Selegiline (transdermal)

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# Black Box Warning

# Overview
Selegiline (transdermal) is a monoamine oxidase inhibitor (MAOI) that is FDA approved for the treatment of major depressive disorder (MDD). There is a Black Box Warning for this drug as shown here.  Common adverse reactions include application site reaction, headache, insomnia, diarrhea, dry mouth, dyspepsia, rash, pharyngitis and sinusitis.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

## Indications
- Selegiline transdermal system is a monoamine oxidase inhibitor (MAOI) indicated for the treatment of major depressive disorder (MDD). The efficacy of selegiline in the treatment of major depressive disorder was established in two short term (6-week and 8-week) trials of outpatients with major depressive disorder. Efficacy was studied in two short term studies and one maintenance study

## Dosage

### Initial Treatment
- Selegiline should be applied to dry, intact skin on the upper torso (below the neck and above the waist), upper thigh or the outer surface of the upper arm once every 24 hours. The recommended starting dose and target dose for selegiline is 6 mg per 24 hours. Selegiline has been systematically evaluated and shown to be effective in a dose range of 6 mg per 24 hours to 12 mg per 24 hours. However, the trials were not designed to assess if higher doses are more effective than the lowest effective dose of 6 mg per 24 hours. Based on clinical judgment, if dose increases are indicated for individual patients, they should occur in dose increments of 3 mg per 24 hours (up to a maximum dose of 12 mg per 24 hours) at intervals of no less than 2 weeks. Full antidepressant effect may be delayed.
- Patients should be informed that tyramine-rich foods and beverages should be avoided beginning on the first day of selegiline 9 mg per 24 hours or 12 mg per 24 hours treatment and should continue to be avoided for 2 weeks after a dose reduction to selegiline 6 mg per 24 hours or following the discontinuation of selegiline 9 mg per 24 hours or 12 mg per 24 hours.

### Maintenance Treatment
- It is generally agreed that episodes of depression require several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in depressed patients on therapy with selegiline at a dose of 6 mg per 24 hours after achieving a responder status for an average duration of about 25 days was demonstrated in a controlled trial.
- The physician who elects to use selegiline for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

### Dietary Modifications Required for Patients Taking selegiline 9 mg per 24 hours and 12 mg per 24 hours
- Selegiline transdermal system contains a monoamine oxidase inhibitor (MAOI). MAOIs including selegiline combined with a high tyramine diet may cause a hypertensive crisis. A hypertensive crisis can be a life-threatening condition.
- The foods and beverages listed in Table 5 should be avoided beginning on the first day of selegiline 9 mg per 24 hours or 12 mg per 24 hours treatment, and should continue to be avoided for 2 weeks after a dose reduction to selegiline 6 mg per 24 hours or following the discontinuation of selegiline 9 mg per 24 hours or 12 mg per 24 hours.

## Dosage Forms and Strengths
- Selegiline transdermal system is supplied as 6 mg per 24 hours (20 mg per 20 cm2), 9 mg per 24 hours (30 mg per 30 cm2) and 12 mg per 24 hours (40 mg per 40 cm2) transdermal systems (TDS).
- Selegiline 6 mg per 24 hours is a translucent TDS printed with selegiline 6mg/24h. Selegiline 9 mg per 24 hours is a translucent TDS printed with selegiline 9mg/24h. Selegiline 12 mg per 24 hours is a translucent TDS printed with selegiline 12mg/24h.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Selegiline (transdermal) in adult patients.

### NonGuideline-Supported Use
- There is limited information regarding Off-Label NonGuideline-Supported Use of Selegiline (transdermal) in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- Use of selegiline in patients less than 12 years of age is contraindicated because of the potential for a hypertensive crisis.
- Efficacy has not been established in pediatric patients ages 12 to 17 years with MDD and selegiline is not recommended for use in this age range

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Selegiline (transdermal) in pediatric patients.

### NonGuideline-Supported Use
- There is limited information regarding Off-Label NonGuideline-Supported Use of Selegiline (transdermal) in pediatric patients.

# Contraindications
- Selegiline transdermal system is contraindicated with selective serotonin reuptake inhibitors (SSRIs, e.g., fluoxetine, sertraline, and paroxetine); serotonin and norepinephrine reuptake inhibitors (SNRIs, e.g., venlafaxine and duloxetine); the tricyclic antidepressants clomipramine and imipramine, the opiate analgesics meperidine, tramadol, methadone, pentazocine, and propoxyphene; and the antitussive agent dextromethorphan because of a risk of serotonin syndrome when selegiline is used with these agents.
- Carbamazepine is contraindicated with selegiline because of a possible increased risk of hypertensive crisis.
- After stopping treatment with drugs contraindicated with selegiline, a time period equal to 4 to 5 half-lives (approximately one week) of the drug or any active metabolite should elapse before starting therapy with selegiline. Because of the long half-life of fluoxetine and its active metabolite, at least 5 weeks should elapse between discontinuation of fluoxetine and initiation of treatment with selegiline.
- At least 2 weeks should elapse after stopping selegiline before starting therapy with any drug that is contraindicated with selegiline.
- Selegiline is contraindicated in patients less than 12 years of age because of the potential for a hypertensive crisis.
- Selegiline is contraindicated in patients with pheochromocytoma because MAOIs may precipitate a hypertensive crisis in such patients.

# Warnings

## Clinical Worsening and Suicide Risk
- Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective serotonin reuptake inhibitors  and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a trend toward risk reduction with antidepressants compared to placebo in adults aged 65 and older.
- The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorders (OCD), or other psychiatric disorders included a total of 24 short-term trials of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of two months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.\
- No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
- It is unknown whether the suicidality risk extends to longer term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
- All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
- The following symptoms anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
- Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patients presenting symptoms.
- Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.

