SELEGILINE: 932 Adverse Event Reports & Safety Profile

EMSAM ® contains selegiline, a MAOI antidepressant. When applied to intact skin, EMSAM is designed to transdermally deliver selegiline over a 24-hour period. Selegiline base is a colorless to yellow liquid, chemically described as (-)-( N )-Methyl- N -[(1 R )-1-methyl-2-phenylethyl]prop-2-yn-1-amine. It has a molecular formula of C 13 H 17 N and a molecular weight of 187.30. The structural formula is: EMSAM 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 cm 2 , 30 cm 2 , or 40 cm 2 containing 20, 30, or 40 mg of selegiline, respectively. The composition of the systems per unit area is identical. EMSAM 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 EMSAM. The inactive ingredients are acrylic adhesive, ethylene vinyl acetate/polyethylene, polyester, polyurethane, and silicone coated polyester.

Figure

1: Side view of EMSAM system. (Not to scale.)

Selegiline Structural Formula Figure

1: Side view of EMSAM

INDICATIONS & USAGE Selegiline hydrochloride capsules, USP are indicated as an adjunct in the management of Parkinsonian patients being treated with levodopa/carbidopa who exhibit deterioration in the quality of their response to this therapy. There is no evidence from controlled studies that selegiline has any beneficial effect in the absence of concurrent levodopa therapy. Evidence supporting this claim was obtained in randomized controlled clinical investigations that compared the effects of added selegiline or placebo in patients receiving levodopa/carbidopa. Selegiline was significantly superior to placebo on all three principal outcome measures employed: change from baseline in daily levodopa/carbidopa dose, the amount of 'off' time, and patient self-rating of treatment success. Beneficial effects were also observed on other measures of treatment success (e.g., measures of reduced end of dose akinesia, decreased tremor and sialorrhea, improved speech and dressing ability and improved overall disability as assessed by walking and comparison to previous state).

AND ADMINISTRATION EMSAM 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 ( 2.1 ).

• Initial Treatment: The recommended starting dose and target dose for EMSAM is 6 mg per 24 hours ( 2.1 ). Based on clinical judgment, dose increases should occur in 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 ( 2.1 ).
• Geriatric Use: The recommended dose for elderly patients (65 years and older) is EMSAM 6 mg per 24 hours daily ( 8.5 ).
• Dietary Modifications with EMSAM 9 mg per 24 hours and 12 mg per 24 hours: Tyramine-rich foods and beverages should be avoided beginning on the first day of EMSAM 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 EMSAM 6 mg per 24 hours or following the discontinuation of EMSAM 9 mg per 24 hours or 12 mg per 24 hours ( 2.3 ).

2.1 Initial Treatment EMSAM 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 EMSAM is 6 mg per 24 hours. EMSAM 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 EMSAM 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 EMSAM 6 mg per 24 hours or following the discontinuation of EMSAM 9 mg per 24 hours or 12 mg per 24 hours <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> .

2.2 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 EMSAM 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 <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> . The physician who elects to use EMSAM for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

2.3 Dietary Modifications Required for Patients Taking EMSAM 9 mg per 24 hours and 12 mg per 24 hours EMSAM (selegiline transdermal system) contains a monoamine oxidase inhibitor (MAOI). MAOIs including EMSAM combined with a high tyramine diet may cause a hypertensive crisis. A hypertensive crisis can be a life-threatening condition <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> . The foods and beverages listed in Table 5 should be avoided beginning on the first day of EMSAM 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 EMSAM 6 mg per 24 hours or following the discontinuation of EMSAM 9 mg per 24 hours or 12 mg per 24 hours <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span> .

2.4 Screen for Bipolar Disorder Prior to Starting EMSAM Prior to initiating treatment with EMSAM or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> .

