Emsam

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Store the patches in their protective pouches and do not open a pouch until you are ready to apply the patch.

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

The following adverse reactions are discussed in greater detail in other sections of the label.

• Suicidal Thoughts and Behaviors [see WARNINGS AND PRECAUTIONS].
• Serotonin Syndrome [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
• Blood Pressure Elevation [see WARNINGS AND PRECAUTIONS].
• Activation of Mania/Hypomania [see WARNINGS AND PRECAUTIONS].
• External Heat [see WARNINGS AND PRECAUTIONS].

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates 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 rates observed in clinical practice.

The premarketing development program for EMSAM included selegiline exposures in patients and/or normal subjects from two different groups of studies: 702 healthy subjects in clinical pharmacology/pharmacokinetics studies and 2,036 exposures from patients in controlled and uncontrolled major depressive disorder clinical trials. The conditions and duration of treatment with EMSAM varied and included double-blind, open-label, fixed-dose, and dose titration studies of short-term and longer-term exposures. Safety was assessed by monitoring adverse reactions, physical examinations, vital signs, body weights, laboratory analyses, and ECGs.

Adverse reactions during exposure were obtained primarily by general inquiry and recorded by clinical investigators. In the tables and tabulations that follow, standard COSTART terminology has been used to classify reported adverse reactions. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Among 817 MDD patients treated with EMSAM at doses of either 3 mg per 24 hours (151 patients), 6 mg per 24 hours (550 patients) or 6 mg per 24 hours, 9 mg per 24 hours, and 12 mg per 24 hours (116 patients) in placebo-controlled trials of up to 8 weeks in duration, 7.1% discontinued treatment due to an adverse reaction as compared with 3.6% of 668 patients receiving placebo. The only adverse reaction associated with discontinuation, in at least 1% of EMSAM-treated patients at a rate at least twice that of placebo, was application site reaction (2% EMSAM vs. 0% placebo).

Table 2 enumerates adverse reactions that occurred at an incidence of 2% or more (rounded to the nearest percent) among 817 MDD patients treated with EMSAM in doses ranging from 3 to 12 mg per 24 hours in placebo-controlled trials of up to 8 weeks in duration. Reactions included are those occurring in 2% or more of patients treated with EMSAM and for which the incidence in patients treated with EMSAM was greater than the incidence in placebo-treated patients.

One adverse reaction was associated with a reporting of at least 5% in the EMSAM group, and a rate at least twice that in the placebo group, in the pool of short-term, placebo-controlled studies: application site reactions (see Application Site Reactions, below). In one such study which utilized higher mean doses of EMSAM than that in the entire study pool, the following reactions met these criteria: application site reactions, insomnia, diarrhea, and pharyngitis.

Table 2: Treatment-Emergent Adverse Reactions: Incidence in Placebo-Controlled Clinical Trials for Major Depressive Disorder with EMSAM1

In the pool of short-term, placebo-controlled major depressive disorder studies, application site reactions (ASRs) were reported in 24% of EMSAM-treated patients and 12% of placebo-treated patients. Most ASRs were mild or moderate in severity. ASRs led to dropout in 2% of EMSAM-treated patients and no placebo-treated patients. In one such study which utilized higher mean doses of EMSAM, ASRs were reported in 40% of EMSAM-treated patients and 20% of placebo-treated patients. Most of the ASRs in this study were described as erythema and most resolved spontaneously, requiring no treatment. When treatment was administered, it most commonly consisted of dermatological preparations of corticosteroids.

Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment.

Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence. Table 3 shows that the incidence rates of sexual side effects in patients with major depressive disorder are comparable to the placebo rates in placebo-controlled trials.

Table 3: Incidence of Sexual Side Effects in Placebo-Controlled Clinical Trials with EMSAM

There are no adequately designed studies examining sexual dysfunction with EMSAM treatment.

EMSAM and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure), and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. In the pool of short-term, placebo-controlled major depressive disorder studies, 3.0% of EMSAM-treated patients and 1.5% of placebo-treated patients experienced a low systolic blood pressure, defined as a reading less than or equal to 90 mmHg with a change from baseline of at least 20 mmHg. In one study which utilized higher mean doses of EMSAM, 6.2% of EMSAM-treated patients and no placebo-treated patients experienced a low standing systolic blood pressure by these criteria.

