SELEGILINE HYDROCHLORIDE

Selegiline hydrochloride is a levorotatory acetylenic derivative of phenethylamine. It is commonly referred to in the clinical and pharmacological literature as l- deprenyl. The chemical name is: (R)-(-)- N ,α-Dimethyl- N-2 -propynylphenethylamine hydrochloride. It is a white to near white crystalline powder, freely soluble in water, chloroform, and methanol, and has a molecular weight of 223.75. The molecular formula is C 13 H 17 N . HCI and the structural formula is as follows: Each capsule, for oral administration contains 5 mg of selegiline hydrochloride. In addition, each capsule contains the following inactive ingredients: Anhydrous Lactose NF, Citric Acid Anhydrous USP, Microcrystalline Cellulose NF PH102, Stearic Acid NF and Talc USP. The capsule shell contains Gelatin NF, FD & C Blue #1 and Titanium Dioxide. The capsule logo ink Black SW-9008/SW-9009 contains the following inactive ingredients: Ammonium Hydroxide; Black Iron Oxide, Bacteria Controlled EEC No. 172; n-Butyl NF; Ethyl Alcohol, Anhydrous, 200 Proof; Isopropyl Alcohol USP; Potassium Hydroxide NF; Propylene Glycol USP; Purified Water USP and Shellac NF.

Selegiline 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).

Selegiline hydrochloride capsules are intended for administration to Parkinsonian patients receiving levodopa/carbidopa therapy who demonstrate a deteriorating response to this treatment. The recommended regimen for the administration of selegiline hydrochloride is 10 mg per day administered as divided doses of 5 mg each taken at breakfast and lunch. There is no evidence that additional benefit will be obtained from the administration of higher doses. Moreover, higher doses should ordinarily be avoided because of the increased risk of side effects. After two to three days of selegiline treatment, an attempt may be made to reduce the dose of levodopa/carbidopa. A reduction of 10 to 30% was achieved with the typical participant in the domestic placebo controlled trials who was assigned to selegiline treatment. Further reductions of levodopa/carbidopa may be possible during continued selegiline therapy.

Selegiline is contraindicated in patients with a known hypersensitivity to this drug. Selegiline is contraindicated for use with meperidine (DEMEROL & other trade names). This contraindication is often extended to other opioids. (See Drug Interactions .)

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 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/Lightheaded/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. * 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. CNS Seizure in dialyzed chronic renal failure patient on concomitant medications.