2.1 General Dosage Recommendations

Initiate treatment with 1.25 mg given once a day for at least 6 weeks. After 6 weeks, the dose may be increased to 2.5 mg given once a day if a desired benefit has not been achieved and the patient is tolerating ZELAPAR. There is no evidence that doses greater than 2.5 mg a day provide additional benefit, and they should ordinarily be avoided because of the potential increased risk of adverse events.

Take ZELAPAR in the morning before breakfast and without liquid. Patients should avoid ingesting food or liquids for 5 minutes before and after taking ZELAPAR.

Patients should not attempt to push ZELAPAR through the foil backing. Patients should PEEL BACK the backing of one or two blisters (as prescribed) with dry hands, and GENTLY remove the tablet(s). Patients should IMMEDIATELY place the ZELAPAR tablet(s) on top of the tongue where it will disintegrate in seconds.

2.2 Patients with Hepatic Impairment

In patients with mild to moderate hepatic disease (Child-Pugh score 5 to 9), the daily dose of ZELAPAR should be reduced (from 2.5 to 1.25 mg daily), depending on the clinical response. ZELAPAR is not recommended in patients with severe hepatic impairment (Child-Pugh score greater than 9) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.3 Patients with Renal Impairment

No dose adjustment of ZELAPAR is required in patients with mild to moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min). The maintenance dose of ZELAPAR (1.25 mg or 2.5 mg) is determined by the individual clinical response. ZELAPAR is not recommended in patients with severe renal impairment and patients with end-stage renal disease [ESRD] (creatinine clearance [CLcr] <30 mL/min) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

5.1 Hypertension

ZELAPAR should not be used at daily doses exceeding those recommended (2.5 mg/day) because of the risks associated with non-selective inhibition of MAO [see Drug Interactions (7.3) and Clinical Pharmacology (12.2)].

The selectivity of ZELAPAR for MAO-B may not be absolute even at the recommended daily dose of 2.5 mg a day. The selectivity of MAO-B inhibitors, typically decreases and it is ultimately lost as the dose is increased beyond recommended doses. Hypertensive reactions associated with ingestion of tyramine containing foods have been reported even in patients taking the recommended daily dose of swallowed selegiline, a dose which is generally believed to be selective for MAO-B. Selectivity for MAO-B inhibition is gradually lost with increasing daily doses. An increase in tyramine sensitivity for blood pressure responses appears to begin at a dose of 5 mg ZELAPAR daily [see Drug Interactions (7.5)]. However, the precise dose at which ZELAPAR becomes a non-selective inhibitor of all MAO enzymes in individual patients is unknown.

Reports of hypertensive reactions have occurred in patients who ingested tyramine-containing consumables (i.e., food or drink) while receiving swallowed selegiline at the recommended dose (a dose believed to be relatively selective for MAO-B).

The safe use of ZELAPAR at doses above 2.5 mg daily without dietary tyramine restrictions has not been established.

A pharmacodynamic study showed increased tyramine sensitivity for increasing blood pressure and decreased selectivity for MAO-B with dosing above the recommended level (2.5 mg daily) [see Clinical Pharmacology (12.2)].

Uncontrolled hypertension has been reported when taking the recommended dose of swallowed selegiline and a sympathomimetic medication (ephedrine).

After starting ZELAPAR, monitor patients for new onset hypertension or exacerbation of hypertension that is not adequately controlled.

5.2 Serotonin Syndrome

Serotonin syndrome and hyperpyrexia have been reported with the combined treatment of an antidepressant (e.g., selective serotonin reuptake inhibitors-SSRIs, serotonin-norepinephrine reuptake inhibitors-SNRIs, tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants) and a non-selective MAOI (e.g., phenelzine, tranylcypromine) or selective MAO-B inhibitors, such as selegiline (ELDEPRYL), rasagiline (AZILECT), and Zydis selegiline (ZELAPAR).