### Screening Patients for Bipolar Disorder
- A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that selegiline is not approved for use in treating bipolar depression.

## Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome has been reported with concomitant use of MAOIs, such as selegiline, with serotonergic drugs. These reactions have also been reported in patients who have discontinued serotonergic drugs and then subsequently started an MAOI.
- Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
- Patients should be monitored for the emergence of serotonin syndrome. Treatment with selegiline and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive treatment should be initiated.

## Blood Pressure Elevation

### Tyramine-Induced Hypertensive Crisis
- Selegiline inhibits the catabolism of dietary amines, such as tyramine, and has the potential to produce a hypertensive crisis following the ingestion of tyramine-rich foods or beverages.
- Hypertensive crises, which in some cases may be fatal, are characterized by some or all of the following symptoms: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea, vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin), dilated pupils, and photophobia. Either tachycardia or bradycardia may be present and can be associated with constricting chest pain. Intracranial bleeding has been reported in association with the increase in blood pressure. Patients should be instructed as to 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 therapy to lower blood pressure should be instituted immediately. Fever should be managed by means of external cooling. Patients must be closely monitored until symptoms have stabilized.
- To prevent a hypertensive crisis, patients receiving treatment with selegiline 9 mg per 24 hours or selegiline 12 mg per 24 hours should follow the advice regarding a low tyramine diet described in Table 5 under Dietary Modifications Required for Patients Taking selegiline 9 mg per 24 hours and 12 mg per 24 hours.

### Blood Pressure Elevation Related to Concomitant Medication
- Carbamazepine is contraindicated with selegiline because carbamazepine has been shown to significantly elevate selegiline levels, which may increase the risk of a hypertensive crisis.
- The use of selegiline with adrenergic drugs or buspirone may produce substantial increases in blood pressure. Therefore, monitor blood pressure if selegiline is used with any of the following drugs: buspirone, amphetamines, or cold products or weight-reducing preparations that contain sympathomimetic amines (e.g., pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine).

## Activation of Mania/Hypomania
- During Phase III trials, a manic reaction occurred in 8 out of 2,036 (0.4%) patients treated with selegiline. Activation of mania/hypomania can occur in a small proportion of patients with major depressive disorder treated with antidepressants. Selegiline should be used cautiously in patients with a history of mania.

## External Heat
- The effect of direct heat applied to the selegiline 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 selegiline patch and produce elevated serum levels of selegiline. Patients should be advised to avoid exposing the selegiline 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.

# Adverse Reactions

## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

### Patient Exposure
- The premarketing development program for selegiline included selegiline exposures in patients and/or normal subjects from two different groups of studies: 702 healthy subjects in clinical pharmacology/pharmacokinetics studies and 2,036 exposures from patients in controlled and uncontrolled major depressive disorder clinical trials. The conditions and duration of treatment with selegiline varied and included double-blind, open-label, fixed-dose, and dose titration studies of short-term and longer-term exposures. Safety was assessed by monitoring adverse reactions, physical examinations, vital signs, body weights, laboratory analyses, and ECGs.
- Adverse reactions during exposure were obtained primarily by general inquiry and recorded by clinical investigators. In the tables and tabulations that follow, standard COSTART terminology has been used to classify reported adverse reactions. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

### Adverse Reactions Leading To Discontinuation of Treatment
- Among 817 MDD patients treated with selegiline at doses of either 3 mg per 24 hours (151 patients), 6 mg per 24 hours (550 patients) or 6 mg per 24 hours, 9 mg per 24 hours, and 12 mg per 24 hours (116 patients) in placebo-controlled trials of up to 8 weeks in duration, 7.1% discontinued treatment due to an adverse reaction as compared with 3.6% of 668 patients receiving placebo. The only adverse reaction associated with discontinuation, in at least 1% of selegiline-treated patients at a rate at least twice that of placebo, was application site reaction (2% selegiline vs. 0% placebo).

### Adverse Reactions Occurring at an Incidence of 2% or More Among Selegiline-Treated Patients
- Table 2 enumerates adverse reactions that occurred at an incidence of 2% or more (rounded to the nearest percent) among 817 MDD patients treated with selegiline in doses ranging from 3 to 12 mg per 24 hours in placebo-controlled trials of up to 8 weeks in duration. Reactions included are those occurring in 2% or more of patients treated with selegiline and for which the incidence in patients treated with selegiline was greater than the incidence in placebo-treated patients.
- One adverse reaction was associated with a reporting of at least 5% in the selegiline group, and a rate at least twice that in the placebo group, in the pool of short-term, placebo-controlled studies: application site reactions. In one such study which utilized higher mean doses of selegiline than that in the entire study pool, the following reactions met these criteria: application site reactions, insomnia, diarrhea, and pharyngitis.

### Application Site Reactions
- In the pool of short-term, placebo-controlled major depressive disorder studies, application site reactions (ASRs) were reported in 24% of selegiline-treated patients and 12% of placebo-treated patients. Most ASRs were mild or moderate in severity. ASRs led to dropout in 2% of selegiline-treated patients and no placebo-treated patients.
- In one such study which utilized higher mean doses of selegiline, ASRs were reported in 40% of selegiline-treated patients and 20% of placebo-treated patients. Most of the ASRs in this study were described as erythema and most resolved spontaneously, requiring no treatment. When treatment was administered, it most commonly consisted of dermatological preparations of corticosteroids.

### Sexual Dysfunction
- Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment.
- Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence. Table 3 shows that the incidence rates of sexual side effects in patients with major depressive disorder are comparable to the placebo rates in placebo-controlled trials.
- There are no adequately designed studies examining sexual dysfunction with selegiline treatment.