In the pool of short-term major depressive disorder trials, 9.8% of EMSAM-treated patients and 6.7% of placebo-treated patients experienced a notable orthostatic change in blood pressure, defined as a decrease of at least 10 mmHg in mean blood pressure with postural change.

In placebo-controlled studies (6 to 8 weeks), the incidence of patients who experienced at least 5% weight gain or weight loss is shown in Table 4.

Table 4: Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials with EMSAM

In these trials, the mean change in body weight among EMSAM-treated patients was a 1.2 lbs loss compared to 0.3 lbs gain in placebo-treated patients.

EMSAM and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with EMSAM.

Electrocardiograms (ECGs) from EMSAM (N = 817) and placebo (N = 668) groups in controlled studies were compared with respect to (1) mean change from baseline in various ECG parameters, and (2) the incidence of patients meeting criteria for clinically significant changes from baseline in these variables.

No clinically meaningful changes in ECG parameters from baseline to final visit were observed for patients in controlled studies.

The following listing does not include reactions: 1) already listed elsewhere in labeling, 2) for which a causal relationship to drug was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.

Cardiovascular System: Tachycardia.

Digestive System: Anorexia.

Nervous System: Agitation, amnesia, tremor, twitching.

Skin and Appendages: Pruritus.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of EMSAM.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous System: Convulsion and hypoesthesia.

Psychiatric System: Disorientation, hallucination (visual), and tension.

Mechanism Of Action

The mechanism of action of selegiline (the drug substance 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 irreversible inhibition of the enzyme monoamine oxidase (MAO).

Pharmacodynamics

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. In an in vivo animal model used to test for antidepressant activity (Forced Swim Test), selegiline administered by transdermal system 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.

In in vitro receptor binding assays, selegiline has demonstrated affinity for the human recombinant adrenergic α2B receptor (Ki = 0.3 mcM). No affinity [Ki greater than 10 mcM] was noted at dopamine receptors, adrenergic β3, glutamate, muscarinic M1-M5, nicotinic, or rolipram receptor/sites.

Selegiline (the drug substance of EMSAM) is an irreversible inhibitor of monoamine oxidase (MAO), a ubiquitous intracellular enzyme. MAO exists as two isoenzymes, referred to as MAO-A and MAO-B. Selegiline shows greater affinity for MAO-B; however, as selegiline concentration increases, this selectivity is lost with resulting dose-related inhibition of MAO-A. Intestinal MAO is predominantly type A, while in the brain both isoenzymes exist.

MAO plays a vital physiological role in terminating the biological activity of both endogenous and exogenous amines. In addition to their role in the catabolism of monoamines in the CNS, MAOs are also important in the catabolism of exogenous amines found in a variety of foods and drugs. MAO in the gastrointestinal tract (primarily type A) provides protection from exogenous amines with vasopressor actions, such as tyramine, which if absorbed intact can cause a hypertensive crisis, the so-called “cheese reaction”. If a large amount of tyramine is absorbed systemically, it is taken up by adrenergic neurons and causes norepinephrine release from neuronal storage sites with resultant elevation of blood pressure. While most foods contain negligible amounts or no tyramine, certain food products may contain large amounts of tyramine that represent a potential risk for hypertensive crisis [see WARNINGS AND PRECAUTIONS].

To define the risk of hypertensive crises with use of EMSAM, several Phase I tyramine challenge studies were conducted both with and without food. Fourteen tyramine challenge studies including 214 healthy subjects (age range 18 to 65; 31 subjects greater than 50 years of age) were conducted to determine the pressor effects of oral tyramine with concurrent EMSAM treatment (6 mg per 24 hours to 12 mg per 24 hours), measured as the dose of tyramine required to raise systolic blood pressure by 30 mmHg (TYR30). Studies were conducted with and without concomitant administration of food. Studies conducted with food are most relevant to clinical practice since tyramine typically will be consumed in food. A high-tyramine meal is considered to contain up to 40 mg of tyramine.

One study using a crossover design in 13 subjects investigated tyramine pressor doses (TYR30) after administration of EMSAM 6 mg per 24 hours and oral selegiline (5 mg twice daily) for 9 days. Mean pressor doses (TYR30) of tyramine capsules administered without food were 338 mg and 385 mg in subjects treated with EMSAM and oral selegiline, respectively.

