurotransmitters (e.g., norepinephrine, dopamine, serotonin). However, the extent to which these metabolites contribute to the therapeutic effects of selegiline is unknown. Selegiline has demonstrated affinity at the adrenergic alpha 2B receptor. No affinity has been noted at dopamine receptors, adrenergic B3, glutamate, muscarinic, nicotinic, or rolapram receptor/sites.
     
    Transdermal selegiline: The mechanism of action of transdermal selegiline as an antidepressant is thought to occur from potentiation of monoamine neurotransmitters (e.g., dopamine, serotonin, norepinephrine) in the CNS resulting from its inhibition of MAO-A and MAO-B. When administered in a transdermal patch, targeted inhibition of MAO-A and MAO-B in the CNS is seen. In vitro studies have shown that transdermal selegiline exhibits antidepressant properties only at doses that inhibit both MAO-A and MAO-B activity in brain. Intestinal MAO is predominantly type A, while in the brain both isoenzymes exist. Clinical trials of transdermal selegiline demonstrated a preservation of MAO-A in the intestinal mucosa and liver, allowing for the breakdown of dietary tyramine and the prevention of gastric absorption of dietary tyramine only at a selegiline dose of 6 mg/24 hour. Higher therapeutic doses (i.e., 9 mg/24 hours and 12 mg/24 hours) must be used with tyramine diet restrictions. Effects resulting from transdermal selegiline administration may also occur through its metabolites. However, transdermal dosing results in significantly higher exposure to selegiline with significantly lower exposure for all metabolites relative to oral administration.
     
    Oral selegiline: At doses used in Parkinson's disease, selegiline typically exhibits a greater affinity for MAO-B. At higher doses, MAO is blocked non-selectively, predisposing patients to the risks (e.g., hypertensive crisis) of traditional MAOIs (e.g., phenelzine) that block both MAO-B and MOA-A. Therefore, the dose limits established for specific oral selegiline products should not be exceeded. An increase in tyramine sensitivity for blood pressure responses appears to begin at a dose of 5 mg/day of selegiline orally disintegrating tablets (ODT); however, the precise dose at which selegiline ODT becomes a non-selective inhibitor of all MAO enzymes in individual patients is unknown. Oral selegiline tablets can ordinarily be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day); however, it should be noted that a few cases of hypertensive reactions have been reported at the recommended dose.

    PHARMACOKINETICS

    Selegiline is available as an oral tablet, oral capsule, orally disintegrating tablet (ODT), and transdermal patch. Approximately 85% to 90% of plasma selegiline is reversibly bound to plasma proteins. Selegiline rapidly penetrates the blood-brain barrier. Although platelet MAO-B activity returns to the normal range within 5 to 7 days of discontinuation of oral selegiline, the link between platelet and brain MAO-B inhibition is not fully understood nor is the relationship of MAO-B inhibition to the clinical effect. Selegiline is extensively metabolized to N-desmethylselegiline and L-methamphetamine. Both of these metabolites may subsequently be converted to L-amphetamine. The metabolites are further converted to their hydroxymetabolites. Transdermal dosing results in significantly higher exposure to selegiline with significantly lower exposure for all metabolites when compared to oral dosing. In a kinetic evaluation, approximately 10% of a radiolabeled transdermal dose was recovered in the urine and 2% recovered in feces, with at least 63% of the dose unabsorbed. The remaining 25% of the transdermal dose was unaccounted for. Selegiline ODT produces a smaller fraction of the administered dose recoverable as the metabolites than the conventional, swallowed formulation of selegiline. Following a single oral or ODT dose, the mean elimination half-life of selegiline was 1.3 to 2 hours. At steady-state, the elimination half-life increased to 10 hours. After IV administration, the half-lives of selegiline and its 3 metabolites (N-desmethylselegiline, L-amphetamine, and L-methamphetamine) ranged from 18 to 25 hours. Following hepatic metabolism, selegiline is excreted primarily in the urine as metabolites (mainly as L-methamphetamine and L-amphetamine) and as a small amount in the feces.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2B6, CYP2A6, CYP3A4, CYP3A5, CYP2D6, CYP2C9
    Selegiline is a substrate for CYP2B6, CYP2C9 and CYP3A4/5. In vitro studies indicate that CYP2B6, CYP2C9, CYP3A4 and CYP3A5 appear to be the major isoenzymes involved in the formation of L-methamphetamine from selegiline, with CYP2A6 having a minor role. CYP2A6, CYP2B6, CYP3A4 and CYP3A5 appear to contribute to the formation of L-amphetamine from N-desmethylselegiline. Selegiline shows competitive inhibitory action at CYP2D6, CYP3A4/5, CYP2C19, and CYP2B6. However, all inhibitory effects of selegiline occur at concentrations that are several orders of magnitude higher than concentrations seen clinically.