### Vital Sign Changes
- Selegiline and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure), and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. In the pool of short-term, placebo-controlled major depressive disorder studies, 3.0% of selegiline-treated patients and 1.5% of placebo-treated patients experienced a low systolic blood pressure, defined as a reading less than or equal to 90 mmHg with a change from baseline of at least 20 mmHg. In one study which utilized higher mean doses of selegiline, 6.2% of selegiline-treated patients and no placebo-treated patients experienced a low standing systolic blood pressure by these criteria.
- In the pool of short-term major depressive disorder trials, 9.8% of selegiline-treated patients and 6.7% of placebo-treated patients experienced a notable orthostatic change in blood pressure, defined as a decrease of at least 10 mmHg in mean blood pressure with postural change.

### Weight Changes
- In placebo-controlled studies (6 to 8 weeks), the incidence of patients who experienced at least 5% weight gain or weight loss is shown in Table 4.
- In these trials, the mean change in body weight among selegiline-treated patients was a 1.2 lbs loss compared to 0.3 lbs gain in placebo-treated patients.

### Laboratory Changes
- Selegiline and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with selegiline.

### Electrocardiogram Changes
- Electrocardiograms (ECGs) from selegiline (N = 817) and placebo (N = 668) groups in controlled studies were compared with respect to (1) mean change from baseline in various ECG parameters, and (2) the incidence of patients meeting criteria for clinically significant changes from baseline in these variables.
- No clinically meaningful changes in ECG parameters from baseline to final visit were observed for patients in controlled studies.
- Other Reactions Observed During the Premarketing Evaluation of selegiline
- The following listing does not include reactions: 1) already listed elsewhere in labeling, 2) for which a causal relationship to drug was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.
- Cardiovascular System: Tachycardia.
- Digestive System: Anorexia.
- Nervous System: Agitation, amnesia, tremor, twitching.
- Skin and Appendages: Pruritus.

## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of selegiline.
- Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Nervous System: Convulsion and hypoesthesia.
- Psychiatric System: Disorientation, hallucination (visual), and tension.

# Drug Interactions

## Serotonergic Drugs
- Serious, sometimes fatal, central nervous system (CNS) toxicity referred to as the serotonin syndrome has been reported with the combination of nonselective MAOIs and serotonergic drugs. Use of selegiline with these drugs is contraindicated.

## Tyramine
- Selegiline has the capacity to inhibit intestinal MAO, which is responsible for the catabolism of tyramine in food and beverages. As a result of this inhibition, large amounts of tyramine may enter the systemic circulation and precipitate a sudden, large rise in blood pressure or hypertensive crisis.
- A diet low in tyramine content may be necessary to avoid this interaction. Studies to evaluate the potential for selegiline to inhibit tyramine metabolism have been conducted and, overall, the data for selegiline 6 mg per 24 hours support a recommendation that a modified diet is not required at this dose. Due to the more limited data available for selegiline 9 mg per 24 hours and the results from the Phase I tyramine challenge study in fed volunteers administered selegiline 12 mg per 24 hours, patients receiving these doses should follow Dietary Modifications Required for Patients Taking selegiline 9 mg per 24 hours and 12 mg per 24 hours below.

### Dietary Modifications Required for Patients Taking selegiline 9 mg per 24 hours and 12 mg per 24 hours
- The foods and beverages listed in Table 5 should be avoided beginning on the first day of selegiline 9 mg per 24 hours or 12 mg per 24 hours treatment, and should continue to be avoided for 2 weeks after a dose reduction to selegiline 6 mg per 24 hours or following the discontinuation of selegiline 9 mg per 24 hours or 12 mg per 24 hours.

## Sympathomimetic Amines and Buspirone
- The use of selegiline with sympathomimetic amines or buspirone may produce substantial elevations in blood pressure. Therefore, monitor blood pressure if selegiline is used with any of the following drugs: buspirone, amphetamines, and cold products or weight-reducing preparations that contain sympathomimetic amines (e.g., pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine).

## Effect of Other Drugs on Selegiline
- Carbamazepine is contraindicated with MAOIs, including selegiline.
- No dose adjustment for selegiline is needed when selegiline is used concomitantly with alcohol, alprazolam, ibuprofen, olanzapine, risperidone, levothyroxine, and CYP3A4 inhibitors (e.g., ketoconazole). No clinically meaningful change in selegiline exposure was seen when selegiline was co-administered with alcohol, alprazolam, ibuprofen, olanzapine, risperidone, levothyroxine, and ketoconazole.

## Effect of Selegiline on Other Drugs
- Use of alcohol while taking selegiline is not recommended, even though selegiline has not been shown to increase the impairment of mental and motor skills caused by alcohol (0.75 mg per kg).
- Monitor blood pressure if sympathomimetic agents (e.g., phenylpropanolamine (PPA) or pseudoephedrine) are used with selegiline, even though selegiline does not appear to affect the pharmacokinetics of PPA or pseudoephedrine.
- No dose adjustment of alprazolam, ibuprofen, levothyroxine, olanzapine, risperdione, warfarin, or strong CYP3A4 inhibitors (e.g., ketoconazole) is necessary when these drugs are used in combination with selegiline. Selegiline had no clinically relevant effect on pharmacokinetics of these drugs.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C

### Risk Summary
- There are no adequate and well controlled studies of selegiline in pregnant women. All human pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. In animal embryo-fetal development studies, transdermal administration of selegiline to rats and rabbits at doses up to 60 and 64 times the maximum recommended human dose (MRHD) respectively, produced slight increases in malformations in both rats and rabbits, and decreased fetal weight, delayed ossification, and embryo-fetal post-implantation loss in rats. Most of these effects were seen at the high dose in both rats and rabbits. In a pre-natal and post-natal development study, transdermal administration of selegiline in rats at doses 8, 24, and 60 times MRHD produced delayed neurobehavioral and sexual development in pups. Selegiline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

### Clinical Considerations
- Disease-associated maternal and embryo/fetal risk
- A prospective longitudinal study was conducted of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with selegiline, the physician should carefully consider both the potential risks of taking an MAOI, along with the established benefits of treating depression with an antidepressant.

