Selegiline Hydrochloride

Dosage Forms And Strengths

ZELAPAR Orally Disintegrating Tablets contain 1.25 mg selegiline hydrochloride.

Storage And Handling

ZELAPAR Orally Disintegrating Tablets are available containing 1.25 mg selegiline hydrochloride in a Zydis® formulation. Each pale yellow tablet is imprinted with a stylized “V”. Ten tablets are contained in a moisture-resistant pouch and packaged in a carton. Neither the blister card nor the pouch is child-resistant.

ZELAPAR (selegiline hydrochloride) is available as: NDC 0187-0453-02, carton of 6 pouches (60 tablets).

Store at controlled room temperature, 25°C (77°F); excursions permitted to 15–30°C (59–86°F). Use within 3 months of opening pouch and immediately upon opening individual blister. Store blister tablets in pouch. Potency cannot be guaranteed after 3 months of opening the pouch.

Distributed by: Valeant Pharmaceuticals North America LLC Bridgewater, NJ 08807 USA. Manufactured by: Catalent Health, Inc. Swindon, Wiltshire, SN5 8RU, UK. Rev. 07/2014

Included as part of the PRECAUTIONS section.

Mechanism Of Action

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.

Pharmacodynamics

A pharmacodynamic study investigating daily ZELAPAR doses of 2.5 mg, 5 mg, and 10 mg for tyramine sensitivity showed that increased tyramine sensitivity resulting in increased blood pressure (because of MAO-A inhibition and decreased selectivity for MAO-B) occurred with dosing above the recommended level (2.5 mg daily). An increase in tyramine sensitivity for blood pressure responses appears to begin at a dose of 5 mg ZELAPAR daily [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

ZELAPAR disintegrates within seconds after placement on the tongue and is rapidly absorbed. Detectable levels of selegiline from ZELAPAR have been measured at 5 minutes after administration, the earliest time point examined.

Selegiline is more rapidly absorbed from the 1.25 or 2.5 mg dose of ZELAPAR (Tmax range: 10-15 minutes) than from the swallowed 5 mg selegiline tablet (Tmax range: 40-90 minutes). Mean (SD) maximum plasma concentrations of 3.34 (1.68) and 4.47 (2.56) ng/mL are reached after single dose of 1.25 and 2.5 mg ZELAPAR compared to 1.12 ng/mL (1.48) for the swallowed 5 mg selegiline tablets (given as 5 mg bid). On a dose-normalized basis, the relative bioavailability of selegiline from ZELAPAR is greater than from the swallowed formulation.

The pre-gastric absorption from ZELAPAR and the avoidance of first-pass metabolism results in higher concentrations of selegiline and lower concentrations of the metabolites compared to the 5 mg swallowed selegiline tablet.

Plasma C and AUC of ZELAPAR were dose proportional at doses between 2.5 and 10 mg daily.

When ZELAPAR is taken with food, the C and AUC of selegiline are about 60% of those seen when ZELAPAR is taken in the fasted state. Since ZELAPAR is placed on the tongue and absorbed through the oral mucosa, the intake of food and liquid should be avoided 5 minutes before and after ZELAPAR administration [see DOSAGE AND ADMINISTRATION].

Up to 85% of plasma selegiline is reversibly bound to proteins.

Following a single dose, the median elimination half-life of selegiline was 1.3 hours at the 1.25 mg dose. Under steady-state conditions, the median elimination half-life increases to 10 hours. Upon repeat dosing, accumulation in the plasma concentration of selegiline is observed both with ZELAPAR and the swallowed 5 mg tablet. Steady state is achieved after 8 days.

Selegiline is metabolized in vivo to l-methamphetamine and N-desmethylselegiline and subsequently to lamphetamine; which in turn are further metabolized to their hydroxymetabolites.

ZELAPAR also produces a smaller fraction of the administered dose recoverable as the metabolites than the conventional, swallowed formulation of selegiline.

In vitro metabolism studies indicate that CYP2B6 and CYP3A4 are involved in the metabolism of selegiline. CYP2A6 may play a minor role in the metabolism.

Following metabolism in the liver, selegiline is excreted primarily in the urine as metabolites (mainly as l-methamphetamine) and as a small amount in the feces.

Special Populations

The effect of age on the pharmacokinetics of selegiline following ZELAPAR administration has not been adequately characterized.

There are no differences between male and female subjects in overall (AUC∞), time to maximum exposure (Tmax), and elimination half-life (t½) after administration of ZELAPAR. Female subjects have an approximate 25% decrease in Cmax compared to male subjects. However, since the overall exposure (AUC∞) is not different between the genders, this pharmacokinetic difference is not likely to be clinically relevant.

No studies have been conducted to evaluate the effects of race on the pharmacokinetics of ZELAPAR.

Following once-daily dosing of ZELAPAR 2.5 mg to selegiline steady-state (10 days) in 6 subjects with mild renal impairment (CLcr >50 to 89 mL/min) and in 6 subjects with moderate renal impairment (CLcr >30 to 50 mL/min), AUC and Cmax of selegiline and desmethylselegiline were not substantially different from healthy subjects; however, methamphetamine and amphetamine exposures were increased by 34-67% in subjects with moderate renal impairment. Following once-daily dosing of ZELAPAR 1.25 mg to steady-state (10 days) in 6 end-stage renal disease patients, off dialysis, selegiline exposure was not substantially different from that in healthy subjects, however methamphetamine and amphetamine exposures were increased approximately 4-fold compared to healthy subjects [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

Subjects with mild hepatic impairment (Child-Pugh score 5 to 6), received once-daily dosing of ZELAPAR 2.5 mg to selegiline until they attained steady-state (10 days). The AUC and C of selegiline were 1.5-fold higher and the AUC and Cmax of the metabolite desmethylselegiline were 1.4- fold and 1.2-fold higher. In subjects with moderate hepatic impairment (Child-Pugh score 7 to 9), the AUC of selegiline and desmethylselegiline increased 1.5-fold and 1.8-fold, respectively, whereas the Cmax of selegiline and demethylselegiline were comparable to healthy subjects. Patients with severe hepatic impairment (Child-Pugh score >9) had a 4-fold increased AUC of selegiline, 3-fold increased C of selegiline, a 1.25-fold increased AUC of desmethylselegeline and 50% reduced Cmax of desmethylselegiline. Methamphetamine and amphetamine metabolite AUC values were not affected by liver dysfunction [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

No studies have been conducted to evaluate drug interactions on the pharmacokinetics of ZELAPAR. Effect of CYP3A inhibitor itraconazole: Itraconazole (200 mg QD) did not affect the pharmacokinetics of selegiline (single 10 mg oral, swallowed dose).

Although adequate studies to investigate the effect of CYP3A4-inducers on selegiline have not been performed, drugs that induce CYP3A4 (e.g., phenytoin, carbamazepine, nafcillin, phenobarbital, and rifampin) should be used with caution.

Drug Interaction Studies

No drug interaction studies have been conducted to evaluate the effects of other drugs on the pharmacokinetics of ZELAPAR or the effect of selegiline on other drugs. In vitro studies have demonstrated that selegiline is not an inhibitor of CYP450 enzymes. Selegiline and two of its metabolites, methamphetamine and desmethylselegiline, have little or no potential to induce CYP1A2 and CYP3A4/5 under clinical conditions.

Clinical Studies

The effectiveness of ZELAPAR as an adjunct to levodopa/carbidopa in the treatment of Parkinson’s disease was established in a multicenter, randomized, placebo-controlled trial (n=140; 94 received ZELAPAR, 46 received placebo) of three months’ duration. Patients randomized to ZELAPAR received a daily dose of 1.25 mg for the first 6 weeks, and a daily dose of 2.5 mg for the last 6 weeks. All patients were treated with concomitant levodopa products and could additionally have been on concomitant dopamine agonists, anticholinergics, amantadine, or any combination of these during the trial. COMT (catechol-O-methyl-transferase) inhibitors were not allowed.

Patients with idiopathic Parkinson’s disease receiving levodopa were enrolled if they demonstrated an average of at least 3 hours of “OFF” time per day on weekly diaries collected during a 2-week screening period. The patients enrolled had a mean duration of Parkinson’s disease of 7 years, with a range from 0.3 years to 22 years.

At selected times during the 12-week study, patients were asked to record the amount of “OFF,” “ON,” “ON with dyskinesia,” or “sleep” time per day for two separate days during the week prior to each scheduled visit. The primary efficacy outcome was the reduction in average percentage daily “OFF” time during waking hours from baseline to the end of the trial (averaging results at Weeks 10 and 12). Both treatment groups had an average of 7 hours per day of “OFF” time at baseline. Table 2 shows the primary efficacy results. Patients treated with ZELAPAR had a 13% reduction from baseline in daily “OFF” time, compared with a 5% reduction for patients treated with placebo. ZELAPAR-treated patients had an average reduction from baseline of “OFF” time of 2.2 hours per day, compared with a reduction of 0.6 hours in placebo-treated patients.

Table 2: Mean Percentage Change from Baseline in Daily "Off" Hours at End of Treatment (Average of Weeks 10 and 12) for Intent-to-Treat Population

Figure 1 shows the mean daily percent “OFF” time during treatment over the whole study period for patients treated with ZELAPAR vs. patients treated with placebo.

Figure 1: Mean daily percent "OFF" time during treatment over the whole study period for patients treated with ZELAPAR vs. patients treated with placebo

Dosage reduction of levodopa was allowed during this study if dopaminergic side effects, including dyskinesia and hallucinations, emerged. In those patients who had levodopa dosage reduced, the dose was reduced on average by 24% in ZELAPAR-treated patients and by 21% in placebo-treated patients.

No difference in effectiveness based on age (patients >66 years old vs. <66 years) was detected. The treatment effect size in males was twice that in females, but, given the size of this single trial, this finding is of doubtful significance.

Relatively selective MAO-B inhibitor.1 2 3

Parkinsonian Syndrome

Used as adjunctive therapy for symptomatic treatment of parkinsonian syndrome in patients who exhibit a deteriorating response to levodopa/carbidopa; designated an orphan drug by FDA for this condition.1 2 4 5 6 7 8 34 35 36 37 38 39 40 65 66 85 92 93 Appears to be most beneficial when used during the early stages of the “wearing off” effect.6 7 36 38 49 Especially useful in improving “end-of-dose” motor fluctuations.5 6 7 49 51 85

Has been used as monotherapy in patients with newly diagnosed parkinsonian syndrome†.5 7 8 37 53 54 55 56 73 84 85 93 130 Because selegiline is well tolerated and possibly neuroprotective (i.e., reduces the rate of progression of parkinsonian syndrome3 5 8 53 54 55 56 57 58 59 60 130 ), some clinicians initiate therapy with selegiline in such patients, reserving levodopa or another agent (i.e., dopamine agonist) until manifestations become severe enough to warrant more aggressive therapy.8 11 57 65 122 130 However, the manufacturers state that there is no evidence from controlled studies indicating that selegiline provides benefit in the absence of concurrent levodopa therapy.1 2

Alzheimer’s Disease

Has been used with equivocal results for the palliative treatment of mild to moderate dementia of the Alzheimer’s type† (Alzheimer’s disease, presenile or senile dementia).61 62 63 104 105 106 107 127 128

General

Concomitant Levodopa/Carbidopa Therapy

• In patients receiving concomitant levodopa/carbidopa, an attempt to reduce levodopa/carbidopa dosage may be made after 2–3 days of selegiline therapy.1 2

• Reduction in levodopa dosage of 10–30% may be needed if dyskinesias develop during selegiline therapy.1 2

• Further reduction in levodopa/carbidopa dosage may be possible during continued selegiline therapy.1 2

Administration

Oral Administration

Administer orally, usually in 2 equally divided doses daily1 2 5 6 11 (generally at breakfast and lunch to avoid interference with sleep1 2 8 11 ).

Dosage

Available as selegiline hydrochloride; dosage expressed in terms of the salt.1

Adults

Usual dosage: 5 mg twice daily.1 2 5 6 11

Some clinicians suggest an initial dosage of 2.5 mg daily in patients receiving concomitant levodopa/carbidopa;122 may increase dosage gradually up to 5 mg twice daily.8

Prescribing Limits

Adults

Maximum 10 mg daily.1 (See Risks Associated with MAO Inhibition under Cautions.)

Special Populations

No special population dosage recommendations.1

• Relatively selective MAO-B inhibitor.1 2 3 At dosage of 10 mg daily, selegiline hydrochloride inhibits cerebral MAO-B while having little effect on MAO-A in the GI tract and liver.1 2 4 5 22 32 84 At high dosages (e.g., 30–40 mg daily), the selectivity usually diminishes and the drug will inhibit MAO-B and MAO-A.1 2 4 5 22 32

• Principal physiologic action in the management of parkinsonian syndrome is irreversible inhibition of MAO-B within the nigrostriatal pathways in the CNS,1 2 4 5 22 thereby blocking microsomal metabolism of dopamine 1 2 4 5 22 and enhancing dopaminergic activity in the substantia nigra.1 2 4 5 22 Reduces the amount of levodopa required to maintain optimum dopamine concentrations in the brain of patients with parkinsonian syndrome.1 2 4 5 22

• May increase dopaminergic activity by mechanisms other than MAO-B inhibition (e.g., interference with dopamine reuptake at the synapse).1 2 5 84

• May prevent or delay neuronal death by protecting the nigral neurons from damage by oxygen free radicals produced through MAO-B activity.4 5 83 84 85 104 105

• Prevents MAO-B mediated production of the neurotoxin methyl-4-phenylpyridinium ion (MPP+) from phenyl-1,2,3,6-tetrahydropyridine (MPTP).4 5 83 84 If an MPTP-like substance contributes to the pathogenesis of parkinsonian syndrome, the inhibition of oxidation of such a substance may protect against its neurotoxic effects.4 5 83 84

• The ability to promote neuronal survival and neurite outgrowth and release of dopamine from intact neurons and also to block activation of N-methyl-d-aspartate (NMDA)-sensitive glutamate receptors may contribute to selegiline’s activity.1 2 4 5 22 23 43 78 79 80 81 82 83 84 85