Serotonin syndrome is a potentially serious condition, which can result in death. Typical clinical signs and symptoms include behavioral and cognitive/mental status changes (e.g., confusion, hypomania, hallucinations, agitation, delirium, headache, and coma), autonomic effects (e.g., syncope, shivering, sweating, high fever/hyperthermia, hypertension, hypotension, tachycardia, nausea, diarrhea), and somatic effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifested by clonus, and tremor).

In the post-marketing period, fatal and non-fatal cases of serotonin syndrome have been reported in patients treated with antidepressants concomitantly with ZELAPAR [see Contraindications (4) and Drug Interactions (7.1, 7.2, 7.3)].

Clinical studies of ZELAPAR did not allow concomitant use of any selective serotonin re-uptake inhibitor (e.g., fluoxetine-Prozac, fluvoxamine-Luvox, paroxetine-Paxil, sertraline, venlafaxine-Effexor, or nefazodone-Serzone) or any non-selective serotonin reuptake inhibiting antidepressant drug (except when taken at a low dose and only at night for the purpose of effective sleep) with ZELAPAR.

Because the mechanisms responsible for these reactions are not fully understood, avoid the combination of ZELAPAR with any antidepressant. At least 14 days should elapse between discontinuation of ZELAPAR and initiation of treatment with a SSRI, SNRI, tricyclic, tetracyclic, or triazolopyridine antidepressant. In patients taking antidepressants with a long half-life (e.g., fluoxetine and its active metabolite), allow at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) to elapse between discontinuation of fluoxetine and initiation of ZELAPAR [see Drug Interactions (7.6)].

5.3 Falling Asleep During Activities of Daily Living and Somnolence

Patients with Parkinson’s disease treated with ZELAPAR or other drugs increasing dopaminergic tone have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence, some did not perceive warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported as late as one year after initiation of treatment.

It has been reported that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment.

Somnolence may occur in patients receiving ZELAPAR. There was an increased risk for somnolence in geriatric patients (≥65 years) vs. non-geriatric patients treated with ZELAPAR. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients should be advised to exercise caution while driving, operating machines, or working at heights during treatment with ZELAPAR. Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities during treatment with ZELAPAR.

Before initiating treatment with ZELAPAR, advise patients about the potential to develop drowsiness and specifically ask about factors that may increase this risk, such as concomitant sedating medications and the presence of sleep disorders. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), ZELAPAR should ordinarily be discontinued. If a decision is made to continue ZELAPAR, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

5.4 Hypotension/Orthostatic Hypotension

Assessments of orthostatic (supine and standing) blood pressures at different times throughout the 12 week study period in two controlled trials showed that the frequency of orthostatic hypotension (>20 mm Hg decrease in systolic blood pressure and/or >10 mm Hg decrease in diastolic blood pressure) was greater with ZELAPAR treatment than with placebo treatment. Patients taking ZELAPAR were most likely to experience a decline in systolic and diastolic blood pressure at 8 weeks (2 weeks after initiating 2.5 mg ZELAPAR). At that time, the incidence of systolic orthostatic hypotension was about 21% in ZELAPAR-treated patients and 9% in placebo-treated patients. The incidence of diastolic orthostatic hypotension was about 12% in ZELAPAR-treated patients and about 4% in placebo-treated patients. Thus, it appears that there may be an increased risk for orthostatic hypotension in the period after increasing the daily dose of ZELAPAR from 1.25 to 2.5 mg.

The incidence of orthostatic hypotension was higher in geriatric patients (≥65 years) than in non-geriatric patients. In the geriatric patients, orthostatic hypotension occurred in about 3% of ZELAPAR-treated patients compared to 0% of placebo-treated patients.

5.5 Dyskinesia

ZELAPAR may potentiate dopaminergic side effects of levodopa and may cause dyskinesia or exacerbate preexisting dyskinesia. In controlled trials, the incidence of dyskinesia was 6% in ZELAPAR-treated patients and 3% in placebo-treated patients. Decreasing the dose of levodopa may lessen dyskinesia. The incidence of dyskinesia causing study discontinuation was greater on ZELAPAR than on placebo.

