Selegiline Hydrochloride

WARNINGS Selegiline should not be used at daily doses exceeding those recommended (10 mg/day) because of the risks associated with non-selective inhibition of MAO. (See CLINICAL PHARMACOLOGY .) The selectivity of selegiline for MAO-B may not be absolute even at the recommended daily dose of 10 mg a day. Rare cases of hypertensive reactions associated with ingestion of tyramine-containing foods have been reported in patients taking the recommended daily dose of selegiline. The selectivity is further diminished with increasing daily doses. The precise dose at which selegiline becomes a non- selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg a day. Severe CNS toxicity associated with hyperpyrexia and death have been reported with the combination of tricyclic antidepressants and non-selective MAOIs (Phenelzine, Tranylcypromine). A similar reaction has been reported for a patient on amitriptyline and selegiline. Another patient receiving protriptyline and selegiline developed tremors, agitation, and restlessness followed by unresponsiveness and death two weeks after selegiline was added. Related adverse events including hypertension, syncope, asystole, diaphoresis, seizures, changes in behavioral and mental status, and muscular rigidity have also been reported in some patients receiving selegiline and various tricyclic antidepressants. Serious, sometimes fatal, reactions with signs and symptoms that may include hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuations of the vital signs, and mental status changes that include extreme agitation progressing to delirium and coma have been reported with patients receiving a combination of fluoxetine hydrochloride and non-selective MAOIs. Similar signs have been reported in some patients on the combination of selegiline (10 mg a day) and selective serotonin reuptake inhibitors including fluoxetine, sertraline and paroxetine. Since the mechanisms of these reactions are not fully understood, it seems prudent, in general, to avoid this combination of selegiline and tricyclic antidepressants as well as selegiline and selective serotonin reuptake inhibitors. At least 14 days should elapse between discontinuation of selegiline and initiation of treatment with a tricyclic antidepressant or selective serotonin reuptake inhibitors. Because of the long half-lives of fluoxetine and its active metabolite, at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) should elapse between discontinuation of fluoxetine and initiation of treatment with selegiline.

ADVERSE REACTIONS Introduction The number of patients who received selegiline in prospectively monitored pre-marketing studies is limited. While other sources of information about the use of selegiline are available (e.g., literature reports, foreign post-marketing reports, etc.) they do not provide the kind of information necessary to estimate the incidence of adverse events. Thus, overall incidence figures for adverse reactions associated with the use of selegiline cannot be provided. Many of the adverse reactions seen have also been reported as symptoms of dopamine excess. Moreover, the importance and severity of various reactions reported often cannot be ascertained. One index of relative importance, however, is whether or not a reaction caused treatment discontinuation. In prospective pre-marketing studies, the following events led, in decreasing order of frequency, to discontinuation of treatment with selegiline: nausea, hallucinations, confusion, depression, loss of balance, insomnia, orthostatic hypotension, increased akinetic involuntary movements, agitation, arrhythmia, bradykinesia, chorea, delusions, hypertension, new or increased angina pectoris and syncope. Events reported only once as a cause of discontinuation are ankle edema, anxiety, burning lips/mouth, constipation, drowsiness/lethargy, dystonia, excess perspiration, increased freezing, gastrointestinal bleeding, hair loss, increased tremor, nervousness, weakness and weight loss. Experience with selegiline obtained in parallel, placebo controlled, randomized studies provides only a limited basis for estimates of adverse reaction rates. The following reactions that occurred with greater frequency among the 49 patients assigned to selegiline as compared to the 50 patients assigned to placebo in the only parallel, placebo-controlled trial performed in patients with Parkinsons disease are shown in the following Table. None of these adverse reactions led to a discontinuation of treatment. ​INCIDENCE OF TREATMENT-EMERGENT ADVERSE EXPERIENCES IN THE PLACEBO-CONTROLLED CLINICAL TRIAL Adverse Events Number of Patients Reporting Events Selegiline Hydrochloride placebo N = 49 N = 50 Nausea 10 3 Dizziness/Light-headed-fainting 7 1 Abdomial Pain 4 2 Confusion 3 0 Hallucinations 3 1 Dry Mouth 3 1 Vivid Dreams 2 0 Dyskinesias 2 5 Headache 2 1 The following events were reported once in either or both groups: Ache, generalized 1 0 Anxiety/Tension 1 1 Anemia 0 1 Diarrhea 1 0 Hair Loss 0 1 Insomnia 1 1 Lethargy 1 0 Leg Pain 1 0 Low back pain 1 0 Malaise 0 1 Palpitations 1 0 Uninary Retention 1 0 Weight Loss 1 0 In all prospectively monitored clinical investigations, enrolling approximately 920 patients, the following adverse events, classified by body system, were reported. Central Nervous System Motor/Coordination/Extrapyramidal Increased tremor, chorea, loss of balance, restlessness, blepharospasm, increased bradykinesia, facial grimace, falling down, heavy leg, muscle twitch*, myoclonic jerks*, stiff neck, tardive dyskinesia, dystonic symptoms, dyskinesia, involuntary movements, freezing, festination, increased apraxia, muscle cramps. Mental Status/Behavioral/Psychiatric Hallucinations, dizziness, confusion, anxiety, depression, drowsiness, behavior/mood change, dreams/nightmares, tiredness, delusions, disorientation, lightheadedness, impaired memory*, increased energy*, transient high*, hollow feeling, lethargy/malaise, apathy, overstimulation, vertigo, personality change, sleep disturbance, restlessness, weakness, transient irritability. Pain/Altered Sensation Headache, back pain, leg pain, tinnitus, migraine, supraorbital pain, throat burning, generalized ache, chills, numbness of toes/fingers, taste disturbance. Autonomic Nervous System Dry mouth, blurred vision, sexual dysfunction. Cardiovascular Orthostatic hypotension, hypertension, arrhythmia, palpitations, new or increased angina pectoris, hypotension, tachycardia, peripheral edema, sinus bradycardia, syncope. Gastrointestinal Nausea/vomiting, constipation, weight loss, anorexia, poor appetite, dysphagia, diarrhea, heartburn, rectal bleeding, bruxism*, gastrointestinal bleeding (exacerbation of preexisting ulcer disease). Genitourinary/Gynecologic/Endocrine Slow urination, transient anorgasmia*, nocturia, prostatic hypertrophy, urinary hesitancy, urinary retention, decreased penile sensation*, urinary frequency. *Indicates events reported only at doses greater than 10 mg/day. Skin and Appendages Increased sweating, diaphoresis, facial hair, hair loss, hematoma, rash, photosensitivity. Miscellaneous Asthma, diplopia, shortness of breath, speech affected. Post-marketing Reports The following experiences were described in spontaneous post-marketing reports. These reports do not provide sufficient information to establish a clear causal relationship with the use of selegiline hydrochloride. CNS Seizure in dialyzed chronic renal failure patient on concomitant medications.

