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)].

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EMSAM should be applied to dry, intact skin on the upper torso (below the neck and above the waist), upper thigh or the outer surface of the upper arm once every 24 hours. The recommended starting dose and target dose for EMSAM is 6 mg per 24 hours. EMSAM has been systematically evaluated and shown to be effective in a dose range of 6 mg per 24 hours to 12 mg per 24 hours. However, the trials were not designed to assess if higher doses are more effective than the lowest effective dose of 6 mg per 24 hours. Based on clinical judgment, if dose increases are indicated for individual patients, they should occur in dose increments of 3 mg per 24 hours (up to a maximum dose of 12 mg per 24 hours) at intervals of no less than 2 weeks. Full antidepressant effect may be delayed.

Patients should be informed that tyramine-rich foods and beverages should be avoided beginning on the first day of EMSAM 9 mg per 24 hours or 12 mg per 24 hours treatment and should continue to be avoided for 2 weeks after a dose reduction to EMSAM 6 mg per 24 hours or following the discontinuation of EMSAM 9 mg per 24 hours or 12 mg per 24 hours [see Warnings and Precautions (5.3)].

It is generally agreed that episodes of depression require several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in depressed patients on therapy with EMSAM at a dose of 6 mg per 24 hours after achieving a responder status for an average duration of about 25 days was demonstrated in a controlled trial [see Clinical Studies (14)].

The physician who elects to use EMSAM for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

EMSAM (selegiline transdermal system) contains a monoamine oxidase inhibitor (MAOI). MAOIs including EMSAM combined with a high tyramine diet may cause a hypertensive crisis. A hypertensive crisis can be a life-threatening condition [see Warnings and Precautions (5.3)].

The foods and beverages listed in Table 5 should be avoided beginning on the first day of EMSAM 9 mg per 24 hours or 12 mg per 24 hours treatment, and should continue to be avoided for 2 weeks after a dose reduction to EMSAM 6 mg per 24 hours or following the discontinuation of EMSAM 9 mg per 24 hours or 12 mg per 24 hours [see Drug Interactions (7.2)].

Prior to initiating treatment with EMSAM or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.4)].

EMSAM (selegiline transdermal system) is supplied as 6 mg per 24 hours (20 mg per 20 cm2), 9 mg per 24 hours (30 mg per 30 cm2) and 12 mg per 24 hours (40 mg per 40 cm2) transdermal systems (TDS).

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EMSAM 6 mg per 24 hours is a translucent TDS printed with ‘EMSAM® 6mg/24h’. EMSAM 9 mg per 24 hours is a translucent TDS printed with ‘EMSAM® 9mg/24h’. EMSAM 12 mg per 24 hours is a translucent TDS printed with ‘EMSAM® 12mg/24h’.

{ "type": "p", "children": [], "text": "EMSAM 6 mg per 24 hours is a translucent TDS printed with ‘EMSAM® 6mg/24h’. EMSAM 9 mg per 24 hours is a translucent TDS printed with ‘EMSAM® 9mg/24h’. EMSAM 12 mg per 24 hours is a translucent TDS printed with ‘EMSAM® 12mg/24h’. " }

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In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1.

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

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients</span> </caption> <col width="17%"/> <col width="83%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Age Range (years)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"></td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Increases Compared to Placebo</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">&lt;18</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">14 additional patients</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">18-24</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">5 additional patients</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"></td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Decreases Compared to Placebo</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">25-64</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">1 fewer patient</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">≥65</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">6 fewer patients</p> </td> </tr> </tbody> </table></div>

It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression.

Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing EMSAM, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

The development of a potentially life-threatening serotonin syndrome has been reported with concomitant use of MAOIs, such as EMSAM, with serotonergic drugs. These reactions have also been reported in patients who have discontinued serotonergic drugs and then subsequently started an MAOI [see Contraindications (4)].

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Patients should be monitored for the emergence of serotonin syndrome. Treatment with EMSAM and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive treatment should be initiated.

EMSAM inhibits the catabolism of dietary amines, such as tyramine, and has the potential to produce a hypertensive crisis following the ingestion of tyramine-rich foods or beverages [see Drug Interactions (7.2) and Clinical Pharmacology (12.2)].

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.

If a hypertensive crisis occurs, EMSAM should be discontinued immediately and therapy to lower blood pressure should be instituted immediately. Fever should be managed by means of external cooling. Patients must be closely monitored until symptoms have stabilized. To prevent a hypertensive crisis, patients receiving treatment with EMSAM 9 mg per 24 hours or EMSAM 12 mg per 24 hours should follow the advice regarding a low tyramine diet described in Table 5 under Dietary Modifications Required for Patients Taking EMSAM 9 mg per 24 hours and 12 mg per 24 hours [see Drug Interactions (7.2)].

Carbamazepine is contraindicated with EMSAM because carbamazepine has been shown to significantly elevate selegiline levels, which may increase the risk of a hypertensive crisis [see Contraindications (4) and Drug Interactions (7.4)].

The use of EMSAM with adrenergic drugs or buspirone may produce substantial increases in blood pressure. Therefore, monitor blood pressure if EMSAM is used with any of the following drugs: buspirone, amphetamines, or cold products or weight-reducing preparations that contain sympathomimetic amines (e.g., pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine).

In patients with bipolar disorder, treating a depressive episode with EMSAM or another antidepressant may precipitate a mixed/manic episode. During Phase III trials, a manic reaction occurred in 8 out of 2,036 (0.4%) patients treated with EMSAM. Prior to initiating treatment with EMSAM, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

The effect of direct heat applied to EMSAM on the bioavailability of selegiline has not been studied. However, in theory, heat may result in an increase in the amount of selegiline absorbed from EMSAM and produce elevated serum levels of selegiline. Patients should be advised to avoid exposing the EMSAM application site to external sources of direct heat, such as heating pads or electric blankets, heat lamps, saunas, hot tubs, heated water beds, and prolonged direct sunlight.

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.

