SELEGILINE HYDROCHLORIDE (Page 3 of 4)

Nursing Mothers:

It is not known whether selegiline 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.

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, hallucin-ations, 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-

headedness/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.

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.

*indicates events reported only at doses greater than 10 mg/day.

OVERDOSAGE:

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 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.

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