### Animal Data
- In an embryofetal development study, rats were treated with transdermal selegiline during the period of organogenesis at doses of 10, 30, and 75 mg/kg/day (8, 24, and 60 times the MRHD of selegiline  on a mg/m2 basis). At the highest dose there was a decrease in fetal weight and slight increases in malformations, delayed ossification (also seen at the mid dose), and embryofetal post-implantation loss. Concentrations of selegiline and its metabolites in fetal plasma were generally similar to those in maternal plasma.
- In an embryofetal development study, rabbits were treated with transdermal selegiline during the period of organogenesis at doses of 2.5, 10, and 40 mg/kg/day (4, 16, and 64 times the MRHD on a mg/m2 basis). A slight increase in visceral malformations was seen at the high dose.
- In a prenatal and postnatal development study, rats were treated with transdermal selegiline at doses of 10, 30, and 75 mg/kg/day (8, 24, and 60 times the MRHD on a mg/m2 basis) on days 6 to 21 of gestation and days 1 to 21 of the lactation period. An increase in post-implantation loss was seen at the mid and high doses, and an increase in stillborn pups was seen at the high dose. Decreases in pup weight (throughout lactation and postweaning periods) and survival (throughout lactation period), delayed pup physical development, and pup epididymal and testicular hypoplasia, were seen at the mid and high doses. Delayed neurobehavioral and sexual development was seen at all doses. Adverse effects on pup reproductive performance, as evidenced by decreases in implantations and litter size, were seen at the high dose. These findings suggest persistent effects on the offspring of treated dams. A no-effect dose was not established in this study for developmental toxicity. In this study, concentrations of selegiline and its metabolites in milk were approximately 15 and 5 times, respectively, the concentrations in maternal plasma, indicating that the pups were directly dosed during the lactation period.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Selegiline (transdermal) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Selegiline (transdermal) during labor and delivery.

### Nursing Mothers
- It is unknown whether selegiline is present in human milk; however, selegiline and its metabolites are present in the milk of lactating rats.
- Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from selegiline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

### Pediatric Use
- Use of selegiline in patients less than 12 years of age is contraindicated because of the potential for a hypertensive crisis.
- Limited pharmacokinetic data with doses lower than in the commercially available formulations suggest that children under age 12 may be exposed to increased levels of selegiline compared to adolescents and adults, administered with and without dietary modifications, therefore, there may be an increased risk of hypertensive crisis, even at the lowest dose of selegiline.
- Efficacy has not been established in pediatric patients ages 12 to 17 years with MDD and selegiline is not recommended for use in this age range.
- A multi-center, randomized, double-blind, placebo-controlled, flexible-dose trial in 308 adolescents (ages 12 to 17 years) with MDD failed to demonstrate the efficacy of selegiline. Diagnosis of major depressive disorder (single episode or recurrent, moderate to severe) was based on according DSM-IV criteria and Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children (K-SADS). Enrolled patients had a Childrens Depression Rating Scale-Revised of  45 at the screening visit. Trial participants were randomized 1:1 to either selegiline or matching placebo without forced titration for a period of 12 weeks. Active treatment consisted of selegiline transdermal system at a dose of 6 mg per 24 hours, 9 mg per 24 hours, or 12 mg per 24 hours. The primary efficacy endpoint was the difference in total score on the Childrens Depression Rating Scale-Revised (CDRS-R) from baseline to the end of study (EOS) (Week 12). There was no observed difference in effect on CDRS-R Total Score at Week 12 (EOS) between treatments. The mean reduction in CDRS-R Total Score was 21.4 in the selegiline-treated subjects and 21.5 in those receiving placebo treatment. Safety endpoints included physical examination, 12-lead electrocardiogram, respiration rate, temperature, supine and standing blood pressure and heart rate, application site assessments, and adverse events. Overall, safety findings were similar to those observed in selegiline trials conducted in adults. Treatment-emergent adverse events reported by at least 5% of selegiline-treated patients at a rate at least twice the placebo rate were insomnia (6%, 3%) and upper respiratory tract infection (7%, 3%).

### Geriatic Use
- The recommended dose of selegiline for elderly patients (65 years and older) is 6 mg per 24 hours daily. The effect of age on the pharmacokinetics or metabolism of selegiline after administration of selegiline has not been systematically evaluated. One hundred ninety-eight (198) elderly (65 years of age and older) patients participated in clinical studies with selegiline 6 mg per 24 hours to 12 mg per 24 hours. There were no overall differences in effectiveness between elderly and younger patients. In short-term, placebo-controlled depression trials, patients age 50 and older appeared to be at higher risk for rash (4.4% selegiline vs. 0% placebo) than younger patients (3.4% selegiline vs. 2.4% placebo).

### Gender
- No adjustment of selegiline dosage based on gender is needed. No gender differences have been observed in the pharmacokinetics or metabolism of selegiline during administration of selegiline.

