Selegiline Hydrochloride

ZELAPAR is indicated as an adjunct in the management of patients with Parkinson’s disease 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 ZELAPAR has any beneficial effect in the absence of concurrent levodopa therapy [see Clinical Studies (14 ) ] . ZELAPAR, a monoamine oxidase type B (MAO-B) inhibitor, is indicated as an adjunct in the management of patients with Parkinson’s disease being treated with levodopa/carbidopa who exhibit deterioration in the quality of their response to this therapy ( 1 )

ZELAPAR Orally Disintegrating Tablets are pale yellow, imprinted with a stylized “V”, and contain 1.25 mg selegiline hydrochloride. Orally Disintegrating Tablets: 1.25 mg ( 3 )

ZELAPAR is contraindicated in patients with:

• Concomitant use of opioid drugs (e.g., meperidine, tramadol, or methadone). Serotonin syndrome, a potentially serious condition, which can result in death, has been reported with concomitant use of meperidine (e.g., Demerol and other trade names). At least 14 days should elapse between discontinuation of ZELAPAR and initiation of treatment with these medications [see Warnings and Precautions (5.2) ] .
• Concomitant use of other drugs in the monoamine oxidase inhibitor (MAOI) class or other drugs that are potent inhibitors of monoamine oxidase, including linezolid), because of an increased risk for hypertensive crisis [see Warnings and Precautions (5.1)]. At least 14 days should elapse between discontinuation of ZELAPAR and initiation of treatment with any MAO inhibitor.
• Concomitant use of St. John’s wort or cyclobenzaprine (a tricyclic muscle relaxant).
• Concomitant use of dextromethorphan, because of reported episodes of psychosis or bizarre behavior. ZELAPAR is contraindicated in patients using the following drugs: opioid drugs (e.g., meperidine, tramadol, methadone), MAO inhibitors including selective MAO-B inhibitors, dextromethorphan, St. John’s wort, and cyclobenzaprine ( 4 )

• May cause hypertension above 2.5 mg/day ( 5.1 )
• May cause serotonin syndrome when used with antidepressants (5.2)
• May cause falling asleep during activities of daily living (5.3)
• May cause hypotension/orthostatic hypotension (5.4)
• May cause or exacerbate dyskinesia (5.5)
• May cause hallucinations and psychotic-like behavior (5.6)
• May cause problems with impulse control and compulsive behaviors (5.7)
• Abrupt discontinuation may cause hyperpyrexia and confusion (5.8)
• May cause irritation of the buccal mucosa ( 5.9 )
• Increased risk for patients with phenylketonuria ( 5.10 )

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 daily. 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 olanzapine (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 following adverse reactions are discussed in more detail in the Warnings and Precautions section of labeling:

• Risk for Hypertension [see Warnings and Precautions (5.1) ]
• Risk of Serotonin Syndrome [see Warnings and Precautions (5.2) ]
• Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.3) ]
• Hypotension/Orthostatic Hypotension [see Warnings and Precautions (5.4) ]
• Dyskinesia [see Warnings and Precautions (5.5) ]
• Hallucinations/Psychotic-Like Behavior [see Warnings and Precautions (5.6) ]
• Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.7) ]
• Withdrawal Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.8) ]
• Irritation of the Buccal Mucosa [see Warnings and Precautions (5.9) ]
• Risk for Patients with Phenylketonuria [see Warnings and Precautions (5.10) ] The most common adverse reactions (incidence at least 3% greater than on placebo) are constipation, skin disorders, vomiting, dizziness, dyskinesia, insomnia, dyspnea, myalgia, and rash (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 reactions. 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. Incidence in Controlled Clinical Trials Table 1 lists the adverse reactions reported in the placebo-controlled trials after at least one dose of ZELAPAR (incidence 2% or greater). Table 1: Adverse Reactions Patients may have reported multiple adverse experiences during the study or at discontinuation; thus patients may be included in more than one category. in Double-Blind, Placebo-Controlled Trials with an Incidence ≥2% of Patients Treated with ZELAPAR and More Frequent than the Placebo Group Body System/ Adverse Event ZELAPAR 1.25/2.5 mg N=194 % Placebo N=98 % Body as a Whole Pain 8 7 Back Pain 5 3 Chest Pain 2 0 Cardiovascular System Hypertension 3 2 Digestive System Nausea 11 9 Stomatitis 5 4 Dyspepsia 5 3 Constipation 4 0 Vomiting 3 0 Diarrhea 2 1 Dysphagia 2 1 Flatulence 2 1 Tooth Disorder 2 1 Hemic and Lymphatic System Ecchymosis 2 0 Metabolic and Nutritional Disorders Hypokalemia 2 0 Musculoskeletal System Leg Cramps 3 1 Myalgia 3 0 Nervous System Dizziness 11 8 Headache 7 6 Insomnia 7 4 Dyskinesia 6 3 Dry Mouth 4 2 Hallucinations 4 2 Somnolence 3 2 Tremor 3 1 Ataxia 3 1 Depression 2 1 Respiratory System Pharyngitis 4 2 Rhinitis 7 6 Dyspnea 3 0 Skin and Appendages Rash 4 1 Skin Disorders Skin disorders represent any new skin abnormality that would not be characterized as rash or neoplastic lesion. These include events such as skin ulcer, fungal dermatitis, skin hypertrophy, contact dermatitis, herpes simplex, dry skin, sweating, urticaria, and pruritus. 6 2 Certain adverse reactions were reported at a higher frequency by patients ≥65 years of age compared to patients <65 years [see Use in Specific Populations ( 8.5 )] . No consistent differences in the incidences of adverse reactions were observed between male and female patients. There were insufficient data to assess the impact of race on the incidence of adverse reactions.