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> <span>Table 2. Treatment-Emergent Adverse Reactions: Incidence in Placebo-Controlled Clinical Trials for Major Depressive Disorder with EMSAM<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></span> </caption> <col width="46%"/> <col width="26%"/> <col width="27%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Reactions reported by at least 2% of patients treated with EMSAM are included, except the following reactions, which had an incidence on placebo treatment greater than or equal to EMSAM: infection, nausea, dizziness, pain, abdominal pain, nervousness, back pain, asthenia, anxiety, flu syndrome, accidental injury, somnolence, rhinitis, and palpitations.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Body System/Preferred Term</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">EMSAM</span> </p> <p> <span class="Bold">(N = 817)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">(N = 668)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule" valign="middle"></td><td align="center" class="Botrule Rrule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">(% of Patients Reporting Reaction)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Body as a Whole</span> </p> </td><td class="Botrule Lrule Rrule" valign="middle"></td><td class="Botrule Lrule Rrule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">   Headache</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">18</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">17</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Digestive</span> </p> </td><td class="Botrule Lrule Rrule" valign="middle"></td><td class="Botrule Lrule Rrule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">   Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">9</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">   Dyspepsia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Nervous</span> </p> </td><td class="Botrule Lrule Rrule" valign="middle"></td><td class="Botrule Lrule Rrule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">   Insomnia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">   Dry Mouth</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Respiratory</span> </p> </td><td class="Botrule Lrule Rrule" valign="middle"></td><td class="Botrule Lrule Rrule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">   Pharyngitis</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">   Sinusitis</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Skin</span> </p> </td><td class="Botrule Lrule Rrule" valign="middle"></td><td class="Botrule Lrule Rrule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">   Application Site Reaction</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">24</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">12</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">   Rash</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">2</p> </td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> <span>Table 3. Incidence of Sexual Side Effects in Placebo-Controlled Clinical Trials with EMSAM</span> </caption> <col width="36%"/> <col width="32%"/> <col width="32%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Adverse Reaction</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">EMSAM</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Placebo</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"></td><td align="center" class="Botrule Lrule Rrule" colspan="2" valign="middle"> <p class="First">IN MALES ONLY</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"></td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">(N = 304)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">(N = 256)</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Abnormal Ejaculation</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">1.0%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">0.0%</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Decreased Libido</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">0.7%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">0.0%</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Impotence</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">0.7%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">0.4%</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Anorgasmia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">0.2%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">0.0%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"></td><td align="center" class="Botrule Lrule Rrule" colspan="2" valign="middle"> <p class="First">IN FEMALES ONLY</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"></td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">(N = 513)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">(N = 412)</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Decreased Libido</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">0.0%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">0.2%</p> </td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> <span>Table 4. Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials with EMSAM</span> </caption> <col width="39%"/> <col width="33%"/> <col width="28%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Weight Change</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">EMSAM</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Placebo</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"></td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">(N = 757)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">(N = 614)</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Gained at least 5%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">2.1%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">2.4%</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Lost at least 5%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">5.0%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">2.8%</p> </td> </tr> </tbody> </table></div>

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.

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.

Serious, sometimes fatal, central nervous system (CNS) toxicity referred to as the “serotonin syndrome” has been reported with the combination of nonselective MAOIs and serotonergic drugs. Use of EMSAM with these drugs is contraindicated [see Contraindications (4) and Warnings and Precautions (5.2)].

EMSAM has the capacity to inhibit intestinal MAO, which is responsible for the catabolism of tyramine in food and beverages. As a result of this inhibition, large amounts of tyramine may enter the systemic circulation and precipitate a sudden, large rise in blood pressure or hypertensive crisis [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.2)].

A diet low in tyramine content may be necessary to avoid this interaction. Studies to evaluate the potential for EMSAM to inhibit tyramine metabolism have been conducted and, 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 below [see Clinical Pharmacology (12.2)].

The foods and beverages listed in Table 5 should be avoided beginning on the first day of EMSAM 9 mg per 24 hours or 12 mg per 24 hours treatment, and should continue to be avoided for 2 weeks after a dose reduction to EMSAM 6 mg per 24 hours or following the discontinuation of EMSAM 9 mg per 24 hours or 12 mg per 24 hours.

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> <span>Table 5. Food and Beverages to Avoid and Those which are Acceptable<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a></span> </caption> <col width="16%"/> <col width="40%"/> <col width="43%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd> <span class="Italics">[see <a href="#ID_5e1c4adc-84ca-4adc-b7fd-8d20157d79a8">References (15)</a>]</span> </dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Class of Food and Beverage</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Tyramine-Rich Foods and Beverages to Avoid</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Acceptable Foods and Drinks,</span> </p> <p> <span class="Bold">Containing No or Little Tyramine</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Underline">Meat, Poultry, and Fish</span></span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">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</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fresh meat, poultry, and fish, including fresh processed meats (e.g., lunch meats, hot dogs, breakfast sausage,<br/>and cooked sliced ham)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Vegetables</span> </p> </td><td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Broad bean pods (fava bean pods)</p> </td><td class="Botrule Lrule Rrule" valign="middle"> <p class="First">All other vegetables</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Dairy</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Aged cheeses</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Processed cheeses, mozzarella, ricotta cheese, cottage cheese, and yogurt</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Beverages</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">All varieties of tap beer and beers that have not been pasteurized so as to allow for ongoing fermentation</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Concomitant use of alcohol with EMSAM is not recommended. (Bottled and canned beers and wines contain little or no tyramine.)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Miscellaneous</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Concentrated yeast extract (e.g., Marmite), sauerkraut, most soybean products (including soy sauce and tofu), OTC supplements containing tyramine</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Brewer’s yeast, baker’s yeast, soy milk, commercial chain restaurant pizzas prepared with cheeses low in tyramine</p> </td> </tr> </tbody> </table></div>

The use of EMSAM with sympathomimetic amines or buspirone may produce substantial elevations in blood pressure. Therefore, monitor blood pressure if EMSAM is used with any of the following drugs: buspirone, amphetamines, and cold products or weight-reducing preparations that contain sympathomimetic amines (e.g., pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine).

Carbamazepine is contraindicated with MAOIs, including selegiline [see Contraindications (4), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

No dose adjustment for EMSAM is needed when EMSAM is used concomitantly with alcohol, alprazolam, ibuprofen, olanzapine, risperidone, levothyroxine, and CYP3A4 inhibitors (e.g., ketoconazole). No clinically meaningful change in selegiline exposure was seen when EMSAM was co-administered with alcohol, alprazolam, ibuprofen, olanzapine, risperidone, levothyroxine, and ketoconazole [see Clinical Pharmacology (12.3)].

Use of alcohol while taking EMSAM is not recommended, even though EMSAM has not been shown to increase the impairment of mental and motor skills caused by alcohol (0.75 mg per kg) [see Clinical Pharmacology (12.3)].

Monitor blood pressure if sympathomimetic agents (e.g., phenylpropanolamine (PPA) or pseudoephedrine) are used with EMSAM, even though selegiline does not appear to affect the pharmacokinetics of PPA or pseudoephedrine [see Clinical Pharmacology (12.3)].

No dose adjustment of alprazolam, ibuprofen, levothyroxine, olanzapine, risperidone, warfarin, or strong CYP3A4 inhibitors (e.g., ketoconazole) is necessary when these drugs are used in combination with EMSAM. EMSAM had no clinically relevant effect on pharmacokinetics of these drugs.

The available data on EMSAM use in pregnant women are not sufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. In animal embryo-fetal development studies, transdermal administration of selegiline to rats and rabbits at doses up to 60 and 64 times the maximum recommended human dose (MRHD) respectively, produced slight increases in malformations in both rats and rabbits, and decreased fetal weight, delayed ossification, and embryo-fetal post-implantation loss in rats. Most of these effects were seen at the high dose in both rats and rabbits. These effects were not seen at 8 times and 16 times the MRHD in rats and rabbits, respectively. In a pre-natal and post-natal development study, transdermal administration of selegiline in rats at doses 8, 24, and 60 times MRHD produced a decrease in pup weight and survival at the medium and high doses, an increase in the number of stillborn pups at the high dose, and delayed neurobehavioral and sexual development in pups

at all doses. A persistent effect on reproductive performance of pups born to mothers treated at the high dose was evident (see Data). When treating a pregnant woman with EMSAM, the physician should carefully consider both the potential risks of taking an MAOI, particularly the risk of hypertensive crisis during pregnancy, along with the established benefits of treating depression with an antidepressant.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

A prospective longitudinal study was conducted of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.

