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Emsam (Selegiline Transdermal) - Warnings and Precautions

 
 



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 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 is not approved for use in pediatric patients. Furthermore, EMSAM at any dose should not be used in children under the age of 12, even when administered with dietary modifications. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)

 

WARNINGS

Clinical Worsening and Suicide Risk

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.

Table 1
AGE RANGE DRUG-PLACEBO DIFFERENCE IN
NUMBER OF CASES OF SUICIDALITY
PER 1,000 PATIENTS TREATED
Increases Compared to Placebo
< 18 14 additional cases
18-24 5 additional cases
Decreases Compared to Placebo
25-64 1 fewer case
≥ 65 6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

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 at any dose should not be used in children under the age of 12 years even when administered with dietary modifications. EMSAM is not approved for use in pediatric patients (See PRECAUTIONS: Pediatric Use).

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.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for EMSAM should be written for the smallest quantity of patches consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that EMSAM is not approved for use in treating bipolar depression.

Hypertensive Crisis

EMSAM is an irreversible MAO inhibitor. MAO is important in the catabolism of dietary amines (e.g., tyramine). In this regard, significant inhibition of intestinal MAO-A activity can impose a cardiovascular safety risk following the ingestion of tyramine-rich foods. As a class, MAOIs have been associated with hypertensive crises caused by the ingestion of foods with a high concentration of tyramine.

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 EMSAM 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 EMSAM, several Phase I tyramine challenge studies were conducted both with and without food (see PRECAUTIONS, Drug Interactions, Tyramine). In its entirety, the data for EMSAM 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 EMSAM 9 mg/24 hours, and the results from the Phase I tyramine challenge study in fed volunteers administered EMSAM 12 mg/24 hours (see PRECAUTIONS, Drug Interactions, Tyramine), patients receiving these doses should follow Dietary Modifications Required for Patients Taking EMSAM 9 mg/24 hours and 12 mg/24 hours.

If a hypertensive crisis occurs, EMSAM 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.

Dietary Modifications Required for Patients Taking EMSAM 9 mg/24 hours and 12 mg/24 hours

The following foods and beverages should be avoided beginning on the first day of EMSAM 9 mg/24 hours or 12 mg/24 hours treatment, and should continue to be avoided for 2 weeks after a dose reduction to EMSAM 6 mg/24 hours or following the discontinuation of EMSAM 9 mg/24 hours or 12 mg/24 hours.

Food and beverages to avoid and those which are acceptable 1:

Class of Food and Beverage Tyramine-Rich Foods andBeverages to Avoid Acceptable Foods and Drinks,
Containing No or Little Tyramine
Meat, Poultry, and Fish Air dried, aged and fermented meats,
sausages and salamis (including cacciatore,
hard salami and mortadella); pickled herring, and any spoiled or improperly stored meat, poultry, and fish (e.g., foods that have undergone changes in coloration, odor, or become moldy); spoiled or improperly stored animal livers
Fresh meat, poultry, and fish, including fresh processed meats (e.g., lunch meats, hot dogs, breakfast sausage, and cooked sliced ham)
Vegetables Broad bean pods (fava bean pods) All other vegetables
Dairy Aged cheeses Processed cheeses, mozzarella, ricotta cheese, cottage cheese, and yogurt
Beverages All varieties of tap beer and beers that have not been pasteurized so as to allow for ongoing fermentation As with other antidepressants, concomitant use of alcohol with EMSAM is not recommended. (Bottled and canned beers and wines contain little or no tyramine.)
Miscellaneous Concentrated yeast extract (e.g., Marmite),
sauerkraut, most soybean products (including soy sauce and tofu),
OTC supplements containing tyramine
Brewer's yeast, baker's yeast, soy milk, commercial chain restaurant pizzas prepared with cheeses low in tyramine

1

Adapted from K.I. Shulman, S.E. Walker, Psychiatric Annals 2001; 31:378-384


Use With Other Drugs Affecting Monoamine Activity

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, EMSAM (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, EMSAM 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 CONTRAINDICATIONS.)

Concomitant use of EMSAM 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 EMSAM. 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 EMSAM. At least 2 weeks should elapse after stopping EMSAM before starting therapy with buspirone HCl or a drug that is contraindicated with EMSAM.

PRECAUTIONS

General

Hypotension

As with other MAOIs, postural hypotension, sometimes with orthostatic symptoms, can occur with EMSAM therapy. In short-term, placebo-controlled depression studies, the incidence of orthostatic hypotension (i.e., a decrease of 10 mmHg or greater in mean blood pressure when changing position from supine or sitting to standing) was 9.8% in EMSAM -treated patients and 6.7% in placebo-treated patients. It is recommended that elderly patients treated with EMSAM be closely observed for postural changes in blood pressure throughout treatment. Dose increases should be made cautiously in patients with pre-existing orthostasis. Postural hypotension may be relieved by having the patient recline until the symptoms have abated. Patients should be cautioned to change positions gradually. Patients displaying orthostatic symptoms should have appropriate dosage adjustments as warranted.