Another study using a crossover design in 10 subjects investigated tyramine pressor doses after administration of EMSAM 6 mg per 24 hours or tranylcypromine 30 mg per day for 10 days. Mean pressor doses (TYR30) of tyramine capsules administered without food were 270 mg in subjects treated with EMSAM 6 mg per 24 hours and 10 mg in subjects treated with tranylcypromine.

In a third crossover study, tyramine without food was administered to 12 subjects. The mean tyramine pressor doses (TYR30) after administration of EMSAM 6 mg per 24 hours for 9 and 33 days were 292 mg and 204 mg, respectively. The lowest pressor dose was 50 mg in one subject in the 33-day group.

Tyramine pressor doses were also studied in 11 subjects after extended treatment with EMSAM 12 mg per 24 hours. At 30, 60, and 90 days, the mean pressor doses (TYR30) of tyramine administered without food were 95 mg, 72 mg, and 88 mg, respectively. The lowest pressor dose without food was 25 mg in three subjects at day 30 while on EMSAM 12 mg per 24 hours. Eight subjects from this study, with a mean tyramine pressor dose of 64 mg at 90 days, were subsequently administered tyramine with food, resulting in a mean pressor dose of 172 mg (2.7 times the mean pressor dose observed without food, p less than 0.003).

With the exception of one study (N = 153), the Phase III clinical development program was conducted without requiring a modified diet (N = 2,553, 1,606 at 6 mg per 24 hours, and 947 at 9 mg per 24 hours or 12 mg per 24 hours). No hypertensive crises were reported in any patient receiving EMSAM.

Overall, the data for EMSAM 6 mg per 24 hours support a recommendation that a modified diet is not required at this dose. Due to the more limited data available for EMSAM 9 mg per 24 hours and the results from the Phase I tyramine challenge study in fed volunteers administered EMSAM 12 mg per 24 hours, patients receiving these doses should follow Dietary Modifications Required for Patients Taking EMSAM 9 mg per 24 hours and 12 mg per 24 hours [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

Following dermal application of EMSAM to humans, 25% to 30% of the selegiline content on average is delivered systemically over 24 hours (range approximately 10% to 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 significantly higher exposure to selegiline with significantly lower exposure for all metabolites when compared to oral dosing, due to extensive first-pass metabolism. In a 10-day study with daily administration of EMSAM to healthy male and female volunteers, steady-state selegiline plasma concentrations indicated selegiline concentration-time profiles were comparable when EMSAM is applied to the upper torso or upper thigh, and absorption from these two sites of administration was equivalent.

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 to 500 ng per mL concentration range. Selegiline does not accumulate in the skin.

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 studies utilizing human liver microsomes demonstrated that several CYP450-dependent enzymes are involved in the metabolism of selegiline and its metabolites. CYP2B6, CYP2C9, CYP3A4 and CYP3A5 appeared to be the major contributing enzymes in the formation of R(-)-methamphetamine from selegiline, with CYP2A6 having a minor role. CYP2A6, CYP2B6, CYP3A4 and CYP3A5 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 mcM. Consistent with competitive inhibition, both selegiline and N-desmethylselegiline caused a concentration dependent inhibition of CYP2D6 at 10 to 250 mcM and CYP3A4 and CYP3A5 at 25 to 250 mcM. CYP2C19 and CYP2B6 were also inhibited at concentrations of 100 mcM or greater. 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 per 24 hours at steady-state was 0.046 mcM) [see DRUG INTERACTIONS].

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 per min, and the mean half-lives of selegiline and its three metabolites, R(-)-N-desmethylselegiline, R(-) amphetamine, and R(-)-methamphetamine, ranged from 18 to 25 hours.

Population Subgroups

Age: EMSAM should not be used in patients less than 18 years of age [see Use in Specific Populations].

Stratification of exposure data following treatment with EMSAM indicated that pre-dose (trough) selegiline plasma concentrations at steady state appeared higher (p = 0.12) in children aged < 12 years old, compared to adolescents aged ≥ 12 years as shown in Table 6.