    Oral Route

    Oral Tablet or Capsule: Following administration of the tablet or capsule dosage form, selegiline is readily absorbed from the GI tract and crosses the blood/brain barrier; however, the absolute bioavailability is unknown. The extent of systemic exposure to selegiline at a given dose varies significantly among individuals. Peak serum concentrations are found in 0.5 to 2 hours. Mean maximum plasma concentrations of 1.12 ng/mL are reached for the oral 5 mg selegiline tablets (given as 5 mg PO twice daily). The bioavailability of selegiline is increased 3 to 4 fold when it is taken with food. The peak plasma levels of the 3 metabolites (N-desmethylselegiline, L-amphetamine and L-methamphetamine) following a single oral dose of 10 mg are from 4 to almost 20 times greater than that of the maximum plasma concentration (Cmax) of selegiline. The maximum concentrations of amphetamine and methamphetamine, however, are far below those ordinarily expected to produce clinically important effects. The duration of action of selegiline depends on the time required to regenerate MAO type B. Like phenelzine, the effects of selegiline are cumulative, with beneficial effects seen in a few days to several months depending on the condition being treated and individual response.
    Orally Disintegrating Tablet (ODT): Following administration of the orally disintegrating tablet, disintegration and absorption occur rapidly. Detectable levels of selegiline from selegiline ODT have been measured 5 minutes after administration. Selegiline ODT is more rapidly absorbed (time to maximal concentration or Tmax range 10 to 15 minutes) than from the swallowed 5 mg selegiline tablet (Tmax range 40 to 90 minutes). When selegiline ODT is taken with food, the Cmax and AUC of selegiline are about 60% of those seen when selegiline ODT is taken in the fasted state. Since selegiline ODT is placed on the tongue and absorbed through the oral mucosa, the intake of food and liquid should be avoided 5 minutes before and after administration. The pre-gastric absorption from selegiline ODT and the avoidance of first-pass metabolism results in higher concentrations of selegiline and lower concentrations of the metabolites compared to the 5 mg swallowed tablet. Mean maximum plasma concentrations of 3.34 and 4.47 ng/mL are reached after single dose of 1.25 and 2.5 mg selegiline ODT, respectively, compared to 1.12 ng/mL for the swallowed 5 mg selegiline tablets (given as 5 mg bid). Plasma Cmax and AUC of selegiline ODT are dose proportional. Steady state is achieved after 8 days. Following a single dose, the median elimination half-life is 1.3 hours at the 1.25 mg dose. Under steady-state conditions, the median elimination half-life increases to 10 hours. Selegiline ODT produces a smaller fraction of the administered dose recoverable as the metabolites than the conventional swallowed formulation of selegiline.

    Other Route(s)

    Transdermal Route
    With transdermal application, roughly 25 to 30% (range: 10% to 40%) of the selegiline content is delivered systemically over a 24-hour period. The degree of drug absorption may variably be one-third higher than the average amounts of transdermal doses of 6 mg/24 hours to 12 mg/24 hours. Transdermal administration avoids first-pass metabolism and results in much higher bioavailability compared to the oral dose form (74% vs. 4%). Additionally, substantially lower metabolite (L-desmethylselegiline, L-amphetamine, L-methamphetamine) concentrations are seen, compared to oral dosing. Steady-state plasma concentrations are achieved within 5 days. Transdermal selegiline does not accumulate in and is not metabolized in the skin and does not undergo extensive first-pass metabolism. In one study, steady-state selegiline plasma concentrations indicated selegiline concentration-time profiles were comparable when transdermal selegiline is applied to the upper torso or upper thigh, and absorption from these two sites of administration was equivalent.