Selegiline Drug Information

Selegiline hydrochloride tablets USP 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 Tablets USP 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.

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/Light-headed/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. Postmarketing 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.

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 and selective serotonin reuptake inhibitors and selegiline. (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).

Pregnancy 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/m 2 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/m 2 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.

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

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

Selegiline No specific information is available about clinically significant overdoses with selegiline hydrochloride. However, experience gained during selegiline's development reveals that some individuals exposed to doses of 600 mg of d,l-selegiline suffered severe hypotension and psychomotor agitation. Since the selective inhibition of MAO B by selegiline hydrochloride is achieved only at doses in the range recommended for the treatment of Parkinson's disease (e.g., 10 mg/day), overdoses are likely to cause significant inhibition of both MAO A and MAO B. Consequently, the signs and symptoms of overdose may resemble those observed with marketed non-selective MAO inhibitors (e.g., tranylcypromine, isocarboxazide, and phenelzine). Overdose with Non-Selective MAO Inhibition NOTE: This section is provided for reference; it does not describe events that have actually been observed with selegiline in overdose.

Characteristically, signs and symptoms of non-selective MAOI overdose may not appear immediately. Delays of up to 12 hours between ingestion of drug and the appearance of signs may occur. Importantly, the peak intensity of the syndrome may not be reached for upwards of a day following the overdose.

Death has been reported following overdosage. Therefore, immediate hospitalization, with continuous patient observation and monitoring for a period of at least two days following the ingestion of such drugs in overdose, is strongly recommended. The clinical picture of MAOI overdose varies considerably; its severity may be a function of the amount of drug consumed.

The central nervous and cardiovascular systems are prominently involved. Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonus, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin. Treatment Suggestions for Overdose NOTE: Because there is no recorded experience with selegiline overdose, the following suggestions are offered based upon the assumption that selegiline overdose may be modeled by non-selective MAOI poisoning.

In any case, up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physicians' Desk Reference (PDR). Treatment of overdose with non-selective MAOIs is symptomatic and supportive. Induction of emesis or gastric lavage with instillation of charcoal slurry may be helpful in early poisoning, provided the airway has been protected against aspiration.

Signs and symptoms of central nervous system stimulation, including convulsions, should be treated with diazepam, given slowly intravenously. Phenothiazine derivatives and central nervous system stimulants should be avoided. Hypotension and vascular collapse should be treated with intravenous fluids and, if necessary, blood pressure titration with an intravenous infusion of a dilute pressor agent.

It should be noted that adrenergic agents may produce a markedly increased pressor response. Respiration should be supported by appropriate measures, including management of the airway, use of supplemental oxygen, and mechanical ventilatory assistance, as required. Body temperature should be monitored closely.

Intensive management of hyperpyrexia may be required. Maintenance of fluid and electrolyte balance is essential.