In an embryofetal development study, rats 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 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 loss. Concentrations of selegiline and its metabolites in fetal plasma were generally similar to those in maternal plasma.

In an embryofetal development study, rabbits 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 a prenatal and postnatal development study, rats 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 to 21 of gestation and days 1 to 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 postweaning periods) and survival (throughout lactation period), delayed pup physical development, and pup epididymal and testicular hypoplasia, were seen at the mid and high doses. Delayed 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 in this study for developmental toxicity.

There is no information regarding the presence of selegiline in human milk, or on its effects on milk production or the breastfed infant. Selegiline and its metabolites are present in the milk of lactating rats (see Data).

Because of the potential for serious adverse reactions in breastfed infants from EMSAM, including the potential for hypertensive crisis, advise a woman that breastfeeding is not recommended during treatment with EMSAM and for 5 days after the final dose.

In a prenatal and postnatal development study where rats were treated with transdermal selegiline at doses approximately 8, 24, and 60 times the MRHD on days 6 to 21 of gestation and days 1 to 21 of the lactation period, concentrations of selegiline and its metabolites in milk were approximately 15 and 5 times, respectively, the concentrations in maternal plasma.

Use of EMSAM in patients less than 12 years of age is contraindicated because of the potential for a hypertensive crisis [see Contraindications (4)].

Limited pharmacokinetic data with doses lower than in the commercially available formulations suggest that children under age 12 may be exposed to increased levels of selegiline compared to adolescents and adults, administered with and without dietary modifications, therefore, there may be an increased risk of hypertensive crisis, even at the lowest dose of EMSAM.

Efficacy has not been established in pediatric patients ages 12 to 17 years with MDD and EMSAM is not recommended for use in this age range [see Clinical Pharmacology (12.3)].

A multi-center, randomized, double-blind, placebo-controlled, flexible-dose trial in 308 adolescents (ages 12 to 17 years) with MDD failed to demonstrate the efficacy of EMSAM. Diagnosis of major depressive disorder (single episode or recurrent, moderate to severe) was based on according DSM-IV criteria and Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children (K-SADS). Enrolled patients had a Children’s Depression Rating Scale-Revised of ≥ 45 at the screening visit. Trial participants were randomized 1:1 to either EMSAM or matching placebo without forced titration for a period of 12 weeks. Active treatment consisted of EMSAM transdermal system at a dose of 6 mg per 24 hours, 9 mg per 24 hours, or 12 mg per 24 hours. The primary efficacy endpoint was the difference in total score on the Children’s Depression Rating Scale-Revised (CDRS-R) from baseline to the end of study (EOS) (Week 12). There was no observed difference in effect on CDRS-R Total Score at Week 12 (EOS) between treatments. The mean reduction in CDRS-R Total Score was 21.4 in the EMSAM-treated subjects and 21.5 in those receiving placebo treatment. Safety endpoints included physical examination, 12-lead electrocardiogram, respiration rate, temperature, supine and standing blood pressure and heart rate, application site assessments, and adverse events. Overall, safety findings were similar to those observed in EMSAM trials conducted in adults. Treatment-emergent adverse events reported by at least 5% of EMSAM-treated patients at a rate at least twice the placebo rate were insomnia (6%, 3%) and upper respiratory tract infection (7%, 3%).

The recommended dose of EMSAM for elderly patients (65 years and older) is 6 mg per 24 hours daily. The effect of age on the pharmacokinetics or metabolism of selegiline after administration of EMSAM has not been systematically evaluated. One hundred ninety-eight (198) elderly (65 years of age and older) patients participated in clinical studies with EMSAM 6 mg per 24 hours to 12 mg per 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).

No adjustment of EMSAM dosage based on gender is needed. No gender differences have been observed in the pharmacokinetics or metabolism of selegiline during administration of EMSAM.

No adjustment of EMSAM dosage is required in patients with mild liver impairment (Child-Pugh 5-6 points) or moderate liver impairment (Child-Pugh 7-9 points). After a single administration of EMSAM 6 mg per 24 hours in eight patients with mild or moderate liver impairment, no differences in either the metabolism or pharmacokinetic behavior of selegiline or its metabolites were observed as compared with data of normal subjects. EMSAM has not been studied in patients with severe liver impairment (Child-Pugh 10-15 points).

No adjustment of EMSAM dosage is required in patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m2), moderate renal impairment (eGFR 30-59 mL/min/1.73 m2), or severe renal impairment (eGFR 15-29 mL/min/1.73 m2). Data from a single dose study examining the pharmacokinetics of EMSAM 6 mg per 24 hours in 12 patients with renal impairment suggest that mild, moderate, or severe renal impairment does not affect the pharmacokinetics of selegiline after transdermal application. EMSAM has not been studied in patients with end-stage renal disease (eGFR < 15 mL/min/1.73 m2 or requiring dialysis).

EMSAM is not a controlled substance.

{ "type": "p", "children": [], "text": "EMSAM is not a controlled substance." }

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.

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.

EMSAM® contains selegiline, a MAOI antidepressant. When applied to intact skin, EMSAM is designed to transdermally deliver selegiline over a 24-hour period.

{ "type": "p", "children": [], "text": "EMSAM® contains selegiline, a MAOI antidepressant. When applied to intact skin, EMSAM is designed to transdermally deliver selegiline over a 24-hour period." }

Selegiline base is a colorless to yellow liquid, chemically described as (-)-(N)-Methyl-N-[(1R)-1-methyl-2-phenylethyl]prop-2-yn-1-amine. It has a molecular formula of C13H17N and a molecular weight of 187.30. The structural formula is:

{ "type": "p", "children": [], "text": "Selegiline base is a colorless to yellow liquid, chemically described as (-)-(N)-Methyl-N-[(1R)-1-methyl-2-phenylethyl]prop-2-yn-1-amine. It has a molecular formula of C13H17N and a molecular weight of 187.30. The structural formula is:" }

EMSAM transdermal systems are available in three strengths that deliver approximately 6 mg, 9 mg, or 12 mg of selegiline over 24 hours. Each corresponding system has an active surface area of 20 cm2, 30 cm2, or 40 cm2 containing 20, 30, or 40 mg of selegiline, respectively. The composition of the systems per unit area is identical.

{ "type": "p", "children": [], "text": "EMSAM transdermal systems are available in three strengths that deliver approximately 6 mg, 9 mg, or 12 mg of selegiline over 24 hours. Each corresponding system has an active surface area of 20 cm2, 30 cm2, or 40 cm2 containing 20, 30, or 40 mg of selegiline, respectively. The composition of the systems per unit area is identical. " }

EMSAM is a matrix-type transdermal system composed of three layers as illustrated in Figure 1 below. Layer 1 is the Backing Film that provides occlusivity, physical integrity and protects the adhesive/drug layer. Layer 2 is the Adhesive/Drug Layer. Layer 3 consists of side-by-side release liners that are peeled off and discarded by the patient prior to applying EMSAM. The inactive ingredients are acrylic adhesive, ethylene vinyl acetate/polyethylene, polyester, polyurethane, and silicone coated polyester.