4 CONTRAINDICATIONS

• EMSAM (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 EMSAM is used with these agents [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] .
• Carbamazepine is contraindicated with EMSAM because of a possible increased risk of hypertensive crisis [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ] .
• After stopping treatment with drugs contraindicated with EMSAM, 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 EMSAM. 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 EMSAM.
• At least 2 weeks should elapse after stopping EMSAM before starting therapy with any drug that is contraindicated with EMSAM.
• EMSAM is contraindicated in patients less than 12 years of age because of the potential for a hypertensive crisis [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3) ] .
• EMSAM is contraindicated in patients with pheochromocytoma because MAOIs may precipitate a hypertensive crisis in such patients.
• Serotonergic drugs: selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), clomipramine and imipramine, meperidine, tramadol, methadone, pentazocine, and propoxyphene; and the antitussive agent dextromethorphan should not be used with EMSAM because of a risk of serotonin syndrome ( 4 , 5.2 ).
• Carbamazepine should not be used with EMSAM ( 4 , 5.3 ).
• After stopping treatment with contraindicated medication, 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 EMSAM. 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 EMSAM ( 4 ).
• At least 2 weeks should elapse after stopping EMSAM before starting therapy with a drug that is contraindicated with EMSAM ( 4 ).
• EMSAM is contraindicated in patients less than 12 years of age ( 4 , 8.4 ).
• Pheochromocytoma ( 4 ).

REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label.

• Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.1) ] .
• Serotonin Syndrome [see Contraindications (4) and Warnings and Precautions (5.2) ] .
• Blood Pressure Elevation [see Warnings and Precautions (5.3) ] .
• Activation of Mania/Hypomania [see Warnings and Precautions (5.4) ] .
• External Heat [see Warnings and Precautions (5.5) ] .
• Adverse Reactions occurring at an incidence of 2% or More Among EMSAM-Treated Patients and greater than placebo: Application site reaction, headache, insomnia, diarrhea, dry mouth, dyspepsia, rash, pharyngitis, sinusitis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-4-INFO-RX (1-877-446-3679) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial 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 EMSAM 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 EMSAM 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 EMSAM 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 EMSAM-treated patients at a rate at least twice that of placebo, was application site reaction (2% EMSAM vs. 0% placebo).

Adverse Reactions

Occurring at an Incidence of 2% or More Among EMSAM-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 EMSAM 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 EMSAM and for which the incidence in patients treated with EMSAM was greater than the incidence in placebo-treated patients. One adverse reaction was associated with a reporting of at least 5% in the EMSAM group, and a rate at least twice that in the placebo group, in the pool of short-term, placebo-controlled studies: application site reactions ( see Application Site Reactions , below ). In one such study which utilized higher mean doses of EMSAM than that in the entire study pool, the following reactions met these criteria: application site reactions, insomnia, diarrhea, and pharyngitis.

Table

2. Treatment-Emergent Adverse Reactions: Incidence in Placebo-Controlled Clinical Trials for Major Depressive Disorder with EMSAM Reactions reported by at least 2% of patients treated with EMSAM are included, except the following reactions, which had an incidence on placebo treatment greater than or equal to EMSAM: infection, nausea, dizziness, pain, abdominal pain, nervousness, back pain, asthenia, anxiety, flu syndrome, accidental injury, somnolence, rhinitis, and palpitations.

Body System/Preferred

Term EMSAM (N = 817) Placebo (N = 668) (% of Patients Reporting Reaction) Body as a Whole Headache 18 17 Digestive Diarrhea 9 7 Dyspepsia 4 3 Nervous Insomnia 12 7 Dry Mouth 8 6 Respiratory Pharyngitis 3 2 Sinusitis 3 1 Skin Application Site Reaction 24 12 Rash 4 2 Application Site Reactions In the pool of short-term, placebo-controlled major depressive disorder studies, application site reactions (ASRs) were reported in 24% of EMSAM-treated patients and 12% of placebo-treated patients. Most ASRs were mild or moderate in severity. ASRs led to dropout in 2% of EMSAM-treated patients and no placebo-treated patients. In one such study which utilized higher mean doses of EMSAM, ASRs were reported in 40% of EMSAM-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.

Table

3. Incidence of Sexual Side Effects in Placebo-Controlled Clinical Trials with EMSAM Adverse Reaction EMSAM Placebo IN MALES ONLY (N = 304) (N = 256)

Abnormal Ejaculation

1.0% 0.0% Decreased Libido 0.7% 0.0% Impotence 0.7% 0.4% Anorgasmia 0.2% 0.0% IN FEMALES ONLY (N = 513) (N = 412)

Decreased Libido

0.0% 0.2% There are no adequately designed studies examining sexual dysfunction with EMSAM treatment.

Vital Sign

Changes EMSAM 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 EMSAM-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 EMSAM, 6.2% of EMSAM-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 EMSAM-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.

Table

4. Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials with EMSAM Weight Change EMSAM Placebo (N = 757) (N = 614) Gained at least 5% 2.1% 2.4% Lost at least 5% 5.0% 2.8% In these trials, the mean change in body weight among EMSAM-treated patients was a 1.2 lbs loss compared to 0.3 lbs gain in placebo-treated patients.