Table 6: Steady State Selegiline Trough Concentrations Associated with Administration of EMSAM 15 mg/15 cm² Daily for 7 Days

Drug-Drug Interactions

Alcohol: The pharmacokinetics and pharmacodynamics of alcohol (0.75 mg per kg) alone or in combination with EMSAM 6 mg per 24 hours for 7 days of treatment was examined in 16 healthy volunteers. No clinically significant differences were observed in the pharmacokinetics or pharmacodynamics of alcohol or the pharmacokinetics of selegiline during co-administration. Although EMSAM has not been shown to increase the impairment of mental and motor skills caused by alcohol (0.75 mg per kg) and failed to alter the pharmacokinetic properties of alcohol, patients should be advised that the use of alcohol is not recommended while taking EMSAM [see DRUG INTERACTIONS].

Alprazolam: In subjects who had received EMSAM 6 mg per 24 hours for 7 days, co-administration with alprazolam (15 mg per day), a CYP3A4 and CYP3A5 substrate, did not affect the pharmacokinetics of alprazolam or selegiline [see DRUG INTERACTIONS].

Carbamazepine: Carbamazepine is an enzyme inducer and typically causes decreases in drug exposure; however, approximately 2-fold increased systemic exposure of selegiline and its metabolites, L-amphetamine and L-methamphetamine were seen after single application of EMSAM 6 mg per 24 hours in subjects who had received carbamazepine (400 mg per day) for 14 days. Changes in plasma selegiline concentrations were nearly 2-fold and variable across the subject population. Such increases may increase the risk of a hypertensive crisis when carbamazepine is used with EMSAM at any dose [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

Ibuprofen: In subjects who had received EMSAM 6 mg per 24 hours for 11 days, combined administration with the CYP2C9 substrate ibuprofen (800 mg single dose) did not affect the pharmacokinetics of either selegiline or ibuprofen [see DRUG INTERACTIONS].

Ketoconazole: Seven-day treatment with ketoconazole (200 mg per day), a potent inhibitor of CYP3A4, did not affect the steady-state pharmacokinetics of selegiline in subjects who received EMSAM 6 mg per 24 hours for 7 days and no differences in the pharmacokinetics of ketoconazole were observed [see DRUG INTERACTIONS].

Levothyroxine: In healthy subjects who had received EMSAM 6 mg per 24 hours for 10 days, single dose administration with levothyroxine (150 mcg) did not alter the pharmacokinetics of either selegiline or levothyroxine [see DRUG INTERACTIONS].

Olanzapine: In subjects who had received EMSAM 6 mg per 24 hours for 10 days, co-administration with olanzapine, a substrate for CYP1A2, CYP2D6, and possibly CYP2A6, did not affect the pharmacokinetics of selegiline or olanzapine [see DRUG INTERACTIONS].

Phenylpropanolamine (PPA): In subjects who had received EMSAM 6 mg per 24 hours for 9 days, co-administration with PPA (25 mg every 4 hours for 24 hours) did not affect the pharmacokinetics of PPA. There was a higher incidence of significant blood pressure elevations with the co-administration of EMSAM and PPA than with PPA alone, suggesting a possible pharmacodynamic interaction [see DRUG INTERACTIONS].

Pseudoephedrine: EMSAM 6 mg per 24 hours for 10 days, co-administered with pseudoephedrine (60 mg, 3 times a day) did not affect the pharmacokinetics of pseudoephedrine. There were no clinically significant changes in blood pressure during pseudoephedrine administration alone, or in combination with EMSAM [see DRUG INTERACTIONS].

Risperidone: In subjects who had received EMSAM 6 mg per 24 hours for 10 days, co-administration with risperidone (2 mg per day for 7 days), a substrate for CYP2D6, did not affect the pharmacokinetics of selegiline or risperidone [see DRUG INTERACTIONS].

Warfarin: Warfarin is a substrate for CYP2C9 and CYP3A4 metabolism pathways. In healthy volunteers titrated with Coumadin®# (warfarin sodium) to clinical levels of anticoagulation (INR of 1.5 to 2), co-administration with EMSAM 6 mg per 24 hours for 7 days did not affect the pharmacokinetics of the individual warfarin enantiomers. EMSAM did not alter the clinical pharmacodynamic effects of warfarin as measured by INR, Factor VII or Factor X levels [see DRUG INTERACTIONS].