{ "type": "p", "children": [], "text": "EMSAM is a matrix-type transdermal system composed of three layers as illustrated in Figure 1 below. Layer 1 is the Backing Film that provides occlusivity, physical integrity and protects the adhesive/drug layer. Layer 2 is the Adhesive/Drug Layer. Layer 3 consists of side-by-side release liners that are peeled off and discarded by the patient prior to applying EMSAM. The inactive ingredients are acrylic adhesive, ethylene vinyl acetate/polyethylene, polyester, polyurethane, and silicone coated polyester." }

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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).

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 (5.3)].

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 (5.3)].

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 (7)].

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.

EMSAM should not be used in patients less than 18 years of age [see Use in Specific Populations (8.4)].

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.

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> <span>Table 6. Steady State Selegiline Trough Concentrations Associated with Administration of EMSAM 15 mg/15 cm<span class="Sup">2</span> Daily for 7 Days</span> </caption> <col width="21%"/> <col width="38%"/> <col width="41%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="middle"> <p class="First"> <span class="Bold">Trough Concentration, pg/mL</span> </p> </td> </tr> <tr> <td class="Lrule Rrule" valign="middle"></td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">6 to 11 year old age group</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">12 to 14 year old age group</span> </p> </td> </tr> <tr> <td class="Lrule Rrule" valign="middle"></td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">(N = 6)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">(N = 4)</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First"> <span class="Bold">Mean (SD)</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">2,562 (974)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">1,821 (146)</p> </td> </tr> </tbody> </table></div>

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 (7.4) and (7.5)].

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 (7.4) and (7.5)].

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 (4), Warnings and Precautions (5.3) and Drug Interaction (7.4)].

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 (7.4) and (7.5)].

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 (7.4) and (7.5)].

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 (7.4) and (7.5)].

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 (7.4) and (7.5)].

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 (7.4) and (7.5)].

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 (7.4) and (7.5)].

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 (7.4) and (7.5)].

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 (7.4) and (7.5)].

In a dermal carcinogenicity study in CD-1 mice, selegiline (the drug substance of EMSAM) was administered daily for 2 years at the same skin site at dose levels of 20, 70, and 200 mg per kg per day (dissolved in acetone). The incidence of systemic tumors was not increased and the high dose provided systemic exposures to selegiline and its three metabolites in mice that were greater than 40 times the exposures in humans at the maximum recommended human dose (MRHD). The incidence of squamous cell carcinoma was slightly increased on treated skin of mice administered the high dose. This finding was associated with an increased incidence of epithelial hyperplasia, dyskeratosis/hyperkeratosis and inflammation.

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 per kg per day), which exposed rats to systemic levels of selegiline and its three metabolites that were comparable to those in humans at the MRHD.

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.

A mating and fertility study was conducted in male and female rats at transdermal doses of 10, 30, and 75 mg per kg per day of selegiline (8, 24, and 60 times the maximum recommended human dose of EMSAM [12 mg per 24 hours] on a mg per 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.

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).

<div class="scrollingtable"><table cellpadding="0pt" class="Noautorules" width="100%"> <caption> <span>Table 7. Primary Efficacy Results from Short-Term Trials</span> </caption> <col width="18%"/> <col width="19%"/> <col width="11%"/> <col width="19%"/> <col width="17%"/> <col width="17%"/> <tfoot> <tr> <td align="left" colspan="6" valign="top">SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.</td> </tr> <tr> <td align="left" colspan="6"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Difference (drug minus placebo) in least-squares mean change from baseline</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Study Number</span> <br/> <span class="Bold">[Primary Measure]</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Treatment Group</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Number of Patients</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Mean Baseline Score (SD)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">LS Mean Change from Baseline (SE)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Placebo-subtracted Difference</span><a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a><span class="Bold"> (95% CI)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">Study 1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">EMSAM (6 mg)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">89</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">22.9 (2.1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">-9.0 (0.8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">-2.5</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">[HAMD-17]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">88</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">23.3 (2.9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">-6.5 (0.8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">(-4.6, -0.4)</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">Study 2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">EMSAM<br/>(6 to 12 mg)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">132</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">28.3 (3.7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">-10.9 (0.8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">-2.4</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">[HAMD-28]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">133</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">28.5 (3.9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">-8.6 (0.8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">(-4.5, -0.3)</p> </td> </tr> </tbody> </table></div>

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.

{ "type": "", "children": [], "text": "" }

How Supplied

{ "type": "p", "children": [], "text": "\nHow Supplied\n" }

EMSAM (selegiline transdermal system) is a transdermal system with the following strengths, sizes, color, backing film printing and presentation:

{ "type": "p", "children": [], "text": "EMSAM (selegiline transdermal system) is a transdermal system with the following strengths, sizes, color, backing film printing and presentation:" }

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <col width="22%"/> <col width="26%"/> <col width="26%"/> <col width="26%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Features</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="middle"> <p class="First"> <span class="Bold">Strengths</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">6 mg per 24 hours</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">9 mg per 24 hours</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">12 mg per 24 hours</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">EMSAM Size</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">20 mg per 20 cm<span class="Sup">2</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">30 mg per 30 cm<span class="Sup">2</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">40 mg per 40 cm<span class="Sup">2</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Color</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Translucent</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Translucent</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Translucent</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Backing Film<br/>Printing</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">EMSAM<span class="Sup">®</span> 6mg/24h</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">EMSAM<span class="Sup">®</span> 9mg/24h</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">EMSAM<span class="Sup">®</span> 12mg/24h</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">NDC number</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">NDC 49502-900-30</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">NDC 49502-901-30</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">NDC 49502-902-30</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Presentation</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Box of 30 transdermal systems</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Box of 30 transdermal systems</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Box of 30 transdermal systems</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"0pt\" width=\"100%\">\n<col width=\"22%\"/>\n<col width=\"26%\"/>\n<col width=\"26%\"/>\n<col width=\"26%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Features</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Strengths</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">6 mg per 24 hours</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">9 mg per 24 hours</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">12 mg per 24 hours</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">EMSAM Size</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">20 mg per 20 cm<span class=\"Sup\">2</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">30 mg per 30 cm<span class=\"Sup\">2</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">40 mg per 40 cm<span class=\"Sup\">2</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Color</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Translucent</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Translucent</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Translucent</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Backing Film<br/>Printing</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">EMSAM<span class=\"Sup\">®</span> 6mg/24h</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">EMSAM<span class=\"Sup\">®</span> 9mg/24h</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">EMSAM<span class=\"Sup\">®</span> 12mg/24h</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">NDC number</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">NDC 49502-900-30</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">NDC 49502-901-30</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">NDC 49502-902-30</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Presentation</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Box of 30 transdermal systems</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Box of 30 transdermal systems</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Box of 30 transdermal systems</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Storage and Handling

{ "type": "p", "children": [], "text": "\nStorage and Handling\n" }

Store at 20° to 25° C (68° to 77° F). [See USP Controlled Room Temperature.] Do not store outside of the sealed pouch.