Activation of Mania/Hypomania

During Phase III trials, a manic reaction occurred in 8/2036 (0.4%) patients treated with EMSAM. Activation of mania/hypomania can occur in a small proportion of patients with major affective disorder treated with other marketed antidepressants. As with all antidepressants, EMSAM should be used cautiously in patients with a history of mania.

Use in Patients With Concomitant Illness

Clinical experience with EMSAM in patients with certain concomitant systemic illnesses is limited. Caution is advised when using EMSAM in patients with disorders or conditions that can produce altered metabolism or hemodynamic responses.

EMSAM has not been systematically evaluated in patients with a history of recent myocardial infarction or unstable heart disease. Such patients were generally excluded from clinical studies during the product's premarketing testing.

No ECG abnormalities attributable to EMSAM were observed in clinical trials.

Although studies of phenylpropanolamine and pseudoephedrine did not reveal pharmacokinetic drug interactions with EMSAM, it is prudent to avoid the concomitant use of sympathomimetic agents, such as some decongestants.

Information for Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with EMSAM and should counsel them in its appropriate use. A patient Medication Guide about “ Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions ” is available for EMSAM. 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 EMSAM.

Clinical Worsening and Suicide Risk

Patients, their families and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment or when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly change in the medication.

General

Patients should be advised not to use oral selegiline while on EMSAM therapy.

Patients should be advised not to use carbamazepine or oxcarbazepine while on EMSAM 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 EMSAM 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 EMSAM therapy.

EMSAM (selegiline transdermal system) has not been shown to impair psychomotor performance; however, any psychoactive drug may potentially impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that EMSAM therapy does not impair their ability to engage in such activities.

Patients should be told that, although EMSAM has not been shown to increase the impairment of mental and motor skills caused by alcohol, the concomitant use of EMSAM 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 EMSAM 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 EMSAM is unknown.

Patients should be advised that certain tyramine-rich foods and beverages should be avoided while on EMSAM 9 mg/24 hours or EMSAM 12 mg/24 hours, and for 2 weeks following discontinuation of EMSAM at these doses (see CONTRAINDICATIONS and WARNINGS).

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 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 since 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 change position gradually if lightheaded, faint, or dizzy while on EMSAM therapy.

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during EMSAM therapy.

Patients should be advised to notify their physician if they are breast-feeding an infant.

While patients may notice improvement with EMSAM 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 EMSAM system into smaller portions.

For instructions on how to use EMSAM, see DOSAGE AND ADMINISTRATION, How to Use EMSAM.

Drug Interactions

The potential for drug interactions between EMSAM and a variety of drugs was examined in several human studies. Drug interaction studies described below were conducted with EMSAM 6 mg/24 hours. Although no differences are expected, drug interaction studies have not been conducted at higher doses (see In vitro Metabolism). In all of the studies described below, no drug-related adverse events were noted that required discontinuation of any subjects. Further, the incidence and nature of the adverse events were consistent with those known for selegiline or the test agent.

Alcohol

The pharmacokinetics and pharmacodynamics of alcohol (0.75 mg/kg) alone or in combination with EMSAM 6 mg/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/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.

Alprazolam

In subjects who had received EMSAM 6 mg/24 hours for 7 days, co-administration with alprazolam (15 mg/day), a CYP3A4/5 substrate, did not affect the pharmacokinetics of either selegiline or alprazolam.

Carbamazepine

Carbamazepine is an enzyme inducer and typically causes decreases in drug exposure; however, slightly increased levels of selegiline and its metabolites were seen after single application of EMSAM 6 mg/24 hours in subjects who had received carbamazepine (400 mg/day) for 14 days. Changes in plasma selegiline concentrations were nearly two-fold, and variable across the subject population. The clinical relevance of these observations is unknown. Carbamazepine is contraindicated with MAOIs, including selegiline (see CONTRAINDICATIONS).

Ibuprofen

In subjects who had received EMSAM 6 mg/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.

Ketoconazole

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

Levothyroxine

In healthy subjects who had received EMSAM 6 mg/24 hours for 10 days, single dose administration with levothyroxine (150 g) did not alter the pharmacokinetics of either selegiline or levothyroxine (as judged by T3 and T4 plasma levels).

Olanzapine

In subjects who had received EMSAM 6 mg/24 hours for 10 days, co-administration with olanzapine, a substrate for CYP1A2, CYP2D6, and possibly CYP2A6, did not affect the pharmacokinetics of either selegiline or olanzapine.