### Race
There is no FDA guidance on the use of Selegiline (transdermal) with respect to specific racial populations.

### Renal Impairment
- No adjustment of selegiline dosage is required in patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m2), moderate renal impairment (eGFR 30-59 mL/min/1.73 m2), or severe renal impairment (eGFR 15-29 mL/min/1.73 m2). Data from a single dose study examining the pharmacokinetics of selegiline 6 mg per 24 hours in 12 patients with renal impairment suggest that mild, moderate, or severe renal impairment does not affect the pharmacokinetics of selegiline after transdermal application. Selegiline has not been studied in patients with end-stage renal disease (eGFR < 15 mL/min/1.73 m2 or requiring dialysis).

### Hepatic Impairment
- No adjustment of selegiline dosage is required in patients with mild liver impairment (Child-Pugh 5-6 points) or moderate liver impairment (Child-Pugh 7-9 points). After a single administration of selegiline 6 mg per 24 hours in eight patients with mild or moderate liver impairment, no differences in either the metabolism or pharmacokinetic behavior of selegiline or its metabolites were observed as compared with data of normal subjects. Selegiline has not been studied in patients with severe liver impairment (Child-Pugh 10-15 points).

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Selegiline (transdermal) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Selegiline (transdermal) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Transdermal.

### Monitoring
- Monitor for worsening and emergence of suicidal thoughts and behaviors.
- Monitor blood pressure if selegiline is used with any of the following drugs: buspirone, amphetamines, or cold products or weight-reducing preparations that contain sympathomimetic amines (e.g., pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine).
- Monitor patients for the emergence of agitation, irritability and unusual changes in behavior.
- Patients should be monitored for the emergence of serotonin syndrome.

# IV Compatibility
There is limited information regarding the compatibility of Selegiline (transdermal) and IV administrations.

# Overdosage

## Signs and Symptoms
- Selegiline overdosage may resemble overdosage with other nonselective, oral MAOI antidepressants and present with any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, convulsions, coma, rapid and irregular pulse, hypertension, hypotension and vascular collapse, precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin.

## Management of Overdose
- There are no specific antidotes for selegiline.
- If symptoms of overdosage occur, immediately remove the selegiline system and institute appropriate supportive therapy. For contemporary information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222.
- Delays of up to 12 hours between ingestion of drug and the appearance of signs may occur, and peak effects may not be observed for 24 to 48 hours. Since death has been reported following overdosage with MAOI agents, hospitalization with close monitoring during this period is strongly recommended.
- In order to avoid the occurrence of hypertensive crisis (cheese reaction), dietary tyramine should be restricted for several weeks beyond recovery to permit regeneration of the peripheral MAO-A isoenzyme.

# Pharmacology

## Mechanism of Action
- The mechanism of action of selegiline as an antidepressant is not fully understood, but is presumed to be linked to potentiation of monoamine neurotransmitter activity in the central nervous system (CNS) resulting from its irreversible inhibition of the enzyme monoamine oxidase (MAO).

## Structure
- EMSAM is a transdermally administered MAOI antidepressant. When applied to intact skin, EMSAM is designed to continuously deliver selegiline over a 24-hour period.
- Selegiline base is a colorless to yellow liquid, chemically described as (-)-(N)-Methyl-N-prop-2-yn-1-amine. It has a molecular formula of C13H17N and a molecular weight of 187.30. The structural formula is:
- Selegiline transdermal systems are available in three strengths that deliver approximately 6 mg, 9 mg, or 12 mg of selegiline over 24 hours. Each corresponding system has an active surface area of 20 cm2, 30 cm2, or 40 cm2 containing 20, 30, or 40 mg of selegiline, respectively. The composition of the systems per unit area is identical.
- Selegiline is a matrix-type transdermal system composed of three layers as illustrated in Figure 1 below. Layer 1 is the Backing Film that provides occlusivity, physical integrity and protects the adhesive/drug layer. Layer 2 is the Adhesive/Drug Layer. Layer 3 consists of side-by-side release liners that are peeled off and discarded by the patient prior to applying Selegiline. The inactive ingredients are acrylic adhesive, ethylene vinyl acetate/polyethylene, polyester, polyurethane, and silicone coated polyester.

## Pharmacodynamics
- MAO exists as two isoenzymes, referred to as MAO-A and MAO-B. Selegiline has a greater affinity for MAO-B, compared to MAO-A. However, at antidepressant doses, selegiline inhibits both isoenzymes. In an in vivo animal model used to test for antidepressant activity (Forced Swim Test), selegiline administered by transdermal system exhibited antidepressant properties only at doses that inhibited both MAO-A and MAO-B activity in the brain. In the CNS, MAO-A and MAO-B play important roles in the catabolism of neurotransmitter amines such as norepinephrine, dopamine, and serotonin, as well as neuromodulators such as phenylethylamine.

### Receptor Binding
- In in vitro receptor binding assays, selegiline has demonstrated affinity for the human recombinant adrenergic 2B receptor (Ki = 0.3 mcM). No affinity  was noted at dopamine receptors, adrenergic 3, glutamate, muscarinic M1-M5, nicotinic, or rolipram receptor/sites.