{ "type": "p", "children": [], "text": "Store at 20° to 25° C (68° to 77° F). [See USP Controlled Room Temperature.] Do not store outside of the sealed pouch. " }

Apply immediately upon removal from the protective pouch. Discard used EMSAM in household trash in a manner that prevents accidental application or ingestion by children, pets or others.

{ "type": "p", "children": [], "text": "Apply immediately upon removal from the protective pouch. Discard used EMSAM in household trash in a manner that prevents accidental application or ingestion by children, pets or others." }

See FDA-approved patient labeling (Medication Guide and Instructions for Use).

{ "type": "p", "children": [], "text": "See FDA-approved patient labeling (Medication Guide and Instructions for Use)." }

Advise patients and their caregivers about the benefits and risks associated with treatment with EMSAM and counsel them in its appropriate use. Advise patients and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of this document.

{ "type": "p", "children": [], "text": "Advise patients and their caregivers about the benefits and risks associated with treatment with EMSAM and counsel them in its appropriate use. Advise patients and their caregivers to read the Medication Guide and assist them in understanding its contents. 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.

{ "type": "p", "children": [], "text": "Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking EMSAM." }

Suicide Risk: Advise patients and caregivers to look for the emergence of suicidal ideation and behavior, especially early during treatment and when the dose is adjusted up or down [see Boxed Warning and Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "\nSuicide Risk: Advise patients and caregivers to look for the emergence of suicidal ideation and behavior, especially early during treatment and when the dose is adjusted up or down [see Boxed Warning and Warnings and Precautions (5.1)]." }

Tyramine Reactions: Patients should be advised that tyramine-rich foods and beverages should be avoided while on EMSAM 9 mg per 24 hours or EMSAM 12 mg per 24 hours, and for 2 weeks following discontinuation of EMSAM at these doses because of the risk of a tyramine reaction [see Warnings and Precautions (5.3), Drug Interactions (7.2), and Clinical Pharmacology (12.2)]. Patients should also be advised to avoid tyramine-containing nutritional supplements. 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.

{ "type": "p", "children": [], "text": "\nTyramine Reactions: Patients should be advised that tyramine-rich foods and beverages should be avoided while on EMSAM 9 mg per 24 hours or EMSAM 12 mg per 24 hours, and for 2 weeks following discontinuation of EMSAM at these doses because of the risk of a tyramine reaction [see Warnings and Precautions (5.3), Drug Interactions (7.2), and Clinical Pharmacology (12.2)]. Patients should also be advised to avoid tyramine-containing nutritional supplements. 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." }

Concomitant Medication: Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications, including herbals, because of a potential for dangerous interactions. Instruct patients not to take EMSAM with medication that is contraindicated or within two weeks of stopping such medication (5 weeks for fluoxetine). Contraindicated medication should not be started within two weeks of stopping EMSAM [see Contraindications (4)].

{ "type": "p", "children": [], "text": "\nConcomitant Medication: Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications, including herbals, because of a potential for dangerous interactions. Instruct patients not to take EMSAM with medication that is contraindicated or within two weeks of stopping such medication (5 weeks for fluoxetine). Contraindicated medication should not be started within two weeks of stopping EMSAM [see Contraindications (4)]." }

Psychomotor Performance: EMSAM 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.

{ "type": "p", "children": [], "text": "\nPsychomotor Performance: EMSAM 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." }

Alcohol: 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.

{ "type": "p", "children": [], "text": "\nAlcohol: 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." }

Pediatrics: Advise patients that EMSAM must not be used in children less than 12 years of age because of an increased risk of severe increases in blood pressure. Also, patients should be advised that EMSAM is not recommended for use in pediatric patients ages 12 to 17 years [see Use in Specific Populations (8.4)].

{ "type": "p", "children": [], "text": "\nPediatrics: Advise patients that EMSAM must not be used in children less than 12 years of age because of an increased risk of severe increases in blood pressure. Also, patients should be advised that EMSAM is not recommended for use in pediatric patients ages 12 to 17 years [see Use in Specific Populations (8.4)]. " }

Pregnancy: Advise the pregnant woman about the potential risk to the fetus [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "\nPregnancy: Advise the pregnant woman about the potential risk to the fetus [see Use in Specific Populations (8.1)].\n" }

Lactation: Advise a woman that breastfeeding is not recommended during treatment with EMSAM treatment and for 5 days after the final dose [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "\nLactation: Advise a woman that breastfeeding is not recommended during treatment with EMSAM treatment and for 5 days after the final dose [see Use in Specific Populations (8.2)]." }

How to Use EMSAM

{ "type": "p", "children": [], "text": "\nHow to Use EMSAM \n" }

Detailed Instructions are provided in the Medication Guide. Prescribers should instruct patients on the following:

{ "type": "p", "children": [], "text": "Detailed Instructions are provided in the Medication Guide. Prescribers should instruct patients on the following: " }

{ "type": "", "children": [], "text": "" }

The brands listed are trademarks of their respective owners.

{ "type": "p", "children": [], "text": "The brands listed are trademarks of their respective owners." }