Laboratory

Changes EMSAM 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 EMSAM.

Electrocardiogram Changes

Electrocardiograms (ECGs) from EMSAM (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 EMSAM 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.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of EMSAM. 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.

AND PRECAUTIONS

• May cause hypertension above 2.5 mg/day (5.1)
• May cause serotonin syndrome when used with antidepressants (5.2)
• May cause falling asleep during activities of daily living (5.3)
• May cause hypotension/orthostatic hypotension (5.4)
• May cause or exacerbate dyskinesia (5.5)
• May cause hallucinations and psychotic-like behavior (5.6)
• May cause problems with impulse control and compulsive behaviors (5.7)
• Abrupt discontinuation may cause hyperpyrexia and confusion (5.8)
• May cause irritation of the buccal mucosa ( 5.9 )
• Increased risk for patients with phenylketonuria ( 5.10 )

5.1 Hypertension ZELAPAR should not be used at daily doses exceeding those recommended (2.5 mg/day) because of the risks associated with non-selective inhibition of MAO <span class="opacity-50 text-xs">[see Drug Interactions (7.3) and Clinical Pharmacology (12.2) ]</span>. The selectivity of ZELAPAR for MAO-B may not be absolute even at the recommended daily dose of 2.5 mg daily. The selectivity of MAO-B inhibitors typically decreases, and it is ultimately lost as the dose is increased beyond recommended doses. Hypertensive reactions associated with ingestion of tyramine-containing foods have been reported even in patients taking the recommended daily dose of swallowed selegiline, a dose which is generally believed to be selective for MAO-B. Selectivity for MAO-B inhibition is gradually lost with increasing daily doses. An increase in tyramine sensitivity for blood pressure responses appears to begin at a dose of 5 mg ZELAPAR daily <span class="opacity-50 text-xs">[see Drug Interactions (7.5) ]</span> . However, the precise dose at which ZELAPAR becomes a non-selective inhibitor of all MAO enzymes in individual patients is unknown. Reports of hypertensive reactions have occurred in patients who ingested tyramine-containing consumables (i.e., food or drink) while receiving swallowed selegiline at the recommended dose (a dose believed to be relatively selective for MAO-B). The safe use of ZELAPAR at doses above 2.5 mg daily without dietary tyramine restrictions has not been established. A pharmacodynamic study showed increased tyramine sensitivity for increasing blood pressure and decreased selectivity for MAO-B with dosing above the recommended level (2.5 mg daily) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span>. Uncontrolled hypertension has been reported when taking the recommended dose of swallowed selegiline and a sympathomimetic medication (ephedrine). After starting ZELAPAR, monitor patients for new onset hypertension or exacerbation of hypertension that is not adequately controlled.

5.2 Serotonin Syndrome Serotonin syndrome and hyperpyrexia have been reported with the combined treatment of an antidepressant (e.g., selective serotonin reuptake inhibitors-SSRIs, serotonin-norepinephrine reuptake inhibitors-SNRIs, tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants) and a non-selective MAOI (e.g., phenelzine, tranylcypromine) or selective MAO-B inhibitors, such as selegiline (ELDEPRYL), rasagiline (AZILECT), and olanzapine (Zydis) selegiline (ZELAPAR). Serotonin syndrome is a potentially serious condition, which can result in death. Typical clinical signs and symptoms include behavioral and cognitive/mental status changes (e.g., confusion, hypomania, hallucinations, agitation, delirium, headache, and coma), autonomic effects (e.g., syncope, shivering, sweating, high fever/hyperthermia, hypertension, hypotension, tachycardia, nausea, diarrhea), and somatic effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifested by clonus, and tremor). In the post-marketing period, fatal and non-fatal cases of serotonin syndrome have been reported in patients treated with antidepressants concomitantly with ZELAPAR <span class="opacity-50 text-xs">[see Contraindications (4) and Drug Interactions ( 7.1 , 7.2 , 7.3 ) ]</span>. Clinical studies of ZELAPAR did not allow concomitant use of any selective serotonin re-uptake inhibitor (e.g., fluoxetine-Prozac, fluvoxamine-Luvox, paroxetine-Paxil, sertraline, venlafaxine-Effexor, or nefazodone-Serzone) or any non-selective serotonin reuptake inhibiting antidepressant drug (except when taken at a low dose and only at night for the purpose of effective sleep) with ZELAPAR. Because the mechanisms responsible for these reactions are not fully understood, avoid the combination of ZELAPAR with any antidepressant. At least 14 days should elapse between discontinuation of ZELAPAR and initiation of treatment with a SSRI, SNRI, tricyclic, tetracyclic, or triazolopyridine antidepressant. In patients taking antidepressants with a long half-life (e.g., fluoxetine and its active metabolite), allow at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) to elapse between discontinuation of fluoxetine and initiation of ZELAPAR <span class="opacity-50 text-xs">[see Drug Interactions (7.6) ]</span>.