### Interaction with Tyramine
- Selegiline is an irreversible inhibitor of monoamine oxidase (MAO), a ubiquitous intracellular enzyme. MAO exists as two isoenzymes, referred to as MAO-A and MAO-B. Selegiline shows greater affinity for MAO-B; however, as selegiline concentration increases, 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.
- MAO plays a vital physiological role in terminating the biological activity of both endogenous and exogenous amines. 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 (primarily type A) provides protection from exogenous amines with vasopressor actions, such as tyramine, which if absorbed intact can cause a hypertensive crisis, the so-called cheese reaction. If a large amount of tyramine is absorbed systemically, it is taken up by adrenergic neurons and causes norepinephrine release from neuronal storage sites with resultant elevation of blood pressure. While most foods contain negligible amounts or no tyramine, certain food products may contain large amounts of tyramine that represent a potential risk for hypertensive crisis.
- To define the risk of hypertensive crises with use of selegiline, several Phase I tyramine challenge studies were conducted both with and without food. Fourteen tyramine challenge studies including 214 healthy subjects (age range 18 to 65; 31 subjects greater than 50 years of age) were conducted to determine the pressor effects of oral tyramine with concurrent selegiline treatment (6 mg per 24 hours to 12 mg per 24 hours), measured as the dose of tyramine required to raise systolic blood pressure by 30 mmHg (TYR30). Studies were conducted with and without concomitant administration of food. Studies conducted with food are most relevant to clinical practice since tyramine typically will be consumed in food. A high-tyramine meal is considered to contain up to 40 mg of tyramine.
- One study using a crossover design in 13 subjects investigated tyramine pressor doses (TYR30) after administration of selegiline 6 mg per 24 hours and oral selegiline (5 mg twice daily) for 9 days. Mean pressor doses (TYR30) of tyramine capsules administered without food were 338 mg and 385 mg in subjects treated with selegiline and oral selegiline, respectively.
- Another study using a crossover design in 10 subjects investigated tyramine pressor doses after administration of selegiline 6 mg per 24 hours or tranylcypromine 30 mg per day for 10 days. Mean pressor doses (TYR30) of tyramine capsules administered without food were 270 mg in subjects treated with selegiline 6 mg per 24 hours and 10 mg in subjects treated with tranylcypromine.
- In a third crossover study, tyramine without food was administered to 12 subjects. The mean tyramine pressor doses (TYR30) after administration of selegiline 6 mg per 24 hours for 9 and 33 days were 292 mg and 204 mg, respectively. The lowest pressor dose was 50 mg in one subject in the 33-day group.
- Tyramine pressor doses were also studied in 11 subjects after extended treatment with selegiline 12 mg per 24 hours. At 30, 60, and 90 days, the mean pressor doses (TYR30) of tyramine administered without food were 95 mg, 72 mg, and 88 mg, respectively. The lowest pressor dose without food was 25 mg in three subjects at day 30 while on selegiline 12 mg per 24 hours. Eight subjects from this study, with a mean tyramine pressor dose of 64 mg at 90 days, were subsequently administered tyramine with food, resulting in a mean pressor dose of 172 mg (2.7 times the mean pressor dose observed without food, p less than 0.003).
- With the exception of one study (N = 153), the Phase III clinical development program was conducted without requiring a modified diet (N = 2,553, 1,606 at 6 mg per 24 hours, and 947 at 9 mg per 24 hours or 12 mg per 24 hours). No hypertensive crises were reported in any patient receiving selegiline.
- Overall, the data for selegiline 6 mg per 24 hours support a recommendation that a modified diet is not required at this dose. Due to the more limited data available for selegiline 9 mg per 24 hours and the results from the Phase I tyramine challenge study in fed volunteers administered selegiline 12 mg per 24 hours, patients receiving these doses should follow Dietary Modifications Required for Patients Taking selegiline 9 mg per 24 hours and 12 mg per 24 hours.

## Pharmacokinetics

### Absorption
- Following dermal application of selegiline to humans, 25% to 30% of the selegiline content on average is delivered systemically over 24 hours (range approximately 10% to 40%). Consequently, the degree of drug absorption may be 1/3 higher than the average amounts of 6 mg to 12 mg per 24 hours. Transdermal dosing results in significantly higher exposure to selegiline with significantly lower exposure for all metabolites when compared to oral dosing, due to extensive first-pass metabolism. In a 10-day study with daily administration of selegiline to healthy male and female volunteers, steady-state selegiline plasma concentrations indicated selegiline concentration-time profiles were comparable when selegiline is applied to the upper torso or upper thigh, and absorption from these two sites of administration was equivalent.

### Distribution
- Following dermal application of radiolabeled selegiline to laboratory animals, selegiline is rapidly distributed to all body tissues. Selegiline rapidly penetrates the blood-brain barrier.
- In humans, selegiline is approximately 90% bound to plasma protein over a 2 to 500 ng per mL concentration range. Selegiline does not accumulate in the skin.

### In vivo Metabolism
- Transdermally absorbed selegiline (via EMSAM) is not metabolized in human skin and does not undergo extensive first-pass metabolism. Selegiline is extensively metabolized by several CYP450-dependent enzyme systems (see In vitro Metabolism). Selegiline is metabolized initially via N-dealkylation or N-depropargylation to form N-desmethylselegiline or R(-)-methamphetamine, respectively. Both of these metabolites can be further metabolized to R(-)-amphetamine. These metabolites are all levorotatory (l-)enantiomers and no racemic biotransformation to the dextrorotatory form (i.e., S(+)-amphetamine or S(+)-methamphetamine) occurs. R(-)-methamphetamine and R(-)-amphetamine are mainly excreted unchanged in urine.

### In vitro Metabolism
- In vitro studies utilizing human liver microsomes demonstrated that several CYP450-dependent enzymes are involved in the metabolism of selegiline and its metabolites. CYP2B6, CYP2C9, CYP3A4 and CYP3A5 appeared to be the major contributing enzymes in the formation of R(-)-methamphetamine from selegiline, with CYP2A6 having a minor role. CYP2A6, CYP2B6, CYP3A4 and CYP3A5 appeared to contribute to the formation of R(-)-amphetamine from N-desmethylselegiline.
- The potential for selegiline or N-desmethylselegiline to inhibit individual CYP450-dependent enzyme pathways was also examined in vitro with human liver microsomes. Each substrate was examined over a concentration range of 2.5 to 250 mcM. Consistent with competitive inhibition, both selegiline and N-desmethylselegiline caused a concentration dependent inhibition of CYP2D6 at 10 to 250 mcM and CYP3A4 and CYP3A5 at 25 to 250 mcM. CYP2C19 and CYP2B6 were also inhibited at concentrations of 100 mcM or greater. All inhibitory effects of selegiline and N-desmethylselegiline occurred at concentrations that are several orders of magnitude higher than concentrations seen clinically (highest predose concentration observed at a dose of 12 mg per 24 hours at steady-state was 0.046 mcM).