<div class="scrollingtable"><table width="100%"> <col width="39%"/> <col width="32%"/> <col width="29%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">EMSAM<span class="Sup">®</span> [EM sam]</span> <br/> <span class="Bold">(selegiline transdermal system)</span> </p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">What is the most important information I should know about EMSAM? </span> </p> <dl> <dt>1.</dt> <dd> <span class="Bold">Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. </span> </dd> <dt>2.</dt> <dd> <span class="Bold">Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have or have a family history of bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. How can I watch for and try to prevent suicidal thoughts and actions?</span> <dl> <dt>•</dt> <dd>Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. </dd> <dt>•</dt> <dd>Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.</dd> <dt>•</dt> <dd>Keep all follow-up visits with your healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. </dd> </dl> </dd> </dl> <p> <span class="Bold">Call a healthcare provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you:</span> </p> </td> </tr> <tr> <td class="Lrule" valign="top"> <dl> <dt>•</dt> <dd>thoughts about suicide or dying </dd> <dt>•</dt> <dd>attempts to commit suicide </dd> <dt>•</dt> <dd>new or worse depression </dd> <dt>•</dt> <dd>new or worse anxiety </dd> <dt>•</dt> <dd>feeling agitated, restless, angry or irritable </dd> <dt>•</dt> <dd>panic attacks </dd> <dt>•</dt> <dd>trouble sleeping</dd> </dl> </td><td class="Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd>new or worse irritability </dd> <dt>•</dt> <dd>acting aggressive, being angry or violent </dd> <dt>•</dt> <dd>acting on dangerous impulses </dd> <dt>•</dt> <dd>an extreme increase in activity or talking (mania) </dd> <dt>•</dt> <dd>other unusual changes in behavior or mood</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">   </span>3.<span class="Bold">    EMSAM is not for children less than 12 years of age. EMSAM may cause a severe increase in blood pressure in children less than 12 years of age.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">What is EMSAM?</span> </p> <p>EMSAM is a prescription medicine used to treat a certain type of depression called Major Depressive Disorder (MDD). EMSAM belongs to the class of medicines known as monoamine oxidase inhibitors (MAOI). EMSAM is a transdermal system (patch) you apply to your skin.</p> <p>It is important to talk with your healthcare provider about the risks of treating depression and also the risk of not treating it. You should discuss all treatment choices with your healthcare provider.</p> <p>Talk to your healthcare provider if you do not think that your condition is getting better with EMSAM treatment.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Who should not use EMSAM?</span> </p> <p> <span class="Bold">Using EMSAM with certain antidepressants and certain pain, cold and cough symptom medicines may cause a potentially life-threatening problem called serotonin syndrome (See “What are the possible side effects of EMSAM?”).</span> </p> <p> <span class="Bold">Do not use EMSAM if you:</span> </p> <dl> <dt>•</dt> <dd> <span class="Bold">take certain medicines including:</span> <dl> <dt>o</dt> <dd>selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, sertraline, or paroxetine</dd> <dt>o</dt> <dd>serotonin and norepinephrine reuptake inhibitors (SNRI) such as venlafaxine or duloxetine</dd> <dt>o</dt> <dd>clomipramine or imipramine (tricyclic antidepressants)</dd> <dt>o</dt> <dd>meperidine, tramadol, methadone, pentazocine, propoxyphene (opioid medicines)</dd> <dt>o</dt> <dd>dextromethorphan</dd> <dt>o</dt> <dd>carbamazepine</dd> </dl> </dd> <dt>•</dt> <dd> <span class="Bold">are less than 12 years of age</span> </dd> <dt>•</dt> <dd> <span class="Bold">have a tumor on your adrenal gland called a pheochromocytoma</span> </dd> </dl> <p>Ask your healthcare provider or pharmacist if you are not sure if you take these medicines.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Before you use EMSAM, tell your healthcare provider about all of your medical conditions, including if you:</span> </p> <dl> <dt>•</dt> <dd>have high blood pressure</dd> <dt>•</dt> <dd>have mania or bipolar disorder (manic depression)</dd> <dt>•</dt> <dd>have or had seizures or convulsions</dd> <dt>•</dt> <dd>drink alcohol</dd> <dt>•</dt> <dd>have any other medical conditions</dd> <dt>•</dt> <dd>are pregnant or plan to become pregnant. EMSAM may harm your unborn baby.</dd> <dt>•</dt> <dd>are breastfeeding or plan to breastfeed<span class="Bold">.</span> It is not known if EMSAM passes into your breast milk. Do not breastfeed during treatment with EMSAM and for 5 days after the final dose. Talk to your healthcare provider about the best way to feed your baby if you use EMSAM.</dd> </dl> <p> <span class="Bold">Tell your doctor about all the medicines you take</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements. EMSAM and some medicines may interact with each other, may not work as well, or may cause serious side effects when taken together.</p> <p> <span class="Bold">Especially tell your healthcare provider if you take:</span> </p> <dl> <dt>•</dt> <dd>other medicines to treat depression (antidepressants) including other MAOI medicines</dd> <dt>•</dt> <dd>decongestant medicines to treat cold or cough symptoms</dd> <dt>•</dt> <dd>over-the-counter diet pills or herbal weight-loss products</dd> <dt>•</dt> <dd>any herbal or dietary supplement that contains tyramine</dd> <dt>•</dt> <dd>medicines called stimulants or uppers (amphetamines)</dd> <dt>•</dt> <dd>buspirone, an anxiety medicine </dd> </dl> <p> <span class="Bold">Some of these medicines need to be stopped for up to 5 weeks before you can start using EMSAM and for 2 weeks after you stop using EMSAM. </span> </p> <p>Ask your healthcare provider or pharmacist if you are not sure if you take these medicines.</p> <p>Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.</p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">How should I use EMSAM?</span> </p> <dl> <dt>•</dt> <dd>Read the<span class="Bold"> “Instructions for Use” </span>at the end of this Medication Guide for information about the right way to use EMSAM.</dd> <dt>•</dt> <dd>Use EMSAM exactly as your healthcare provider tells you to use it. </dd> <dt>•</dt> <dd>Use only 1 patch at a time.</dd> <dt>•</dt> <dd>Apply your patch right after you open the sealed pouch.</dd> <dt>•</dt> <dd>Change your patch 1 time each day at the same time each day. Choose a time of day that works best for you.</dd> <dt>•</dt> <dd>Your healthcare provider may need to change your dose of EMSAM until it is the right dose for you.</dd> <dt>•</dt> <dd>If you use too much EMSAM (overdose) you may have the following symptoms:</dd> </dl> </td> </tr> <tr> <td class="Lrule" valign="top"> <dl> <dt>o</dt> <dd>drowsiness</dd> <dt>o</dt> <dd>irritable</dd> <dt>o</dt> <dd>severe headache</dd> <dt>o</dt> <dd>your head, neck and spine arch backwards</dd> <dt>o</dt> <dd>fast or irregular pulse</dd> <dt>o</dt> <dd>blood circulation problem</dd> <dt>o</dt> <dd>high fever</dd> </dl> </td><td valign="top"> <dl> <dt>o</dt> <dd>dizziness</dd> <dt>o</dt> <dd>hyperactive</dd> <dt>o</dt> <dd>seeing things that are not there</dd> <dt>o</dt> <dd>seizures</dd> <dt>o</dt> <dd>high blood pressure</dd> <dt>o</dt> <dd>chest pain</dd> <dt>o</dt> <dd>sweating</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>o</dt> <dd>fainting</dd> <dt>o</dt> <dd>agitated</dd> <dt>o</dt> <dd>stiff jaw</dd> <dt>o</dt> <dd>coma</dd> <dt>o</dt> <dd>low blood pressure</dd> <dt>o</dt> <dd>trouble breathing</dd> <dt>o</dt> <dd>cool, clammy skin</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <dl> <dt> </dt> <dd>If you have any of these symptoms of EMSAM overdosage, remove your patch right away and call your healthcare provider or go to the nearest hospital emergency room right away. It may take up to 12 hours before you have these symptoms, and they may be worse 24 to 48 hours after you apply your EMSAM patch.