5.3 Falling Asleep During Activities of Daily Living and Somnolence Patients with Parkinson’s disease treated with ZELAPAR or other drugs increasing dopaminergic tone have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence, some did not perceive warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported as late as one year after initiation of treatment. It has been reported that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Somnolence may occur in patients receiving ZELAPAR. There was an increased risk for somnolence in geriatric patients (≥65 years) vs. non-geriatric patients treated with ZELAPAR. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients should be advised to exercise caution while driving, operating machines, or working at heights during treatment with ZELAPAR. Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities during treatment with ZELAPAR. Before initiating treatment with ZELAPAR, advise patients about the potential to develop drowsiness and specifically ask about factors that may increase this risk, such as concomitant sedating medications and the presence of sleep disorders. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), ZELAPAR should ordinarily be discontinued. If a decision is made to continue ZELAPAR, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

5.4 Hypotension/Orthostatic Hypotension Assessments of orthostatic (supine and standing) blood pressures at different times throughout the 12 week study period in two controlled trials showed that the frequency of orthostatic hypotension (&gt;20 mm Hg decrease in systolic blood pressure and/or &gt;10 mm Hg decrease in diastolic blood pressure) was greater with ZELAPAR treatment than with placebo treatment. Patients taking ZELAPAR were most likely to experience a decline in systolic and diastolic blood pressure at 8 weeks (2 weeks after initiating 2.5 mg ZELAPAR). At that time, the incidence of systolic orthostatic hypotension was about 21% in ZELAPAR-treated patients and 9% in placebo-treated patients. The incidence of diastolic orthostatic hypotension was about 12% in ZELAPAR-treated patients and about 4% in placebo-treated patients. Thus, it appears that there may be an increased risk for orthostatic hypotension in the period after increasing the daily dose of ZELAPAR from 1.25 to 2.5 mg. The incidence of orthostatic hypotension was higher in geriatric patients (≥65 years) than in non-geriatric patients. In the geriatric patients, orthostatic hypotension occurred in about 3% of ZELAPAR-treated patients compared to 0% of placebo-treated patients.

5.5 Dyskinesia ZELAPAR may potentiate dopaminergic side effects of levodopa and may cause dyskinesia or exacerbate preexisting dyskinesia. In controlled trials, the incidence of dyskinesia was 6% in ZELAPAR-treated patients and 3% in placebo-treated patients. Decreasing the dose of levodopa may lessen dyskinesia. The incidence of dyskinesia causing study discontinuation was greater on ZELAPAR than on placebo.

5.6 Hallucinations/Psychotic-Like Behavior In controlled trials, hallucination was reported by 4% of ZELAPAR-treated patients and 2% in placebo-treated patients. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in about 1% of ZELAPAR-treated patients, compared to no patient on placebo. Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during ZELAPAR treatment or after starting or increasing the dose of ZELAPAR. 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 one 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 should ordinarily not be treated with ZELAPAR because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson&apos;s disease and may decrease the effectiveness of ZELAPAR <span class="opacity-50 text-xs">[see Drug Interactions (7.8) ]</span>.

5.7 Impulse Control/Compulsive Behaviors Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including ZELAPAR, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge eating, or other urges while being treated with ZELAPAR. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ZELAPAR.

5.8 Withdrawal Emergent Hyperpyrexia and Confusion Although not reported with ZELAPAR in the clinical development program, 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.

5.9 Irritation of the Buccal Mucosa In the controlled clinical trials, periodic examinations of the tongue and oral mucosa were performed. At the end of the study, the frequency of mild oropharyngeal abnormality (e.g., swallowing pain, mouth pain, discrete areas of focal reddening, multiple foci of reddening, edema, and/or ulceration) in patients without similar abnormality at baseline was 10% in ZELAPAR-treated patients compared to 3% in placebo-treated patients.

