Emsam Information
Emsam (Selegiline) Suicidality And Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Emsam (Selegiline) or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised for the need for close observation and communication with the prescriber. Emsam (Selegiline) is not approved for use in pediatric patients. Furthermore, Emsam (Selegiline) at any dose should not be used in children under the age of 12, even when administered with dietary modifications. (See , , and .)
Emsam (Selegiline) Description
Selegiline base is a colorless to yellow liquid, chemically described as (-)-()-Methyl--[(1)-1-methyl-2-phenylethyl]prop-2-yn-1-amine. It has an empirical formula of CHN and a molecular weight of 187.30. The structural formula is:
Emsam (Selegiline) Clinical Pharmacology
Selegiline (the drug substance of ) 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 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 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 αreceptors. In receptor binding assays, selegiline has demonstrated affinity for the human recombinant adrenergic α receptor (K = 284 µM). No affinity [K > 10 µM] was noted at dopamine receptors, adrenergic β, glutamate, muscarinic M-M, nicotinic, or rolipram receptor/sites.
The efficacy of 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 or placebo. The 6-week trial (N = 176) showed that 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 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 6 mg/24 hours were randomized either to continuation of at the same dose (N = 159) or to placebo (N = 163) under double-blind conditions for observation of relapse. About 52% of the -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
An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender, or race.
Emsam (Selegiline) Indications And Usage
The efficacy of in the treatment of major depressive disorder was established in 6- and 8-week placebo-controlled trials of outpatients with diagnoses of DSM-IV category of major depressive disorder (see ).
A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and suicide attempt or suicidal ideation.
The benefit of maintaining patients with major depressive disorder on therapy with after achieving a responder status for an average duration of about 25 days was demonstrated in a controlled trial (see ). The physician who elects to use for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see ).
The antidepressant action of in hospitalized depressed patients has not been studied.
Emsam (Selegiline) Contraindications
Carbamazepine and oxcarbazepine are contraindicated in patients taking selegiline (see ).
As with other MAOIs, is contraindicated for use with sympathomimetic amines, including amphetamines as well as cold products and weight-reducing preparations that contain vasoconstrictors (e.g., pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine).
As with other MAOIs, patients taking should not undergo elective surgery requiring general anesthesia. Also, they should not be given cocaine or local anesthesia containing sympathomimetic vasoconstrictors. should be discontinued at least 10 days prior to elective surgery. If surgery is necessary sooner, benzodiazepines, mivacurium, rapacuronium, fentanyl, morphine, and codeine may be used cautiously.
As with other MAOIs, is contraindicated for use in patients with pheochromocytoma.
Emsam (Selegiline) Warnings
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorders (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressants in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.
No suicides occurred in any of the pediatric trials.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
Due to the limited data, Emsam (Selegiline) at any dose should not be used in children under the age of 12 years even when administered with dietary modifications. Emsam (Selegiline) is not approved for use in pediatric patients (See ).
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Emsam (Selegiline)
Hypertensive crises, which in some cases may be fatal, are characterized by some or all of the following symptoms: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea, vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin), dilated pupils, and photophobia. Either tachycardia or bradycardia may be present and can be associated with constricting chest pain. Intracranial bleeding has been reported in association with the increase in blood pressure. Patients should be instructed as to the signs and symptoms of severe hypertension and advised to seek immediate medical attention if these signs or symptoms are present.
In 6 of the 7 clinical studies conducted with at doses of 6 mg/24 hours - 12 mg/24 hours, patients were not limited to a modified diet typically associated with this class of compounds. Although no hypertensive crises were reported as part of the safety assessment, the likelihood of developing this reaction cannot be fully determined since the amount of tyramine typically consumed during the course of treatment is not known and blood pressure was not continuously monitored.
To further define the likelihood of hypertensive crises with use of , several Phase I tyramine challenge studies were conducted both with and without food (see ). In its entirety, the data for 6 mg/24 hours support the recommendation that a modified diet is not required at this dose. Due to the more limited data available for 9 mg/24 hours, and the results from the Phase I tyramine challenge study in fed volunteers administered 12 mg/24 hours (see ), patients receiving these doses should follow .