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">What should I avoid while using EMSAM?</span> </p> <dl> <dt>•</dt> <dd>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.</dd> <dt>•</dt> <dd> <span class="Bold">Do not </span>eat foods or drink beverages that contain high amounts of tyramine while using EMSAM 9 mg or EMSAM 12 mg <span class="Bold">or</span> for 2 weeks after you stop using EMSAM 9 mg or EMSAM 12 mg. Continue to avoid tyramine-rich foods or beverages for 2 weeks after a dose reduction to EMSAM 6 mg.</dd> <dt>•</dt> <dd> <span class="Bold">If you start and continue EMSAM 6 mg you do not need to make any diet changes.</span> </dd> <dt>•</dt> <dd> <span class="Bold">The table below lists foods and drinks you should avoid while you use EMSAM 9 mg and EMSAM 12 mg.</span> </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Type of Food and Drink</span> </p> </td><td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Foods and drinks you should avoid that contain Tyramine</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Meat, Poultry, and Fish</p> </td><td class="Botrule Lrule Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd>air dried, aged and fermented meats, sausages and salamis</dd> <dt>•</dt> <dd>pickled herring</dd> <dt>•</dt> <dd>any spoiled or improperly stored meat, poultry, and fish. These are foods that have a change in color, odor, or become moldy.</dd> <dt>•</dt> <dd>spoiled or improperly stored animal livers</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Vegetables</p> </td><td class="Botrule Lrule Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd>broad bean pods (fava bean pods)</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dairy (milk products)</p> </td><td class="Botrule Lrule Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd>aged cheeses</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Drinks</p> </td><td class="Botrule Lrule Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd>all tap beers and other beers that have not been pasteurized</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Other</p> </td><td class="Botrule Lrule Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd>concentrated yeast extract (such as Marmite)</dd> <dt>•</dt> <dd>sauerkraut</dd> <dt>•</dt> <dd>most soybean products (including soy sauce and tofu) </dd> <dt>•</dt> <dd>over-the-counter supplements containing tyramine</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <dl> <dt>•</dt> <dd>All foods you eat must be fresh or properly frozen.</dd> <dt>•</dt> <dd>Avoid foods when you do not know how those foods should be stored.</dd> <dt>•</dt> <dd>Ask your healthcare provider if you are not sure if certain foods and drinks contain tyramine.</dd> <dt>•</dt> <dd>Do not drive, operate heavy machinery or do other dangerous activities until you know how EMSAM affects you. </dd> <dt>•</dt> <dd>You should not drink alcohol while using EMSAM.</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">What are the possible side effects of EMSAM?</span> </p> <p> <span class="Bold">EMSAM may cause serious side effects, including:</span> </p> <dl> <dt>•</dt> <dd> <span class="Bold">See “What is the most important information I should know about EMSAM?”</span> </dd> <dt>•</dt> <dd> <span class="Bold">serotonin syndrome.</span> A potentially life-threatening problem called serotonin syndrome can happen when you use EMSAM while you take certain medicines called MAOIs. Symptoms of serotonin syndrome include: </dd> </dl> </td> </tr> <tr> <td class="Lrule" valign="top"> <dl> <dt>o</dt> <dd>agitation</dd> <dt>o</dt> <dd>coma</dd> <dt>o</dt> <dd>dizziness</dd> <dt>o</dt> <dd>fever</dd> <dt>o</dt> <dd>stiff muscles</dd> <dt>o</dt> <dd>nausea</dd> </dl> </td><td valign="top"> <dl> <dt>o</dt> <dd>seeing things that are not there (hallucinations)</dd> <dt>o</dt> <dd>rapid pulse</dd> <dt>o</dt> <dd>sweating</dd> <dt>o</dt> <dd>seizures</dd> <dt>o</dt> <dd>muscle twitching</dd> <dt>o</dt> <dd>vomiting</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>o</dt> <dd>confusion</dd> <dt>o</dt> <dd>low blood pressure</dd> <dt>o</dt> <dd>flushing</dd> <dt>o</dt> <dd>tremors</dd> <dt>o</dt> <dd>become unstable</dd> <dt>o</dt> <dd>diarrhea</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First">If you suddenly have these symptoms, stop using EMSAM immediately by removing the patch and go to the nearest hospital emergency room right away.</p> <dl> <dt>•</dt> <dd> <span class="Bold">a sudden, severe increase in blood pressure (hypertensive crisis). A hypertensive crisis can happen when you eat certain foods and drink certain beverages while you use EMSAM. </span>A hypertensive crisis can lead to stroke and death. <br/>See<span class="Bold"> “What should I avoid while using EMSAM?” </span> <br/> <span class="Bold">A hypertensive crisis can also happen if you use EMSAM with certain other medicines. See “Who should not use EMSAM?”</span> <br/>Symptoms of a hypertensive crisis include:</dd> </dl> </td> </tr> <tr> <td class="Lrule" valign="top"> <dl> <dt>o</dt> <dd>sudden, severe headache</dd> <dt>o</dt> <dd>vomiting</dd> <dt>o</dt> <dd>a fast heartbeat (palpitations) or a change in the way your heart beats </dd> <dt>o</dt> <dd>the pupils in your eyes increase in size</dd> <dt>o</dt> <dd>fast or slow heart beat with chest pain</dd> </dl> </td><td class="Rrule" colspan="2" valign="top"> <dl> <dt>o</dt> <dd>nausea</dd> <dt>o</dt> <dd>stiff or sore neck</dd> <dt>o</dt> <dd>excessive sweating, sometimes with fever or cold clammy skin</dd> <dt>o</dt> <dd>light bothers your eyes</dd> <dt>o</dt> <dd>bleeding in your brain</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <dl> <dt> </dt> <dd>If you suddenly have these symptoms, go to the nearest hospital emergency room right away.</dd> <dt>•</dt> <dd> <span class="Bold">mania or hypomania</span> (manic episodes) in people who have a history of mania. Symptoms of manic episodes include:</dd> </dl> </td> </tr> <tr> <td class="Lrule" valign="top"> <dl> <dt>o</dt> <dd>greatly increased energy</dd> <dt>o</dt> <dd>severe problems sleeping</dd> <dt>o</dt> <dd>racing thoughts</dd> </dl> </td><td valign="top"> <dl> <dt>o</dt> <dd>reckless behavior</dd> <dt>o</dt> <dd>unusually grand ideas</dd> <dt>o</dt> <dd>excessive happiness or irritability</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>o</dt> <dd>talking more or faster than usual</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">The most common side effects of EMSAM include:</span> </p> <dl> <dt>•</dt> <dd>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 healthcare provider.</dd> <dt>•</dt> <dd>headache</dd> <dt>•</dt> <dd>trouble sleeping (insomnia)</dd> <dt>•</dt> <dd>diarrhea</dd> <dt>•</dt> <dd>dry mouth</dd> <dt>•</dt> <dd>indigestion</dd> <dt>•</dt> <dd>rash</dd> <dt>•</dt> <dd>sore throat</dd> <dt>•</dt> <dd>sinus infection</dd> </dl> <p>These are not all the possible side effects of EMSAM. <span class="Bold">Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">How should I store EMSAM?</span> </p> <dl> <dt>•</dt> <dd>Store EMSAM at room temperature between 68°F to 77°F (20°C to 25°C).</dd> <dt>•</dt> <dd>Store EMSAM in the sealed pouch it comes in until you are ready to use it.</dd> <dt>•</dt> <dd>Keep EMSAM and all medicines out of the reach of children.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">General information about the safe and effective use of EMSAM.</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use EMSAM for a condition for which it was not prescribed. Do not give EMSAM to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about EMSAM that is written for health professionals.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">What are the ingredients in EMSAM?