5.6 Hallucinations/Psychotic-Like Behavior

5.7 Impulse Control/Compulsive Behaviors

Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including ZELAPAR, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge eating, or other urges while being treated with ZELAPAR. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ZELAPAR.

5.8 Withdrawal Emergent Hyperpyrexia and Confusion

Although not reported with ZELAPAR in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.

5.9 Melanoma

Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using ZELAPAR for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

5.10 Irritation of the Buccal Mucosa

In the controlled clinical trials, periodic examinations of the tongue and oral mucosa were performed. At the end of the study, the frequency of mild oropharyngeal abnormality (e.g., swallowing pain, mouth pain, discrete areas of focal reddening, multiple foci of reddening, edema, and/or ulceration) in patients without similar abnormality at baseline was 10% in ZELAPAR-treated patients compared to 3% in placebo-treated patients.

5.11 Risk for Phenylketonuric Patients

It is important to note that each ZELAPAR tablet contains 1.25 mg phenylalanine (a component of aspartame). Patients taking the 2.5 mg dose of ZELAPAR will receive 2.5 mg phenylalanine.

5.12 Effect on Renal Function

Small increments in serum BUN and creatinine have been observed in patients treated with high dose ZELAPAR (10 mg daily; 4 times the recommended dose).

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction per total number of patients treated) observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the incidence of adverse reactions observed in clinical practice.

Because the controlled trials performed during premarketing development both used a titration design (1.25 mg per day for 6 weeks, followed by 2.5 mg per day for 6 weeks), with a resultant confounding of time and dose, it was impossible to adequately evaluate the effects of dose on the incidence of adverse events.

The most common adverse reactions (treatment difference incidence at least 3% greater than placebo incidence) reported in the double-blind, placebo-controlled trials during ZELAPAR treatment were constipation, skin disorders, vomiting, dizziness, dyskinesia, insomnia, dyspnea, myalgia, and rash (see Table 1).

Of the 194 patients treated with ZELAPAR in the double-blind, placebo-controlled trials, 5% discontinued due to adverse reactions compared to 1% of the 98 patients who received placebo. Most common adverse reactions causing discontinuation of treatment included dizziness, chest pain, accidental injury, and myasthenia.

7.1 Meperidine

Serious, sometimes fatal reactions have been reported in patients treated with concomitant meperidine (e.g., Demerol and other tradenames) and MAO inhibitors including selective MAO-B inhibitors [see Contraindications (4)].

7.2 Dextromethorphan

The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. Therefore, in view of ZELAPAR’s MAO inhibitory activity, dextromethorphan should not be used concomitantly with ZELAPAR [see Contraindications (4)].

7.3 MAO Inhibitors

ZELAPAR should not be administered along with other selegiline products (e.g., EMSAM or ELDEPRYL®) because of the increased risk of non-selective MAO inhibition that may lead to a hypertensive crisis [see Contraindications (4)].

7.4 Sympathomimetic Medications

Uncontrolled hypertension, including hypertensive crisis, has been reported when taking the recommended dose of swallowed selegiline and a sympathomimetic medication (ephedrine).

7.5 Tyramine/Selegiline Interaction

The enzyme, monoamine oxidase (MAO) (primarily type A), in the gastrointestinal tract and liver provides protection from ingested amines (e.g., tyramine) that, if absorbed, have the capacity to cause uncontrolled hypertension (tyramine reaction). If MAO is inhibited in the gastrointestinal tract and liver, ingestion of exogenous amines contained in some foods such as fermented cheese, herring, or over-the-counter cough/cold medicines may be absorbed systemically causing release of norepinephrine and a rise in systemic blood pressure with the potential for uncontrolled hypertension. Selective MAO-B inhibitors lose their selectivity for MAO-B when taken in doses higher than recommended. Non-selective MAO-A inhibitors or MAO-B inhibitors in higher than recommended doses may result in MAO-A inhibition in the gastrointestinal tract and liver.