Clinical Studies

Major Depressive Disorder

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 per 24 hours was statistically significantly more effective than placebo on the 17-item Hamilton Depression Rating Scale (HAM-D) total score (Study 1 in Table 7). In an 8-week dose titration trial, depressed patients (N = 265), who received EMSAM or placebo at a starting dose of 6 mg per 24 hours, with possible increases to 9 mg per 24 hours or 12 mg per 24 hours based on clinical response, showed significant improvement compared with placebo on the primary outcome measure, the 28-item HAM-D total score (Study 2 in Table 7).

Table 7: Primary Efficacy Results from Short-Term Trials

In another trial (Study 3), 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 per 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 total score less than 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 of 14 or greater, (2) a CGI-S score of 3 or greater (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 at least 11 days apart. In the double-blind phase, patients receiving continued EMSAM experienced a significantly longer time to relapse (Figure 2).

Figure 2: Kaplan-Meier Estimates of Cumulative Percent of Patients with Relapse (Study 3)

An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender, or race.

• Somerset Pharmaceuticals, Inc.

Emsam can cause serious and potentially life-threatening reactions if used with certain other medicines. Do not take the following medicines while using Emsam, and for 2 weeks after stopping Emsam:

• other medicines to treat depression (antidepressants) including other MAOI medicines
• medicine which contains selegiline (such as Eldepryl)
• St. John’s wort (a herbal supplement)
• Demerol (meperidine), or medicines that contain meperidine (a narcotic pain medicine) or the pain medicines tramadol, methadone, or propoxyphene
• Tegretol (carbamazepine), or other medicines that contain carbamazepine (a seizure medicine)
• Trileptal (oxcarbazepine), or other medicines that contain oxcarbazepine (a seizure medicine)
• Cold or cough preparations that contain dextromethorphan
• Flexeril or other medicines that contain cyclobenzaprine (a medicine used to treat muscle spasms)
• decongestant medicines, found in many products to treat cold symptoms
• over-the-counter diet pills or herbal weight-loss products
• any herbal or dietary supplement that contains tyramine
• medicines called amphetamines, also called stimulants or “uppers”
• BuSpar (buspirone), an anxiety medicine

Some of these medicines will have to be stopped for at least a week before you can start using Emsam. Be sure to tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

This is not a complete list of Emsam drug interactions. Ask your doctor or pharmacist for more information.

Use Emsam exactly as prescribed by your doctor. Use only one patch at a time. Change the patch once a day (every 24 hours). Choose a time of day that works best for you.

• Your doctor will prescribe a dose of Emsam based on your condition. Your doctor may change your dose if needed.
• Talk to your doctor often about your condition. You may notice an improvement in your condition with Emsam therapy after several weeks. Do not stop or change your treatment with Emsam without talking to your doctor.
• Make sure you do not eat foods or drink beverages that contain high amounts of tyramine while using Emsam 9 mg/24 hours or Emsam 12 mg/24 hours patches, and for 2 weeks after you stop using them. (See "Food Interactions" section.)
• If you use more than one Emsam patch at a time, remove Emsam patches right away and call your doctor or local Poison Control Center.
• 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.
• Tell your doctor if you plan to have surgery. Also, tell your surgeon that you take Emsam. Emsam should be stopped 10 days before you have elective surgery.
• Do not take other medicines while using selegiline or for 2 weeks after you stop using it unless your doctor has told you it is okay. See “Drug Precautions".
• Do not drive or operate dangerous machinery until you know how Emsam affects you. Selegiline may reduce your judgment, ability to think, or coordination.
• Drinking alcoholic beverages is not recommended while using Emsam.