If a hypertensive crisis occurs, should be discontinued immediately and therapy to lower blood pressure should be instituted immediately. Phentolamine 5 mg or labetalol 20 mg administered slowly intravenously is recommended therapy to control hypertension. Alternately, nitroprusside delivered by continuous intravenous infusion may be used. Fever should be managed by means of external cooling. Patients must be closely monitored until symptoms have stabilized.
The following foods and beverages should be avoided beginning on the first day of 9 mg/24 hours or 12 mg/24 hours treatment, and should continue to be avoided for 2 weeks after a dose reduction to 6 mg/24 hours or following the discontinuation of 9 mg/24 hours or 12 mg/24 hours.
Food and beverages to avoid and those which are acceptable:
Serious, sometimes fatal, central nervous system (CNS) toxicity referred to as the “serotonin syndrome” has been reported with the combination of non-selective MAOIs with certain other drugs, including tricyclic or selective serotonin reuptake inhibitor antidepressants, amphetamines, meperidine, or pentazocine. Serotonin syndrome is characterized by signs and symptoms that may include hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuations of the vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Similar less severe syndromes have been reported in a few patients receiving a combination of oral selegiline with one of these agents.
Therefore, (selegiline transdermal system) should not be used in combination with selective serotonin reuptake inhibitors (SSRIs, e.g., fluoxetine, sertraline, paroxetine); dual serotonin and norepinephrine reuptake inhibitors (SNRIs, e.g., venlafaxine and duloxetine); tricyclic antidepressants (TCAs, e.g., imipramine and amitriptyline); oral selegiline or other MAOIs (e.g., isocarboxazid, phenelzine, and tranylcypromine); mirtazapine; bupropion hydrochloride; meperidine and analgesic agents such as tramadol, methadone, and propoxyphene; the antitussive agent dextromethorphan; or St. John’s wort because of the risk of life-threatening adverse reactions. Also, should not be used with sympathomimetic amines, including amphetamines as well as cold products and weight-reducing preparations that contain vasoconstrictors (e.g., pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine). (See .)
Concomitant use of with buspirone hydrochloride is not advised since several cases of elevated blood pressure have been reported in patients taking MAOIs who were then given buspirone HCl.
After stopping treatment with SSRIs; SNRIs; TCAs; MAOIs; meperidine and analgesics such as tramadol, methadone, and propoxyphene; dextromethorphan; St. John’s wort; mirtazapine; bupropion HCl; or buspirone HCl, a time period equal to 4 - 5 half-lives (approximately 1 week) of the drug or any active metabolite should elapse before starting therapy with . Because of the long half-life of fluoxetine and its active metabolite, at least 5 weeks should elapse between discontinuation of fluoxetine and initiation of treatment with . At least 2 weeks should elapse after stopping before starting therapy with buspirone HCl or a drug that is contraindicated with .
Emsam (Selegiline) Precautions
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with and should counsel them in its appropriate use. A patient about “” is available for . The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking .
Patients should be advised not to use oral selegiline while on therapy.
Patients should be advised not to use carbamazepine or oxcarbazepine while on therapy.
Patients should be advised not to use meperidine and analgesic agents such as tramadol, methadone, and propoxyphene.
Patients should be advised not to use sympathomimetic agents while on therapy.
Patients should be advised not to use selective serotonin reuptake inhibitors (SSRIs, e.g., fluoxetine, sertraline, paroxetine, and St. John’s wort), dual serotonin and norepinephrine reuptake inhibitors (SNRIs, e.g., venlafaxine and duloxetine), tricyclic antidepressants (TCAs, e.g., imipramine and amitriptyline), mirtazapine, oral selegiline or other MAOIs (e.g., isocarboxazid, phenelzine, and tranylcypromine), bupropion hydrochloride or buspirone hydrochloride while on therapy.
Patients should be told that, although has not been shown to increase the impairment of mental and motor skills caused by alcohol, the concomitant use of and alcohol in depressed patients is not recommended.
Patients should be advised to notify their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbals, because of the potential for drug interactions. Patients should also be advised to avoid tyramine-containing nutritional supplements and any cough medicine containing dextromethorphan.