<table border="0" width="85%"><caption>&#x200B;INCIDENCE OF TREATMENT-EMERGENT ADVERSE EXPERIENCES IN THE PLACEBO-CONTROLLED CLINICAL TRIAL</caption><tbody><tr><td><content styleCode="bold">Adverse Events</content></td><td colspan="2" rowspan="1"><content styleCode="bold">Number of Patients Reporting Events</content></td></tr><tr><td/><td>Selegiline Hydrochloride</td><td>placebo</td></tr><tr><td/><td>N = 49</td><td>N = 50</td></tr><tr><td>Nausea</td><td>10</td><td>3</td></tr><tr><td>Dizziness/Light-headed-fainting</td><td>7</td><td>1</td></tr><tr><td>Abdomial Pain</td><td>4</td><td>2</td></tr><tr><td>Confusion</td><td>3</td><td>0</td></tr><tr><td>Hallucinations</td><td>3</td><td>1</td></tr><tr><td>Dry Mouth</td><td>3</td><td>1</td></tr><tr><td>Vivid Dreams</td><td>2</td><td>0</td></tr><tr><td>Dyskinesias</td><td>2</td><td>5</td></tr><tr><td>Headache</td><td>2</td><td>1</td></tr><tr><td colspan="3" styleCode="Toprule"><content styleCode="bold">The following events were reported once in either or both groups:</content></td></tr><tr><td>Ache, generalized</td><td>1</td><td>0</td></tr><tr><td>Anxiety/Tension</td><td>1</td><td>1</td></tr><tr><td>Anemia</td><td>0</td><td>1</td></tr><tr><td>Diarrhea</td><td>1</td><td>0</td></tr><tr><td>Hair Loss</td><td>0</td><td>1</td></tr><tr><td>Insomnia</td><td>1</td><td>1</td></tr><tr><td>Lethargy</td><td>1</td><td>0</td></tr><tr><td>Leg Pain</td><td>1</td><td>0</td></tr><tr><td>Low back pain</td><td>1</td><td>0</td></tr><tr><td>Malaise</td><td>0</td><td>1</td></tr><tr><td>Palpitations</td><td>1</td><td>0</td></tr><tr><td>Uninary Retention</td><td>1</td><td>0</td></tr><tr><td>Weight Loss</td><td>1</td><td>0</td></tr></tbody></table>