7.1 Opioid Drugs Because serious, sometimes fatal reactions have been precipitated with concomitant use of opioid drugs (e.g., meperidine and its derivatives, methadone, or tramadol) and MAOIs, including selective MAO-B inhibitors, concomitant use of these drugs with ZELAPAR is contraindicated [see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )] . At least 14 days should elapse between discontinuation of ZELAPAR and initiation of treatment with these drugs.

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 is contraindicated for concomitant use with other drugs in the MAOI class or other drugs that are potent inhibitors of monoamine oxidase (including linezolid, an oxazolidinone antibacterial, which also has reversible nonselective MAO inhibition activity) because of the increased risk for hypertensive crisis [see Contraindications (4) and Warnings and Precautions (5.1 )] . At least 14 days should elapse between discontinuation of ZELAPAR and initiation of treatment with other MAOIs.

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.

• Pregnancy: Based on animal data, may cause fetal harm ( 8.1 )
• Renal Impairment: ZELAPAR is not recommended in patients with severe renal impairment (CLcr <30 mL/min) ( 2.3 , 8.7 )

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of ZELAPAR in pregnant women. In animal studies, administration of selegiline during pregnancy was associated with developmental toxicity (decreased embryofetal and postnatal offspring growth and survival) at doses greater than those used clinically. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage in the indicated population is unknown. Data Animal Data In rats administered selegiline orally (5, 10, and 40 mg/kg/day) throughout the period of organogenesis, a decrease in fetal body weight was observed at the mid and high doses. The no-effect dose for embryofetal developmental toxicity in rats (5 mg/kg/day) is approximately 20 times the maximum recommended human dose (MRHD) of 2.5 mg/day on a mg/m 2 basis. In rabbits administered selegiline orally (5, 30, and 60 mg/kg/day) throughout the period of organogenesis, embryolethality was observed at the highest dose tested and reduced fetal body weight was observed at the mid and high doses. The no-effect dose for embryofetal developmental toxicity in rabbits (5 mg/kg/day) is approximately 40 times the MRHD on a mg/m 2 basis. In rats administered selegiline orally (0.3, 1, and 10 mg/kg/day) during gestation and lactation, decreases in offspring survival and body weights were observed at the highest dose tested. The no-effect dose for pre- and postnatal developmental toxicity (1 mg/kg/day) is approximately 4 times the MRHD on a mg/m 2 basis.

8.2 Lactation Risk Summary There are no data on the presence of selegiline or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Selegiline and metabolites were detected in rat milk at levels higher than those in maternal plasma. Because of the potential for serious adverse reactions in breastfed infants from ZELAPAR, including the potential for hypertensive reactions, advise a woman that breastfeeding is not recommended during treatment with ZELAPAR and for 7 days after the final dose.

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 )] .

Selegiline is an irreversible inhibitor of monoamine oxidase (MAO), which regulates the metabolic degradation of catecholamines and serotonin in the central nervous system and peripheral tissues. At recommended doses, selegiline is selective for MAO type B (MAO-B), the major form in the brain. Inhibition of MAO-B activity, by blocking the catabolism of dopamine, may result in increased dopamine levels; however, there is evidence that selegiline may act through other mechanisms to increase dopaminergic activity.