Selegiline Hydrochloride - Selegiline Hydrochloride tablet prescribing information
INDICATIONS AND USAGE
Selegiline Hydrochloride Tablets, 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).
DOSAGE AND ADMINISTRATION
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.
CONTRAINDICATIONS
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 .)
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.
Adverse Event | Number of Patients Reporting Events | |
| selegiline hydrochloride | placebo | |
| N = 49 | 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.
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.
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).
DESCRIPTION
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 ,2-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 223.74. The molecular formula is C 13 H 17 N•HCl. The structural formula is as follows:
Each tablet, for oral administration, contains 5 mg selegiline hydrochloride. Inactive ingredients are corn starch, lactose monohydrate, microcrystalline cellulose, povidone, and stearic acid.
CLINICAL PHARMACOLOGY
The mechanisms accounting for selegiline’s beneficial adjunctive action in the treatment of Parkinson’s disease are not fully understood. Inhibition of monoamine oxidase, type B, activity is generally considered to be of primary importance; in addition, there is evidence that selegiline may act through other mechanisms to increase dopaminergic activity.
Selegiline is best known as an irreversible inhibitor of monoamine oxidase (MAO), an intracellular enzyme associated with the outer membrane of mitochondria. Selegiline inhibits MAO by acting as a ‘suicide’ substrate for the enzyme; that is, it is converted by MAO to an active moiety which combines irreversibly with the active site and/or the enzyme’s essential FAD cofactor. Because selegiline has greater affinity for type B rather than for type A active sites, it can serve as a selective inhibitor of MAO type B if it is administered at the recommended dose.
MAOs are widely distributed throughout the body; their concentration is especially high in liver, kidney, stomach, intestinal wall, and brain. MAOs are currently subclassified into two types, A and B, which differ in their substrate specificity and tissue distribution. In humans, intestinal MAO is predominantly type A, while most of that in brain is type B.
In CNS neurons, MAO plays an important role in the catabolism of catecholamines (dopamine, norepinephrine and epinephrine) and serotonin. MAOs are also important in the catabolism of various exogenous amines found in a variety of foods and drugs. MAO in the GI tract and liver (primarily type A), for example, is thought to provide vital protection from exogenous amines (e.g., tyramine) that have the capacity, if absorbed intact, to cause a ‘hypertensive crisis,’ the so-called ‘cheese reaction.’ (If large amounts of certain exogenous amines gain access to the systemic circulation - e.g., from fermented cheese, red wine, herring, over-the-counter cough/cold medications, etc. - they are taken up by adrenergic neurons and displace norepinephrine from storage sites within membrane bound vesicles. Subsequent release of the displaced norepinephrine causes the rise in systemic blood pressure, etc.)
In theory, since MAO-A of the gut is not inhibited, patients treated with selegiline at a dose of 10 mg a day should be able to take medications containing pharmacologically active amines and consume tyramine-containing foods without risk of uncontrolled hypertension. Although rare, a few reports of hypertensive reactions have occurred in patients receiving selegiline at the recommended dose, with tyramine-containing foods. In addition, one case of hypertensive crisis has been reported in a patient taking the recommended dose of selegiline and a sympathomimetic medication, ephedrine. The pathophysiology of the ‘cheese reaction’ is complicated and, in addition to its ability to inhibit MAO-B selectively, selegiline's relative freedom from this reaction has been attributed to an ability to prevent tyramine and other indirect acting sympathomimetics from displacing norepinephrine from adrenergic neurons. However, until the pathophysiology of the ‘cheese reaction’ is more completely understood, it seems prudent to assume that selegiline can ordinarily only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day).
In short, attention to the dose dependent nature of selegiline’s selectivity is critical if it is to be used without elaborate restrictions being placed on diet and concomitant drug use although, as noted above, a few cases of hypertensive reactions have been reported at the recommended dose. (See WARNINGS and PRECAUTIONS .)
It is important to be aware that selegiline may have pharmacological effects unrelated to MAO-B inhibition. As noted above, there is some evidence that it may increase dopaminergic activity by other mechanisms, including interfering with dopamine re-uptake at the synapse. Effects resulting from selegiline administration may also be mediated through its metabolites. Two of its three principal metabolites, amphetamine and methamphetamine, have pharmacological actions of their own; they interfere with neuronal uptake and enhance release of several neurotransmitters (e.g., norepinephrine, dopamine, serotonin). However, the extent to which these metabolites contribute to the effects of selegiline are unknown.
Rationale for the Use of a Selective Monoamine Oxidase Type B Inhibitor in Parkinson’s disease
Many of the prominent symptoms of Parkinson’s disease are due to a deficiency of striatal dopamine that is the consequence of a progressive degeneration and loss of a population of dopaminergic neurons which originate in the substantia nigra of the midbrain and project to the basal ganglia or striatum. Early in the course of Parkinson’s Disease, the deficit in the capacity of these neurons to synthesize dopamine can be overcome by administration of exogenous levodopa, usually given in combination with a peripheral decarboxylase inhibitor (carbidopa).