5.10 Risk for Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU). ZELAPAR contains phenylalanine, a component of aspartame. Each ZELAPAR 1.25 mg tablet contains 1.25 mg phenylalanine. Patients taking the 2.5 mg dose of ZELAPAR will receive 2.5 mg phenylalanine. Before prescribing ZELAPAR to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including ZELAPAR .

PRECAUTIONS GENERAL PRECAUTIONS Some patients given selegiline may experience an exacerbation of levodopa associated side effects, presumably due to the increased amounts of dopamine reaction with super sensitive, post-synaptic receptors. These effects may often be mitigated by reducing the dose of levodopa/carbidopa by approximately 10 to 30%. The decision to prescribe selegiline should take into consideration that the MAO system of enzymes is complex and incompletely understood and there is only a limited amount of carefully documented clinical experience with selegiline. Consequently, the full spectrum of possible responses to selegiline may not have been observed in pre-marketing evaluation of the drug. It is advisable, therefore, to observe patients closely for atypical responses.

Melanoma

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2-to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using selegiline for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Information For Patients

Patients should be advised of the possible need to reduce levodopa dosage after the initiation of selegiline therapy. Patients (or their families if the patient is incompetent) should be advised not to exceed the daily recommended dose of 10 mg. The risk of using higher daily doses of selegiline should be explained, and a brief description of the `cheese reaction' provided. Rare hypertensive reactions with selegiline at recommended doses associated with dietary influences have been reported. Consequently, it may be useful to inform patients (or their families) about the signs and symptoms associated with MAOI induced hypertensive reactions. In particular, patients should be urged to report, immediately, any severe headache or other atypical or unusual symptoms not previously experienced. There have been reports of patients experiencing intense urges to gamble, increased sexual urges, other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson’s disease, including selegiline hydrochloride capsules. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with selegiline hydrochloride capsules. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking selegiline hydrochloride capsules. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking selegiline hydrochloride capsules.

Laboratory Tests

No specific laboratory tests are deemed essential for the management of patients on selegiline hydrochloride capsules. Periodic routine evaluation of all patients, however, is appropriate.

Drug Interactions

The occurrence of stupor, muscular rigidity, severe agitation, and elevated temperature has been reported in some patients receiving the combination of selegiline and meperidine. Symptoms usually resolve over days when the combination is discontinued. This is typical of the interaction of meperidine and MAOIs. Other serious reactions (including severe agitation, hallucinations, and death) have been reported in patients receiving this combination (see CONTRAINDICATIONS ). Severe toxicity has also been reported in patients receiving the combination of tricyclic antidepressants and selegiline hydrochloride capsules and selective serotonin reuptake inhibitors and selegiline hydrochloride capsules. (see WARNINGS for details.) One case of hypertensive crisis has been reported in a patient taking the recommended doses of selegiline and a sympathomimetic medication (ephedrine). CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY Assessment of the carcinogenic potential of selegiline in mice and rats is ongoing. Selegiline did not induce mutations or chromosomal damage when tested in the bacterial mutation assay in Salmonella typhimurium and in an in vivo chromosomal aberration assay. While these studies provide some reassurance that selegiline is not mutagenic or clastogenic, they are not definitive because of methodological limitations. No definitive in vitro chromosomal aberration or in vitro mammalian gene mutation assays have been performed. The effect of selegiline on fertility has not been adequately assessed. PREGNANCY T eratogenic Effects Pregnancy Category C No teratogenic effects were observed in a study of embryo-fetal development in Sprague-Dawley rats at oral doses of 4, 12, and 36 mg/kg or 4, 12 and 35 times the human therapeutic dose on a mg/m 2 basis. No teratogenic effects were observed in a study of embryo-fetal development in New Zealand White rabbits at oral doses of 5, 25, and 50 mg/kg or 10, 48, and 95 times the human therapeutic dose on a mg/m2 basis; however, in this study, the number of litters produced at the two higher doses was less than recommended for assessing teratogenic potential. In the rat study, there was a decrease in fetal body weight at the highest dose tested. In the rabbit study, increases in total resorptions and % post- implantation loss, and a decrease in the number of live fetuses per dam occurred at the highest dose tested. In a peri- and postnatal development study in Sprague-Dawley rats (oral doses of 4, 16, and 64 mg/kg or 4, 15, and 62 times the human therapeutic dose on a mg/m2 basis), an increase in the number of stillbirths and decreases in the number of pups per dam, pup survival, and pup body weight (at birth and throughout the lactation period) were observed at the two highest doses. At the highest dose tested, no pups born alive survived to Day 4 postpartum. Postnatal development at the highest dose tested in dams could not be evaluated because of the lack of surviving pups. The reproductive performance of the untreated offspring was not assessed. There are no adequate and well-controlled studies in pregnant women. Selegiline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether selegiline hydrochloride is excreted in human milk. Because many drugs are excreted in human milk, consideration should be given to discontinuing the use of all but absolutely essential drug treatments in nursing women.