Results of a tyramine challenge study indicate that ZELAPAR is relatively selective for MAO-B at the recommended dose. In most cases, there is no need for dietary tyramine restriction in patients prescribed ZELAPAR [see Clinical Pharmacology (12.2)] at the recommended dose. Because the selectivity for inhibiting MAO-B diminishes as the dose of ZELAPAR is increased above the recommended daily dose, patients should not take more than 2.5 mg of ZELAPAR daily.

Reports of hypertensive reactions have occurred in patients who ingested tyramine-containing consumables (i.e., food or drink) while receiving swallowed selegiline at the recommended dose (a dose believed to be relatively selective for MAO-B). Hypertensive crisis has also been reported with ZELAPAR use that was not above the recommended dosing.

Uncontrolled hypertension has been reported when taking the recommended dose of swallowed selegiline and a sympathomimetic medication (ephedrine).

7.6 Tricyclic Antidepressants and Selective Serotonin Reuptake Inhibitors

Severe toxicity has also been reported in patients receiving the combination of tricyclic antidepressants and swallowed selegiline, or selective serotonin reuptake inhibitors and swallowed selegiline [see Warnings and Precautions (5.2)].

7.7 Drugs that Induce CYP450

Adequate studies have not been done investigating the effect of CYP3A4 inducers on selegiline. Drugs that induce CYP3A4 (e.g., phenytoin, carbamazepine, nafcillin, phenobarbital, and rifampin) should be used with caution.

7.8 Dopaminergic Antagonists

It is possible that dopamine antagonists, such as antipsychotics or metoclopramide, could diminish the effectiveness of ZELAPAR.

8.1 Pregnancy

8.3 Nursing Mothers

Selegiline and metabolites were detected in rat milk at levels higher than those in maternal plasma. It is not known whether this drug or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ZELAPAR is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

The overall incidence of adverse reactions was increased in geriatric patients (≥65 years) compared to non-geriatric patients (<65 years). Clinical studies did not include a sufficient number of geriatric subjects older than 75 years to determine whether they respond differently to ZELAPAR.

Analysis of adverse reaction incidence in each group was conducted to calculate and compare relative risk (ZELAPAR % / Placebo %) for each treatment. The relative risk was ≥2 fold higher for ZELAPAR treatment in the geriatric patients compared to the non-geriatric patients for hypertension, orthostatic/postural hypotension [see Warnings and Precautions (5.4)]. The incidence of orthostatic hypotension by measurement of blood pressure was also higher in geriatric patients than in non-geriatric patients. In the geriatric patients, the treatment difference for incidence of orthostatic hypotension determined by supine and standing blood measurements was 3%.

8.6 Hepatic Impairment

Patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9) may require a dose reduction of ZELAPAR (from 2.5 to 1.25 mg daily) depending on the clinical response. ZELAPAR is not recommended in patients with severe hepatic impairment (Child-Pugh score >9) [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No dose adjustment of ZELAPAR is required in patients with mild to moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min). ZELAPAR is not recommended in patients with severe renal impairment and patients with end-stage renal disease [ESRD] (CLcr <30 mL/min) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

10.1 Selegiline

No specific information is available about clinically significant overdoses with swallowed selegiline or ZELAPAR. However, experience gained during development of the 5 mg swallowed dosage form 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 ZELAPAR is achieved only at doses in the range recommended for the treatment of Parkinson’s disease (e.g., 2.5 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 (PARNATE®), isocarboxazid (MARPLAN®), and phenelzine (NARDIL®)]. For this reason, in cases of overdose with selegiline, dietary tyramine restriction should be observed for several weeks to avoid the risk of a hypertensive reaction.

10.2 Overdose with Non-selective MAO Inhibitors

NOTE: The following description of presenting symptoms and clinical course is based upon overdose descriptions of non-selective MAO inhibitors and does not include information from patients who have overdosed on oral selegiline or ZELAPAR.

Characteristically, signs and symptoms of non-selective MAO inhibitor 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 MAO inhibitor 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, opisthotonos, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin.

10.3 Treatment or Management of Overdose

Treatment of overdose with non-selective MAO inhibitors 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.

Support respiration, 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.

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility