CLINICAL PHARMACOLOGY
Pharmacodynamics
Selegiline (the drug substance of EMSAM) is an irreversible inhibitor of monoamine oxidase (MAO), an intracellular enzyme associated with the outer membrane of mitochondria. MAO exists as two isoenzymes, referred to as MAO-A and MAO-B. Selegiline has a greater affinity for MAO-B, compared to MAO-A. However, at antidepressant doses, selegiline inhibits both isoenzymes (see below).
The mechanism of action of EMSAM as an antidepressant is not fully understood, but is presumed to be linked to potentiation of monoamine neurotransmitter activity in the central nervous system (CNS) resulting from its inhibition of MAO activity. In an in vivo animal model used to test for antidepressant activity (Forced Swim Test), selegiline administered by transdermal patch exhibited antidepressant properties only at doses that inhibited both MAO-A and MAO-B activity in the brain. In the CNS, MAO-A and MAO-B play important roles in the catabolism of neurotransmitter amines such as norepinephrine, dopamine, and serotonin, as well as neuromodulators such as phenylethylamine. Other molecular sites of action have also been explored and in this regard, a direct pharmacological interaction may also occur between selegiline and brain neuronal alpha2B receptors. In in vitro receptor binding assays, selegiline has demonstrated affinity for the human recombinant adrenergic alpha2B receptor (Ki = 284 µM). No affinity [Ki > 10 µM] was noted at dopamine receptors, adrenergic beta3, glutamate, muscarinic M1-M5, nicotinic, or rolipram receptor/sites.
Pharmacokinetics
Absorption
Following dermal application of EMSAM to humans, 25% - 30% of the selegiline content on average is delivered systemically over 24 hours (range ~ 10% - 40%). Consequently, the degree of drug absorption may be 1/3 higher than the average amounts of 6 mg to 12 mg per 24 hours. Transdermal dosing results in substantially higher exposure to selegiline and lower exposure to metabolites compared to oral dosing, where extensive first-pass metabolism occurs (Figure 2). In a 10-day study with EMSAM administered to normal volunteers, steady-state selegiline plasma concentrations were achieved within 5 days of daily dosing. Absorption of selegiline is similar when EMSAM is applied to the upper torso or upper thigh. Mean (95% CI) steady-state plasma concentrations in healthy men and women following application of EMSAM to the upper torso or upper thigh are shown in Figure 3.
 Figure 2: Average AUCinf (ng•hr/mL) of selegiline and the three major metabolites estimated for a single, 24-hour application of an EMSAM 6 mg/24 hours patch and a single, 10 mg oral immediate release dose of selegiline HCl in 12 healthy male and female volunteers.  Figure 3: Average plasma (± 95% CI) selegiline concentrations in healthy male and female volunteers at steady-state after application of EMSAM 6 mg/24 hours to the upper torso.
Distribution
Following dermal application of radiolabeled selegiline to laboratory animals, selegiline is rapidly distributed to all body tissues. Selegiline rapidly penetrates the blood-brain barrier.
In humans, selegiline is approximately 90% bound to plasma protein over a 2 - 500 ng/mL concentration range. Selegiline does not accumulate in the skin.
In vivo Metabolism
Transdermally absorbed selegiline (via EMSAM) is not metabolized in human skin and does not undergo extensive first-pass metabolism. Selegiline is extensively metabolized by several CYP450-dependent enzyme systems (see In vitro Metabolism). Selegiline is metabolized initially via N-dealkylation or N-depropargylation to form N-desmethylselegiline or R(-)-methamphetamine, respectively. Both of these metabolites can be further metabolized to R(-)-amphetamine. These metabolites are all levorotatory (l-)enantiomers and no racemic biotransformation to the dextrorotatory form (i.e., S(+)-amphetamine or S(+)-methamphetamine) occurs. R(-)-methamphetamine and R(-)-amphetamine are mainly excreted unchanged in urine.
In vitro Metabolism
In vitro studies utilizing human liver microsomes demonstrated that several CYP450-dependent enzymes are involved in the metabolism of selegiline and its metabolites. CYP2B6, CYP2C9, and CYP3A4/5 appeared to be the major contributing enzymes in the formation of R(-)-methamphetamine from selegiline, with CYP2A6 having a minor role. CYP2A6, CYP2B6, and CYP3A4/5 appeared to contribute to the formation of R(-)-amphetamine from N-desmethylselegiline.
The potential for selegiline or N-desmethylselegiline to inhibit individual CYP450-dependent enzyme pathways was also examined in vitro with human liver microsomes. Each substrate was examined over a concentration range of 2.5 to 250 µM. Consistent with competitive inhibition, both selegiline and N-desmethylselegiline caused a concentration dependent inhibition of CYP2D6 at 10 - 250 µM and CYP3A4/5 at 25 - 250 µM. CYP2C19 and CYP2B6 were also inhibited at concentrations ≥ 100 µM.All inhibitory effects of selegiline and N-desmethylselegiline occurred at concentrations that are several orders of magnitude higher than concentrations seen clinically (highest predose concentration observed at a dose of 12 mg/24 hours at steady-state was 0.046 µM) (see PRECAUTIONS, Drug Interactions).
Excretion
Approximately 10% and 2% of a radiolabeled dose applied dermally, as a DMSO solution, was recovered in urine and feces respectively, with at least 63% of the dose remaining unabsorbed. The remaining 25% of the dose was unaccounted for. Urinary excretion of unchanged selegiline accounted for 0.1% of the applied dose with the remainder of the dose recovered in urine being metabolites.
The systemic clearance of selegiline after intravenous administration was 1.4 L/min, and the mean half-lives of selegiline and its three metabolites, R(-)-N-desmethylselegiline, R(-)-amphetamine, and R(-)-methamphetamine, ranged from 18 - 25 hours.
Population Subgroups
Age -- The effect of age on the pharmacokinetics or metabolism of selegiline during administration of EMSAM has not been systematically evaluated. The recommended dose for elderly patients is EMSAM 6 mg/24 hours. (See DOSAGE AND ADMINISTRATION.)
Gender -- No gender differences have been observed in the pharmacokinetics or metabolism of selegiline during administration of EMSAM. No adjustment of EMSAM dosage based on gender is needed.
Reduced Hepatic Function
After a single administration of EMSAM 6 mg/24 hours in 8 patients with mild or moderate liver impairment (Child-Pugh classifications of A or B), no differences in either the metabolism or pharmacokinetic behavior of selegiline or its metabolites were observed as compared with data of normal subjects. No adjustment of EMSAM dosage is required in patients with moderate liver impairment.
Reduced Renal Function
Data from a single dose study examining the pharmacokinetics of EMSAM 6 mg/24 hours in 12 patients with renal impairment suggest that mild, moderate, or severe renal impairment does not affect the pharmacokinetics of selegiline after transdermal application. Therefore, no adjustment of EMSAM dosage is required in patients with renal impairment.
Dermal Adhesion
Dermal adhesion of EMSAM was examined after application of 6 mg/24 hours selegiline patches for 10 days to the upper torso. Approximately 88% - 89% of 6 mg/24 hours selegiline patches applied to the upper torso exhibited < 10% lift with approximately 6% - 7% of patches becoming detached.
External Heat
The effect of direct heat applied to the EMSAM patch on the bioavailability of selegiline has not been studied. However, in theory, heat may result in an increase in the amount of selegiline absorbed from the EMSAM patch and produce elevated serum levels of selegiline. Patients should be advised to avoid exposing the EMSAM application site to external sources of direct heat, such as heating pads or electric blankets, heat lamps, saunas, hot tubs, heated water beds, and prolonged direct sunlight.
Clinical Efficacy Trials
The efficacy of EMSAM as a treatment for major depressive disorder was established in two placebo-controlled studies of 6 and 8 weeks duration in adult outpatients (ages 18 to 70 years) meeting DSM-IV criteria for major depressive disorder. In both studies, patients were randomized to double-blind treatment with EMSAM or placebo. The 6-week trial (N = 176) showed that EMSAM 6 mg/24 hours was significantly more effective than placebo on the 17-item Hamilton Depression Rating Scale (HAM-D). In an 8-week dose titration trial, depressed patients (N = 265), who received EMSAM or placebo at a starting dose of 6 mg/24 hours, with possible increases to 9 mg/24 hours or 12 mg/24 hours based on clinical response, showed significant improvement compared with placebo on the primary outcome measure, the 28-item HAM-D total score.
In another trial, 322 patients meeting DSM-IV criteria for major depressive disorder who had responded during an initial 10-week open-label treatment phase for about 25 days, on average, to EMSAM 6 mg/24 hours were randomized either to continuation of EMSAM at the same dose (N = 159) or to placebo (N = 163) under double-blind conditions for observation of relapse. About 52% of the EMSAM -treated patients, as well as about 52% of the placebo-treated patients, had discontinued treatment by week 12 of the double-blind phase. Response during the open-label phase was defined as 17-item HAM-D score < 10 at either week 8 or 9 and at week 10 of the open-label phase. Relapse during the double-blind phase was defined as follows: (1) a 17-item HAM-D score ≥ 14, (2) a CGI-S score of ≥ 3 (with at least a 2-point increase from double-blind baseline), and (3) meeting DSM-IV criteria for major depressive disorder on two consecutive visits ≥ 11 days apart. In the double-blind phase, patients receiving continued EMSAM experienced a significantly longer time to relapse.
An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender, or race.
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