Phenylpropanolamine (PPA)

In subjects who had received EMSAM 6 mg/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. It is prudent to avoid the concomitant use of sympathomimetic agents with EMSAM.

Pseudoephedrine

EMSAM 6 mg/24 hours for 10 days, co-administered with pseudoephedrine (60 mg, 3 times a day) did not affect the pharmacokinetics of pseudoephedrine. The effect of pseudoephedrine on EMSAM was not examined. There were no clinically significant changes in blood pressure during pseudoephedrine administration alone, or in combination with EMSAM. Nonetheless, it is prudent to avoid the concomitant use of sympathomimetic agents with EMSAM.

Risperidone

In subjects who had received EMSAM 6 mg/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 either selegiline or risperidone.

Tyramine

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, a few food products (see WARNINGS) may contain large amounts of tyramine that represent a potential risk for patients with significant inhibition of intestinal MAO-A resulting from administration of MAOIs. Tyramine-containing nutritional supplements should be avoided by patients taking EMSAM (selegiline transdermal system).

Animal studies have indicated the transdermal administration of selegiline via EMSAM 6 mg/24 hours allows for critical levels of MAO inhibition to be achieved in the brain while avoiding levels of gastrointestinal inhibition. To further 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 - 65; 31 subjects > 50 years of age) were conducted to determine the pressor effects of oral tyramine with concurrent EMSAM treatment (6 mg/24 hours - 12 mg/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/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/24 hours or tranylcypromine 30 mg/day for 10 days. Mean pressor doses (TYR30) of tyramine capsules administered without food were 270 mg in subjects treated with EMSAM 6 mg/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/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/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 3 subjects at day 30 while on EMSAM 12 mg/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 < 0.003).

With the exception of one study (N = 153), the Phase III clinical development program was conducted without requiring a modified diet (N = 2553, 1606 at 6 mg/24 hours, and 947 at 9 mg/24 hours or 12 mg/24 hours). No hypertensive crises were reported in any patient receiving EMSAM.

In its entirety, the data for EMSAM 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 EMSAM 9 mg/24 hours and 12 mg/24 hours, patients receiving these doses should follow Dietary Modifications Required for Patients Taking EMSAM 9 mg/24 hours and 12 mg/24 hours. (See WARNINGS.)

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/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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In an oral carcinogenicity study in rats, selegiline given in the diet for 104 weeks was not carcinogenic up to the highest evaluable dose tested (3.5 mg/kg/day, which is 3 times the oral maximum recommended human dose on a mg/m2 basis).

Carcinogenicity studies have not been conducted with transdermal administration of selegiline.

Mutagenesis

Selegiline induced mutations and chromosomal damage when tested in the in vitro mouse lymphoma assay with and without metabolic activation. Selegiline was negative in the Ames assay, the in vitro mammalian chromosome aberration assay in human lymphocytes, and the in vivo oral mouse micronucleus assay.

Impairment of Fertility

A mating and fertility study was conducted in male and female rats at transdermal doses of 10, 30, and 75 mg/kg/day of selegiline (8, 24, and 60 times the maximum recommended human dose of EMSAM [12 mg/24 hours] on a mg/m2 basis). Slight decreases in sperm concentration and total sperm count were observed at the high dose; however, no significant adverse effects on fertility or reproductive performance were observed.

Teratogenic Effects - Pregnancy Category C

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 EMSAM [12 mg/24 hours] on a mg/m2 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 oral 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/m2 basis). A slight increase in visceral malformations was seen at the high dose. In an oral 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/m2 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. EMSAM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

The effect of EMSAM on labor and delivery in humans is unknown.

Nursing Mothers

In a prenatal and postnatal study of transdermal selegiline in rats, selegiline and metabolites were excreted into the milk of lactating rats. The levels of selegiline and metabolites in milk were approximately 15 and 5 times, respectively, steady-state levels of selegiline and metabolites in maternal plasma. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised administering EMSAM to a nursing mother.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk).

Anyone considering the use of EMSAM (selegiline transdermal system) in a child or adolescent must balance the potential risks with the clinical need.

Due to limited data, EMSAM at any dose should not be used in children under the age of 12 years even when administered with dietary modifications. EMSAM is not approved for use in pediatric patients.

Commercially available doses of EMSAM 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 EMSAM 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 EMSAM, when administered without dietary modifications.

Geriatric Use

One hundred ninety-eight (198) elderly (≥ 65 years of age) patients participated in clinical studies with EMSAM 6 mg/24 hours to 12 mg/24 hours. There were no overall differences in effectiveness between elderly and younger patients. In short-term, placebo-controlled depression trials, patients age 50 and older appeared to be at higher risk for rash (4.4% EMSAM vs. 0% placebo) than younger patients (3.4% EMSAM vs. 2.4% placebo).

Page last updated: 2009-08-03

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