### Excretion
- Approximately 10% and 2% of a radiolabeled dose applied dermally, as a DMSO solution, was recovered in urine and feces respectively, with at least 63% of the dose remaining unabsorbed. The remaining 25% of the dose was unaccounted for. Urinary excretion of unchanged selegiline accounted for 0.1% of the applied dose with the remainder of the dose recovered in urine being metabolites.
- The systemic clearance of selegiline after intravenous administration was 1.4 L per min, and the mean half-lives of selegiline and its three metabolites, R(-)-N-desmethylselegiline, R(-)-amphetamine, and R(-)-methamphetamine, ranged from 18 to 25 hours.

### Population Subgroups
- Age
- Selegiline should not be used in patients less than 18 years of age.
- Stratification of exposure data following treatment with selegiline indicated that pre-dose (trough) selegiline plasma concentrations at steady state appeared higher (p = 0.12) in children aged < 12 years old, compared to adolescents aged  12 years as shown in Table 6.

### Drug-Drug Interactions
- Alcohol
- The pharmacokinetics and pharmacodynamics of alcohol (0.75 mg per kg) alone or in combination with selegiline 6 mg per 24 hours for 7 days of treatment was examined in 16 healthy volunteers. No clinically significant differences were observed in the pharmacokinetics or pharmacodynamics of alcohol or the pharmacokinetics of selegiline during co-administration. Although selegiline has not been shown to increase the impairment of mental and motor skills caused by alcohol (0.75 mg per kg) and failed to alter the pharmacokinetic properties of alcohol, patients should be advised that the use of alcohol is not recommended while taking selegiline.
- Alprazolam
- In subjects who had received selegiline 6 mg per 24 hours for 7 days, co-administration with alprazolam (15 mg per day), a CYP3A4 and CYP3A5 substrate, did not affect the pharmacokinetics of alprazolam or selegiline.
- Carbamazepine
- Carbamazepine is an enzyme inducer and typically causes decreases in drug exposure; however, approximately 2-fold increased systemic exposure of selegiline and its metabolites, L-amphetamine and L-methamphetamine were seen after single application of selegiline 6 mg per 24 hours in subjects who had received carbamazepine (400 mg per day) for 14 days. Changes in plasma selegiline concentrations were nearly 2-fold and variable across the subject population. Such increases may increase the risk of a hypertensive crisis when carbamazepine is used with selegiline at any dose.
- Ibuprofen
- In subjects who had received selegiline 6 mg per 24 hours for 11 days, combined administration with the CYP2C9 substrate ibuprofen (800 mg single dose) did not affect the pharmacokinetics of either selegiline or ibuprofen.
- Ketoconazole
- Seven-day treatment with ketoconazole (200 mg per day), a potent inhibitor of CYP3A4, did not affect the steady-state pharmacokinetics of selegiline in subjects who received selegiline 6 mg per 24 hours for 7 days and no differences in the pharmacokinetics of ketoconazole were observed.
- Levothyroxine
- In healthy subjects who had received selegiline 6 mg per 24 hours for 10 days, single dose administration with levothyroxine (150 mcg) did not alter the pharmacokinetics of either selegiline or levothyroxine.
- Olanzapine
- In subjects who had received selegiline 6 mg per 24 hours for 10 days, co-administration with olanzapine, a substrate for CYP1A2, CYP2D6, and possibly CYP2A6, did not affect the pharmacokinetics of selegiline or olanzapine.
- Phenylpropanolamine (PPA)
- In subjects who had received selegiline 6 mg per 24 hours for 9 days, co-administration with PPA (25 mg every 4 hours for 24 hours) did not affect the pharmacokinetics of PPA. There was a higher incidence of significant blood pressure elevations with the co-administration of selegiline and PPA than with PPA alone, suggesting a possible pharmacodynamic interaction.
- Pseudoephedrine
- Selegiline 6 mg per 24 hours for 10 days, co-administered with pseudoephedrine (60 mg, 3 times a day) did not affect the pharmacokinetics of pseudoephedrine. There were no clinically significant changes in blood pressure during pseudoephedrine administration alone, or in combination with selegiline.
- Risperidone
- In subjects who had received selegiline 6 mg per 24 hours for 10 days, co-administration with risperidone (2 mg per day for 7 days), a substrate for CYP2D6, did not affect the pharmacokinetics of selegiline or risperidone.
- Warfarin
- Warfarin is a substrate for CYP2C9 and CYP3A4 metabolism pathways. In healthy volunteers titrated with Coumadin# (warfarin sodium) to clinical levels of anticoagulation (INR of 1.5 to 2), co-administration with selegiline 6 mg per 24 hours for 7 days did not affect the pharmacokinetics of the individual warfarin enantiomers. Selegiline did not alter the clinical pharmacodynamic effects of warfarin as measured by INR, Factor VII or Factor X levels.

