FDA label b0a51a4f-d681-2710-e053-2995a90a56e7

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 (NARDIL ® , PARNATE ® ). A similar reaction has been reported for a patient on amitriptyline and selegiline hydrochloride capsules. Another patient receiving protriptyline and selegiline hydrochloride capsules developed tremors, agitation, and restlessness followed by unresponsiveness and death two weeks after selegiline hydrochloride capsules were 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 hydrochloride capsules 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 (PROZAC ® ) and non-selective MAOIs. Similar signs have been reported in some patients on the combination of selegiline hydrochloride capsules (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 hydrochloride capsules and tricyclic antidepressants as well as selegiline hydrochloride capsules and selective serotonin reuptake inhibitors. At least 14 days should elapse between discontinuation of selegiline hydrochloride capsules 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 hydrochloride capsules.

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 (eg, 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 hydrochloride 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 Parkinson’s 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 Event Number of Patients Reporting Events selegiline hydrochloride N=49 placebo N=50 Nausea 10 3 Dizziness/Lightheadedness/Fainting 7 1 Abdominal 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 Urinary 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. 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. *indicates events reported only at doses greater than 10 mg/day.

<table><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td align="center" colspan="3" styleCode=" Botrule Toprule "> <paragraph><content styleCode="bold">INCIDENCE OF TREATMENT-EMERGENT </content></paragraph><paragraph><content styleCode="bold">ADVERSE EXPERIENCES IN THE </content></paragraph><paragraph><content styleCode="bold">PLACEBO-CONTROLLED CLINICAL TRIAL</content></paragraph></td></tr><tr><td styleCode=" Toprule "> <paragraph><content styleCode="bold">Adverse Event</content></paragraph></td><td colspan="2" styleCode=" Toprule "> <paragraph><content styleCode="bold"> Number of Patients</content></paragraph><paragraph><content styleCode="bold"> Reporting Events</content></paragraph></td></tr><tr><td> </td><td> <paragraph><content styleCode="bold">selegiline</content></paragraph><paragraph><content styleCode="bold">hydrochloride</content></paragraph><paragraph><content styleCode="bold">N=49</content></paragraph></td><td> <paragraph><content styleCode="bold">placebo</content></paragraph><paragraph><content styleCode="bold">N=50</content></paragraph></td></tr><tr><td> <paragraph>Nausea</paragraph></td><td> <paragraph>10</paragraph></td><td> <paragraph>3</paragraph></td></tr><tr><td> <paragraph>Dizziness/Lightheadedness/Fainting</paragraph></td><td> <paragraph>7</paragraph></td><td> <paragraph>1</paragraph></td></tr><tr><td> <paragraph>Abdominal Pain</paragraph></td><td> <paragraph>4</paragraph></td><td> <paragraph>2</paragraph></td></tr><tr><td> <paragraph>Confusion</paragraph></td><td> <paragraph>3</paragraph></td><td> <paragraph>0</paragraph></td></tr><tr><td> <paragraph>Hallucinations</paragraph></td><td> <paragraph>3</paragraph></td><td> <paragraph>1</paragraph></td></tr><tr><td> <paragraph>Dry mouth</paragraph></td><td> <paragraph>3</paragraph></td><td> <paragraph>1</paragraph></td></tr><tr><td> <paragraph>Vivid Dreams</paragraph></td><td> <paragraph>2</paragraph></td><td> <paragraph>0</paragraph></td></tr><tr><td> <paragraph>Dyskinesias</paragraph></td><td> <paragraph>2</paragraph></td><td> <paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule "> <paragraph>Headache</paragraph></td><td styleCode=" Botrule "> <paragraph>2</paragraph></td><td styleCode=" Botrule "> <paragraph>1</paragraph></td></tr><tr><td colspan="3" styleCode=" Toprule "> <paragraph><content styleCode="bold">The following events were reported once in either or both groups:</content></paragraph></td></tr><tr><td> <paragraph>Ache, generalized</paragraph></td><td> <paragraph>1</paragraph></td><td> <paragraph>0</paragraph></td></tr><tr><td> <paragraph>Anxiety/Tension</paragraph></td><td> <paragraph>1</paragraph></td><td> <paragraph>1</paragraph></td></tr><tr><td> <paragraph>Anemia</paragraph></td><td> <paragraph>0</paragraph></td><td> <paragraph>1</paragraph></td></tr><tr><td> <paragraph>Diarrhea</paragraph></td><td> <paragraph>1</paragraph></td><td> <paragraph>0</paragraph></td></tr><tr><td> <paragraph>Hair Loss</paragraph></td><td> <paragraph>0</paragraph></td><td> <paragraph>1</paragraph></td></tr><tr><td> <paragraph>Insomnia</paragraph></td><td> <paragraph>1</paragraph></td><td> <paragraph>1</paragraph></td></tr><tr><td> <paragraph>Lethargy</paragraph></td><td> <paragraph>1</paragraph></td><td> <paragraph>0</paragraph></td></tr><tr><td> <paragraph>Leg pain</paragraph></td><td> <paragraph>1</paragraph></td><td> <paragraph>0</paragraph></td></tr><tr><td> <paragraph>Low back pain</paragraph></td><td> <paragraph>1</paragraph></td><td> <paragraph>0</paragraph></td></tr><tr><td> <paragraph>Malaise</paragraph></td><td> <paragraph>0</paragraph></td><td> <paragraph>1</paragraph></td></tr><tr><td> <paragraph>Palpitations</paragraph></td><td> <paragraph>1</paragraph></td><td> <paragraph>0</paragraph></td></tr><tr><td> <paragraph>Urinary Retention</paragraph></td><td> <paragraph>1</paragraph></td><td> <paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule "> <paragraph>Weight Loss</paragraph></td><td styleCode=" Botrule "> <paragraph>1</paragraph></td><td styleCode=" Botrule "> <paragraph>0</paragraph></td></tr></tbody></table>