How to use and apply an Emsam patch

• Apply a new Emsam patch every day (24 hours).
• Wear only one Emsam patch at a time. Wear one Emsam patch all the time until it is time to apply a new one.
• Remove a used patch before applying a new one.
• Change the patch at the same time each day.
• Apply an Emsam patch to dry, smooth skin on your upper chest or back (below the neck and above the waist), upper thigh, or to the outer surface of the upper arm. Choose a new site each time you change your patch. Do not use the same site 2 days in a row.
• Apply an Emsam patch to an area of skin that is not hairy, oily, irritated, broken, scarred, or calloused. Do not place the patch where your clothing is tight, which could cause the patch to rub off.
• After you have selected the site for your patch, wash the area gently and well with soap and warm water. Rinse until all soap is removed. Dry the area with a clean dry towel.
• Just before you apply the patch, remove it from its sealed pouch. Do not keep or store the patch outside of the sealed pouch. Never cut an Emsam patch into smaller pieces to use.
• Remove half of the protective backing and throw it away. Try not to touch the exposed side (sticky side) of the patch, because the medicine could come off on your fingers. With your fingertips, press the sticky side of the patch firmly against the skin site that was just washed and dried. Remove the second half of the protective liner and press the remaining sticky side firmly against your skin. Make sure that the patch is flat against the skin (there should be no bumps or folds in the patch) and is sticking securely. Be sure the edges are stuck to the skin surface.
• After you have applied the patch, wash your hands well with soap and water to remove any medicine that may have gotten on them. Do not touch your eyes until after you have washed your hands.
• After 24 hours, remove the patch slowly and carefully to avoid damaging the skin. Do not touch the sticky side. As soon as you have removed the patch, fold it so that the sticky side sticks to itself.
• Throw away the folded patch so that children and pets cannot reach it. This patch still contains some medicine and could harm a child or pet.
• Gently wash the old application site with warm water and a mild soap to remove any sticky material (adhesive) that stays on your skin after removing the patch. A small amount of baby oil may also be used to remove any adhesive. You may need to use a medical adhesive removal pad that you can get from your pharmacist. Alcohol or other dissolving liquids such as nail polish remover may cause skin irritation and should not be used.
• Wash your hands with soap and water.
• If the patch becomes loose, press it back in place. If your Emsam patch falls off, apply a new Emsam patch to a new site and resume your normal schedule for changing patches.
• If you forget to change your patch after 24 hours, remove the old patch, put on a new patch in a different area and continue to follow your original schedule.

If you take too much this medication, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If this medication is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Store patches in pouch until ready for use.

Emsam (selegiline transdermal system) is a monoamine oxidase inhibitor (MAOI) indicated for the treatment of adults with major depressive disorder (MDD) [see Clinical Studies (14)].

Signs and Symptoms

Emsam overdosage may resemble overdosage with other nonselective, oral MAOI antidepressants and present with any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, convulsions, coma, rapid and irregular pulse, hypertension, hypotension and vascular collapse, precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin.

Management of Overdose

There are no specific antidotes for Emsam.

If symptoms of overdosage occur, immediately remove the Emsam system and institute appropriate supportive therapy. For contemporary information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222.

Delays of up to 12 hours between ingestion of drug and the appearance of signs may occur, and peak effects may not be observed for 24 to 48 hours. Since death has been reported following overdosage with MAOI agents, hospitalization with close monitoring during this period is strongly recommended.

In order to avoid the occurrence of hypertensive crisis (“cheese reaction”), dietary tyramine should be restricted for several weeks beyond recovery to permit regeneration of the peripheral MAO-A isoenzyme.

Major Depressive Disorder

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 per 24 hours was statistically significantly more effective than placebo on the 17-item Hamilton Depression Rating Scale (HAM-D) total score (Study 1 in Table 7). In an 8-week dose titration trial, depressed patients (N = 265), who received Emsam or placebo at a starting dose of 6 mg per 24 hours, with possible increases to 9 mg per 24 hours or 12 mg per 24 hours based on clinical response, showed significant improvement compared with placebo on the primary outcome measure, the 28-item HAM-D total score (Study 2 in Table 7).

In another trial (Study 3), 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 per 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 total score less than 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 of 14 or greater, (2) a CGI-S score of 3 or greater (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 at least 11 days apart. In the double-blind phase, patients receiving continued Emsam experienced a significantly longer time to relapse (Figure 2).

Figure 2. Kaplan-Meier Estimates of Cumulative Percent of Patients with Relapse (Study 3)

Figure 2. Kaplan-Meier Estimates of Cumulative Percent of Patients with Relapse (Study 3)

An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender, or race.

This Medication Guide has been approved by the U.S. Food and Drug Administration
Issued: 07/2017