Patients should be advised to use exactly as prescribed. The need for dietary modifications at higher doses should be explained, and a brief description of hypertensive crisis provided. Rare hypertensive reactions with oral selegiline at doses recommended for Parkinson’s disease and associated with dietary influences have been reported. The clinical relevance to is unknown.
Patients should be advised that certain tyramine-rich foods and beverages should be avoided while on 9 mg/24 hours or 12 mg/24 hours, and for 2 weeks following discontinuation of at these doses (see and ).
Patients should be instructed to immediately report the occurrence of the following acute symptoms: severe headache, neck stiffness, heart racing or palpitations, or other sudden or unusual symptoms.
Patients should be advised to avoid exposing the 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 since heat may result in an increase in the amount of selegiline absorbed from the patch and produce elevated serum levels of selegiline.
Patients should be advised to change position gradually if lightheaded, faint, or dizzy while on therapy.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
Patients should be advised to notify their physician if they are breast-feeding an infant.
While patients may notice improvement with therapy in 1 to several weeks, they should be advised of the importance of continuing drug treatment as directed.
Patients should be advised not to cut the system into smaller portions.
For instructions on how to use , see .
In an embryofetal development study in rats, dams were treated with transdermal selegiline during the period of organogenesis at doses of 10, 30, and 75 mg/kg/day (8, 24, and 60 times the maximum recommended human dose [MRHD] of [12 mg/24 hours] on a mg/m basis). At the highest dose there was a decrease in fetal weight and slight increases in malformations, delayed ossification (also seen at the mid dose), and embryofetal post-implantation lethality. Concentrations of selegiline and its metabolites in fetal plasma were generally similar to those in maternal plasma. In an embryofetal development study in rats, a decrease in fetal weight occurred at the highest dose tested (36 mg/kg; no-effect dose 12 mg/kg); no increase in malformations was seen.
In an embryofetal development study in rabbits, dams were treated with transdermal selegiline during the period of organogenesis at doses of 2.5, 10, and 40 mg/kg/day (4, 16, and 64 times the MRHD on a mg/m basis). A slight increase in visceral malformations was seen at the high dose. In an embryofetal development study in rabbits, increases in total resorptions and post-implantation loss, and a decrease in the number of live fetuses per dam, occurred at the highest dose tested (50 mg/kg; no-effect dose 25 mg/kg).
In a prenatal and postnatal development study in rats, dams were treated with transdermal selegiline at doses of 10, 30, and 75 mg/kg/day (8, 24, and 60 times the MRHD on a mg/m basis) on days 6 - 21 of gestation and days 1 - 21 of the lactation period. An increase in post-implantation loss was seen at the mid and high doses, and an increase in stillborn pups was seen at the high dose. Decreases in pup weight (throughout lactation and post-weaning periods) and survival (throughout lactation period), retarded pup physical development, and pup epididymal and testicular hypoplasia, were seen at the mid and high doses. Retarded neurobehavioral and sexual development was seen at all doses. Adverse effects on pup reproductive performance, as evidenced by decreases in implantations and litter size, were seen at the high dose. These findings suggest persistent effects on the offspring of treated dams. A no-effect dose was not established for developmental toxicity. In this study, concentrations of selegiline and its metabolites in milk were ~ 15 and 5 times, respectively, the concentrations in plasma, indicating that the pups were directly dosed during the lactation period.
There are no adequate and well-controlled studies in pregnant women. should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Safety and effectiveness in the pediatric population have not been established (see and ).
Anyone considering the use of (selegiline transdermal system) in a child or adolescent must balance the potential risks with the clinical need.
Due to limited data, at any dose should not be used in children under the age of 12 years even when administered with dietary modifications. is not approved for use in pediatric patients.
Commercially available doses of have not been studied in children under the age of 12 years. Limited pharmacokinetic data with lower doses than in the commercially available formulations suggest that children under the age of 12 years treated with may be exposed to increased levels of selegiline compared to adolescents or adults. Therefore, the possibility exists for an increased risk of hypertensive crisis, even at the lowest dose of commercially available , when administered without dietary modifications.