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenesis
- In a dermal carcinogenicity study in CD-1 mice, selegiline was administered daily for 2 years at the same skin site at dose levels of 20, 70, and 200 mg per kg per day (dissolved in acetone). The incidence of systemic tumors was not increased and the high dose provided systemic exposures to selegiline and its three metabolites in mice that were greater than 40 times the exposures in humans at the maximum recommended human dose (MRHD). The incidence of squamous cell carcinoma was slightly increased on treated skin of mice administered the high dose. This finding was associated with an increased incidence of epithelial hyperplasia, dyskeratosis/hyperkeratosis and inflammation.
- In an oral carcinogenicity study in rats, selegiline given in the diet for 104 weeks was not carcinogenic up to the highest evaluable dose tested (3.5 mg per kg per day), which exposed rats to systemic levels of selegiline and its three metabolites that were comparable to those in humans at the MRHD.
- Mutagenesis
- Selegiline induced mutations and chromosomal damage when tested in the in vitro mouse lymphoma assay with and without metabolic activation. Selegiline was negative in the Ames assay, the in vitro mammalian chromosome aberration assay in human lymphocytes, and the in vivo oral mouse micronucleus assay.
- Impairment of Fertility
- A mating and fertility study was conducted in male and female rats at transdermal doses of 10, 30, and 75 mg per kg per day of selegiline (8, 24, and 60 times the maximum recommended human dose of selegiline  on a mg per m2 basis). Slight decreases in sperm concentration and total sperm count were observed at the high dose; however, no significant adverse effects on fertility or reproductive performance were observed.

# Clinical Studies

## Major Depressive Disorder
- The efficacy of selegiline as a treatment for major depressive disorder was established in two placebo-controlled studies of 6 and 8 weeks duration in adult outpatients (ages 18 to 70 years) meeting DSM-IV criteria for major depressive disorder. In both studies, patients were randomized to double-blind treatment with selegiline or placebo. The 6-week trial (N = 176) showed that selegiline 6 mg per 24 hours was statistically significantly more effective than placebo on the 17-item Hamilton Depression Rating Scale (HAM-D) total score (Study 1 in Table 7). In an 8-week dose titration trial, depressed patients (N = 265), who received selegiline or placebo at a starting dose of 6 mg per 24 hours, with possible increases to 9 mg per 24 hours or 12 mg per 24 hours based on clinical response, showed significant improvement compared with placebo on the primary outcome measure, the 28-item HAM-D total score (Study 2 in Table 7).
- In another trial (Study 3), 322 patients meeting DSM-IV criteria for major depressive disorder who had responded during an initial 10-week open-label treatment phase for about 25 days, on average, to selegiline 6 mg per 24 hours were randomized either to continuation of selegiline at the same dose (N = 159) or to placebo (N = 163) under double-blind conditions for observation of relapse. About 52% of the selegiline-treated patients, as well as about 52% of the placebo-treated patients, had discontinued treatment by week 12 of the double-blind phase. Response during the open-label phase was defined as 17-item HAM-D total score less than 10 at either week 8 or 9 and at week 10 of the open-label phase. Relapse during the double-blind phase was defined as follows: (1) a 17-item HAM-D score of 14 or greater, (2) a CGI-S score of 3 or greater (with at least a 2-point increase from double-blind baseline), and (3) meeting DSM-IV criteria for major depressive disorder on two consecutive visits at least 11 days apart. In the double-blind phase, patients receiving continued selegiline experienced a significantly longer time to relapse (Figure 2).
Figure 2. Kaplan-Meier Estimates of Cumulative Percent of Patients with Relapse (Study 3).
- An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender, or race.

# How Supplied
- Selegiline transdermal system is a transdermal system with the following strengths, sizes, color, backing film printing and presentation:

## Storage
- Store at 20 to 25 C (68 to 77 F).  Do not store outside of the sealed pouch.
- Apply immediately upon removal from the protective pouch. Discard used selegiline in household trash in a manner that prevents accidental application or ingestion by children, pets or others.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- See FDA-approved patient labeling (MEDICATION GUIDE and INSTRUCTIONS FOR USE).
- Advise patients and their caregivers about the benefits and risks associated with treatment with EMSAM and counsel them in its appropriate use. Advise patients and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of this document.
- Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking EMSAM.
- Suicide Risk: Advise patients and caregivers to look for the emergence of suicidal ideation and behavior, especially early during treatment and when the dose is adjusted up or down.
- Tyramine Reactions: Patients should be advised that tyramine-rich foods and beverages should be avoided while on EMSAM 9 mg per 24 hours or EMSAM 12 mg per 24 hours, and for 2 weeks following discontinuation of EMSAM at these doses because of the risk of a tyramine reaction. Patients should also be advised to avoid tyramine-containing nutritional supplements. Patients should be instructed to immediately report the occurrence of the following acute symptoms: severe headache, neck stiffness, heart racing or palpitations, or other sudden or unusual symptoms.
- Concomitant Medication: Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications, including herbals, because of a potential for dangerous interactions. Instruct patients not to take EMSAM with medication that is contraindicated or within two weeks of stopping such medication (5 weeks for fluoxetine). Contraindicated medication should not be started within two weeks of stopping EMSAM.
- Psychomotor Performance: EMSAM 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 EMSAM therapy does not impair their ability to engage in such activities.
- Alcohol: Patients should be told that, although EMSAM has not been shown to increase the impairment of mental and motor skills caused by alcohol, the concomitant use of EMSAM and alcohol in depressed patients is not recommended.
- Pediatrics: Advise patients that EMSAM must not be used in children less than 12 years of age because of an increased risk of severe increases in blood pressure. Also, patients should be advised that EMSAM is not recommended for use in pediatric patients ages 12 to 17 years.
- Breastfeeding: Advise nursing mothers to discontinue the use of EMSAM or discontinue nursing.

## How to Use Emsam

## Medication Guide

## Instructions For Use

# Precautions with Alcohol
- Alcohol-Selegiline (transdermal) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- EMSAM

# Look-Alike Drug Names
selegiline - Salagen.

# Drug Shortage Status

# Price