With the passage of time, due to the progression of the disease and/or the effect of sustained treatment, the efficacy and quality of the therapeutic response to levodopa diminishes. Thus, after several years of levodopa treatment, the response, for a given dose of levodopa, is shorter, has less predictable onset and offset (i.e., there is 'wearing off'), and is often accompanied by side effects (e.g., dyskinesia, akinesias, on-off phenomena, freezing, etc.).
This deteriorating response is currently interpreted as a manifestation of the inability of the ever decreasing population of intact nigrostriatal neurons to synthesize and release adequate amounts of dopamine.
MAO-B inhibition may be useful in this setting because, by blocking the catabolism of dopamine, it would increase the net amount of dopamine available (i.e., it would increase the pool of dopamine). Whether or not this mechanism or an alternative one actually accounts for the observed beneficial effects of adjunctive selegiline is unknown.
Selegiline's benefit in Parkinson's disease has only been documented as an adjunct to levodopa/carbidopa. Whether or not it might be effective as a sole treatment is unknown, but past attempts to treat Parkinson's disease with nonselective MAOI monotherapy are reported to have been unsuccessful. It is important to note that attempts to treat Parkinsonian patients with combinations of Levodopa and currently marketed non-selective MAO inhibitors were abandoned because of multiple side effects including hypertension, increase in involuntary movement and toxic delirium.
Pharmacokinetic Information (Absorption, Distribution, Metabolism and Elimination - ADME)
The absolute bioavailability of selegiline following oral dosing is not known; however, selegiline undergoes extensive metabolism (presumably attributable to presystemic clearance in gut and liver). The major plasma metabolites are N-desmethylselegiline, L-amphetamine and L-methamphetamine. Only N-desmethylselegiline has MAO-B inhibiting activity. The peak plasma levels of these metabolites following a single oral dose of 10 mg are from 4 to almost 20 times greater than that of the maximum plasma concentration of selegiline (1 ng/mL). The maximum concentrations of amphetamine and methamphetamine, however, are far below those ordinarily expected to produce clinically important effects.
Single oral dose studies do not predict multiple dose kinetics, however, at steady state the peak plasma level of selegiline is 4-fold that obtained following a single dose. Metabolite concentrations increase to a lesser extent; averaging 2-fold that seen after a single dose.
The bioavailability of selegiline is increased 3 to 4-fold when it is taken with food.
The extent of systemic exposure to selegiline at a given dose varies considerably among individuals. Estimates of systemic clearance of selegiline are not available. Following a single oral dose, the mean elimination half-life of selegiline is two hours. Under steady state conditions the elimination half-life increases to ten hours.
Because selegiline’s inhibition of MAO-B is irreversible, it is impossible to predict the extent of MAO-B inhibition from steady state plasma levels. For the same reason, it is not possible to predict the rate of recovery of MAO-B activity as a function of plasma levels. The recovery of MAO-B activity is a function of de novo protein synthesis; however, information about the rate of de novo protein synthesis is not yet available. Although platelet MAO-B activity returns to the normal range within 5 to 7 days of selegiline discontinuation, the linkage between platelet and brain MAO-B inhibition is not fully understood nor is the relationship of MAO-B inhibition to the clinical effect established (see CLINICAL PHARMACOLOGY ).
Special Populations
Renal Impairment
No pharmacokinetic information is available on selegiline or its metabolites in renally impaired subjects.
Hepatic Impairment
No pharmacokinetic information is available on selegiline or its metabolites in hepatically impaired subjects.
Age
Although a general conclusion about the effects of age on the pharmacokinetics of selegiline is not warranted because of the size of the sample evaluated (12 subjects greater than 60 years of age, 12 subjects between the ages of 18 to 30), systemic exposure was about twice as great in older as compared to a younger population given a single oral dose of 10 mg.
Gender
No information is available on the effects of gender on the pharmacokinetics of selegiline.
HOW SUPPLIED
Selegiline Hydrochloride Tablets, USP 5 mg are available for oral administration as white, unscored, round tablets debossed with “i3” on one side and “6” on the other side. They are supplied as bottle of 60 (NDC 73141-006-02).
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions 15˚C to 30˚C (59˚F to 86˚F). [see USP Controlled Room Temperature].
Dispense in a tight, light-resistant container [see USP] with a child-resistant closure as required.
A2A Integrated Pharmaceuticals SELEGILINE HYDROCHLORIDE TABLETS, USP 5 mg
Distributed by: A2A Integrated Pharmaceuticals Franklin, KY 42134
PI0006-02 R02/25 Revised: February 2025