Emsam (Selegiline) Adverse Events
The premarketing development program for included selegiline exposures in patients and/or normal subjects from two different groups of studies: 702 healthy subjects in clinical pharmacology/pharmacokinetics studies and 2036 exposures from patients in controlled and uncontrolled major depressive disorder clinical trials. The conditions and duration of treatment with 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 events, physical examinations, vital signs, body weights, laboratory analyses, and ECGs.
Adverse events 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 events. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
Emsam (Selegiline) Drug Abuse And Dependence
Emsam (Selegiline)
Several animal studies have assessed potential for abuse and/or dependence with chronic selegiline administration. None of these studies demonstrated a potential for selegiline abuse or dependence.
Emsam (Selegiline) Overdosage
There are no specific antidotes for . If symptoms of overdosage occur, immediately remove the system and institute appropriate supportive therapy. For contemporary consultation on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222.
Emsam (Selegiline) Dosage And Administration
Patients should be informed that tyramine-rich foods and beverages should be avoided beginning on the first day of 9 mg/24 hours or 12 mg/24 hours treatment and should continue to be avoided for 2 weeks after a dose reduction to 6 mg/24 hours or following the discontinuation of 9 mg/24 hours or 12 mg/24 hours (see ).
Emsam (Selegiline) at any dose should not be used in children under the age of 12 years even when administered with dietary modifications. Emsam (Selegiline) is not approved for use in pediatric patients.
No dosage adjustment is required for patients with mild to moderate renal or hepatic impairment. The recommended dose for elderly patients (≥ 65 years) is 6 mg/24 hours daily. Dose increases, in the elderly, should be made with caution and patients should be closely observed for postural changes in blood pressure throughout treatment.
Emsam (Selegiline) How Supplied
They are available as:NDC 49502-900-30: 6 mg/24 hours (20 mg/20 cm) box of 30 transdermal systems.NDC 49502-901-30: 9 mg/24 hours (30 mg/30 cm) box of 30 transdermal systems.NDC 49502-902-30: 12 mg/24 hours (40 mg/40 cm) box of 30 transdermal systems.
Emsam (Selegiline) Storage And Disposal
Store at 20º to 25º C (68º to 77º F). [See USP Controlled Room Temperature.] Do not store outside of the sealed pouch. Apply immediately upon removal from the protective pouch. Discard used in household trash in a manner that prevents accidental application or ingestion by children, pets or others.
DISTRIBUTED BY:Dey Pharma, L.P.Napa, CA 94558
MANUFACTURED FOR:Somerset Pharmaceuticals, Inc.Morgantown, WV 26505
JANUARY 2010Emsam (Selegiline) :PIR803-943-01
Emsam (Selegiline) Medication Guide Emsam [em Sam] Generic Name: Selegiline Transdermal System
Read this Medication Guide carefully before you start using and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about , ask your doctor or pharmacist.
Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This section of the Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines.
The most common side effect of is a skin reaction where the patch is placed. You may see mild redness at the site when a patch is removed. This redness should go away within several hours after removing the patch. If irritation or itching continues, tell your doctor.
These are not all the side effects of . For more information, ask your doctor or pharmacist.
Medicines are sometimes prescribed for conditions that are not mentioned in Medication Guides. Do not give to other people, even if they have the same symptoms you have. It may harm them.
This Medication Guide summarizes the most important information about . If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about that is written for health professionals.
DISTRIBUTED BY:Dey Pharma, L.P.Napa, CA 94558
MANUFACTURED FOR:Somerset Pharmaceuticals, Inc.Morgantown, WV 26505
*Prozac is a registered trademark of Eli Lilly and Company*Zoloft is a registered trademark of Pfizer Pharmaceuticals*Anafranil is a registered trademark of Mallinckrodt Inc.*Demerol is a registered trademark of Sanofi*Eldepryl is a registered trademark of Somerset Pharmaceuticals *Tegretol and Trileptal are registered trademarks of Novartis Pharmaceuticals Corporation*Flexeril is a registered trademark of ALZA Corporation*BuSpar is registered trademark of Bristol-Myers Squibb Company
JANUARY 2010Emsam (Selegiline) :PLR803-944-01
Emsam (Selegiline)
Emsam (Selegiline)
Emsam (Selegiline)