Pediatric Use

The effects of selegiline hydrochloride in children have not been evaluated.

INTERACTIONS

7.1 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 EMSAM with these drugs is contraindicated <span class="opacity-50 text-xs">[see Contraindications (4) and Warnings and Precautions (5.2) ]</span> .

7.2 Tyramine EMSAM 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) and Clinical Pharmacology (12.2) ]</span> . A diet low in tyramine content may be necessary to avoid this interaction. Studies to evaluate the potential for EMSAM to inhibit tyramine metabolism have been conducted and, overall, the data for EMSAM 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 EMSAM 9 mg per 24 hours and the results from the Phase I tyramine challenge study in fed volunteers administered EMSAM 12 mg per 24 hours, patients receiving these doses should follow Dietary Modifications Required for Patients Taking EMSAM 9 mg per 24 hours and 12 mg per 24 hours below <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> .

Dietary Modifications

Required for Patients Taking EMSAM 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 EMSAM 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 EMSAM 6 mg per 24 hours or following the discontinuation of EMSAM 9 mg per 24 hours or 12 mg per 24 hours.

Table

5. Food and Beverages to Avoid and Those which are Acceptable [see References (15) ] Class of Food and Beverage Tyramine-Rich Foods and Beverages to Avoid Acceptable Foods and Drinks, Containing No or Little Tyramine Meat, Poultry, and Fish Air dried, aged and fermented meats, sausages and salamis (including cacciatore, hard salami and mortadella); pickled herring; and any spoiled or improperly stored meat, poultry, and fish (e.g., foods that have undergone changes in coloration, odor, or become moldy); spoiled or improperly stored animal livers Fresh meat, poultry, and fish, including fresh processed meats (e.g., lunch meats, hot dogs, breakfast sausage, and cooked sliced ham)

Vegetables

Broad bean pods (fava bean pods) All other vegetables Dairy Aged cheeses Processed cheeses, mozzarella, ricotta cheese, cottage cheese, and yogurt Beverages All varieties of tap beer and beers that have not been pasteurized so as to allow for ongoing fermentation Concomitant use of alcohol with EMSAM is not recommended. (Bottled and canned beers and wines contain little or no tyramine.)

Miscellaneous

Concentrated yeast extract (e.g., Marmite), sauerkraut, most soybean products (including soy sauce and tofu), OTC supplements containing tyramine Brewer’s yeast, baker’s yeast, soy milk, commercial chain restaurant pizzas prepared with cheeses low in tyramine

7.3 Sympathomimetic Amines and Buspirone The use of EMSAM with sympathomimetic amines or buspirone may produce substantial elevations in blood pressure. Therefore, monitor blood pressure if EMSAM 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).

7.4 Effect of Other Drugs on EMSAM Carbamazepine is contraindicated with MAOIs, including selegiline <span class="opacity-50 text-xs">[see Contraindications (4) , Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ]</span> . No dose adjustment for EMSAM is needed when EMSAM 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 EMSAM was co-administered with alcohol, alprazolam, ibuprofen, olanzapine, risperidone, levothyroxine, and ketoconazole <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.5 Effect of EMSAM on Other Drugs Use of alcohol while taking EMSAM is not recommended, even though EMSAM has not been shown to increase the impairment of mental and motor skills caused by alcohol (0.75 mg per kg) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Monitor blood pressure if sympathomimetic agents (e.g., phenylpropanolamine (PPA) or pseudoephedrine) are used with EMSAM, even though selegiline does not appear to affect the pharmacokinetics of PPA or pseudoephedrine <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . No dose adjustment of alprazolam, ibuprofen, levothyroxine, olanzapine, risperidone, warfarin, or strong CYP3A4 inhibitors (e.g., ketoconazole) is necessary when these drugs are used in combination with EMSAM. EMSAM had no clinically relevant effect on pharmacokinetics of these drugs.