</span> </p> <p> <span class="Bold">Active Ingredient:</span> selegiline</p> <p> <span class="Bold">Inactive Ingredients:</span> acrylic adhesive, ethylene vinyl acetate, polyethylene, polyester, polyurethane, and silicone coated polyester</p> <p>Distributed by: <span class="Bold">Mylan Specialty L.P., </span>Morgantown, WV 26505 U.S.A.</p> <p>Manufactured for:<br/> <span class="Bold">Somerset Pharmaceuticals, Inc.</span> <br/>Morgantown, WV 26505 U.S.A.</p> <p>For more information, go to <span class="Underline">www.EMSAM.com</span> or call 1-800-395-3376.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"39%\"/>\n<col width=\"32%\"/>\n<col width=\"29%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">EMSAM<span class=\"Sup\">®</span> [EM sam]</span>\n<br/>\n<span class=\"Bold\">(selegiline transdermal system)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about EMSAM? </span>\n</p>\n<dl>\n<dt>1.</dt>\n<dd>\n<span class=\"Bold\">Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. </span>\n</dd>\n<dt>2.</dt>\n<dd>\n<span class=\"Bold\">Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have or have a family history of bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. How can I watch for and try to prevent suicidal thoughts and actions?</span>\n<dl>\n<dt>•</dt>\n<dd>Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. </dd>\n<dt>•</dt>\n<dd>Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.</dd>\n<dt>•</dt>\n<dd>Keep all follow-up visits with your healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. </dd>\n</dl>\n</dd>\n</dl>\n<p>\n<span class=\"Bold\">Call a healthcare provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you:</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>thoughts about suicide or dying </dd>\n<dt>•</dt>\n<dd>attempts to commit suicide </dd>\n<dt>•</dt>\n<dd>new or worse depression </dd>\n<dt>•</dt>\n<dd>new or worse anxiety </dd>\n<dt>•</dt>\n<dd>feeling agitated, restless, angry or irritable </dd>\n<dt>•</dt>\n<dd>panic attacks </dd>\n<dt>•</dt>\n<dd>trouble sleeping</dd>\n</dl>\n</td><td class=\"Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>new or worse irritability </dd>\n<dt>•</dt>\n<dd>acting aggressive, being angry or violent </dd>\n<dt>•</dt>\n<dd>acting on dangerous impulses </dd>\n<dt>•</dt>\n<dd>an extreme increase in activity or talking (mania) </dd>\n<dt>•</dt>\n<dd>other unusual changes in behavior or mood</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">   </span>3.<span class=\"Bold\">    EMSAM is not for children less than 12 years of age. EMSAM may cause a severe increase in blood pressure in children less than 12 years of age.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is EMSAM?</span>\n</p>\n<p>EMSAM is a prescription medicine used to treat a certain type of depression called Major Depressive Disorder (MDD). EMSAM belongs to the class of medicines known as monoamine oxidase inhibitors (MAOI). EMSAM is a transdermal system (patch) you apply to your skin.</p>\n<p>It is important to talk with your healthcare provider about the risks of treating depression and also the risk of not treating it. You should discuss all treatment choices with your healthcare provider.</p>\n<p>Talk to your healthcare provider if you do not think that your condition is getting better with EMSAM treatment.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Who should not use EMSAM?</span>\n</p>\n<p>\n<span class=\"Bold\">Using EMSAM with certain antidepressants and certain pain, cold and cough symptom medicines may cause a potentially life-threatening problem called serotonin syndrome (See “What are the possible side effects of EMSAM?”).</span>\n</p>\n<p>\n<span class=\"Bold\">Do not use EMSAM if you:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">take certain medicines including:</span>\n<dl>\n<dt>o</dt>\n<dd>selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, sertraline, or paroxetine</dd>\n<dt>o</dt>\n<dd>serotonin and norepinephrine reuptake inhibitors (SNRI) such as venlafaxine or duloxetine</dd>\n<dt>o</dt>\n<dd>clomipramine or imipramine (tricyclic antidepressants)</dd>\n<dt>o</dt>\n<dd>meperidine, tramadol, methadone, pentazocine, propoxyphene (opioid medicines)</dd>\n<dt>o</dt>\n<dd>dextromethorphan</dd>\n<dt>o</dt>\n<dd>carbamazepine</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">are less than 12 years of age</span>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">have a tumor on your adrenal gland called a pheochromocytoma</span>\n</dd>\n</dl>\n<p>Ask your healthcare provider or pharmacist if you are not sure if you take these medicines.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Before you use EMSAM, tell your healthcare provider about all of your medical conditions, including if you:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>have high blood pressure</dd>\n<dt>•</dt>\n<dd>have mania or bipolar disorder (manic depression)</dd>\n<dt>•</dt>\n<dd>have or had seizures or convulsions</dd>\n<dt>•</dt>\n<dd>drink alcohol</dd>\n<dt>•</dt>\n<dd>have any other medical conditions</dd>\n<dt>•</dt>\n<dd>are pregnant or plan to become pregnant. EMSAM may harm your unborn baby.</dd>\n<dt>•</dt>\n<dd>are breastfeeding or plan to breastfeed<span class=\"Bold\">.</span> It is not known if EMSAM passes into your breast milk. Do not breastfeed during treatment with EMSAM and for 5 days after the final dose. Talk to your healthcare provider about the best way to feed your baby if you use EMSAM.</dd>\n</dl>\n<p>\n<span class=\"Bold\">Tell your doctor about all the medicines you take</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements. EMSAM and some medicines may interact with each other, may not work as well, or may cause serious side effects when taken together.</p>\n<p>\n<span class=\"Bold\">Especially tell your healthcare provider if you take:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>other medicines to treat depression (antidepressants) including other MAOI medicines</dd>\n<dt>•</dt>\n<dd>decongestant medicines to treat cold or cough symptoms</dd>\n<dt>•</dt>\n<dd>over-the-counter diet pills or herbal weight-loss products</dd>\n<dt>•</dt>\n<dd>any herbal or dietary supplement that contains tyramine</dd>\n<dt>•</dt>\n<dd>medicines called stimulants or uppers (amphetamines)</dd>\n<dt>•</dt>\n<dd>buspirone, an anxiety medicine </dd>\n</dl>\n<p>\n<span class=\"Bold\">Some of these medicines need to be stopped for up to 5 weeks before you can start using EMSAM and for 2 weeks after you stop using EMSAM. </span>\n</p>\n<p>Ask your healthcare provider or pharmacist if you are not sure if you take these medicines.</p>\n<p>Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I use EMSAM?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Read the<span class=\"Bold\"> “Instructions for Use” </span>at the end of this Medication Guide for information about the right way to use EMSAM.</dd>\n<dt>•</dt>\n<dd>Use EMSAM exactly as your healthcare provider tells you to use it. </dd>\n<dt>•</dt>\n<dd>Use only 1 patch at a time.</dd>\n<dt>•</dt>\n<dd>Apply your patch right after you open the sealed pouch.</dd>\n<dt>•</dt>\n<dd>Change your patch 1 time each day at the same time each day. Choose a time of day that works best for you.</dd>\n<dt>•</dt>\n<dd>Your healthcare provider may need to change your dose of EMSAM until it is the right dose for you.</dd>\n<dt>•</dt>\n<dd>If you use too much EMSAM (overdose) you may have the following symptoms:</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>drowsiness</dd>\n<dt>o</dt>\n<dd>irritable</dd>\n<dt>o</dt>\n<dd>severe headache</dd>\n<dt>o</dt>\n<dd>your head, neck and spine arch backwards</dd>\n<dt>o</dt>\n<dd>fast or irregular pulse</dd>\n<dt>o</dt>\n<dd>blood circulation problem</dd>\n<dt>o</dt>\n<dd>high fever</dd>\n</dl>\n</td><td valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>dizziness</dd>\n<dt>o</dt>\n<dd>hyperactive</dd>\n<dt>o</dt>\n<dd>seeing things that are not there</dd>\n<dt>o</dt>\n<dd>seizures</dd>\n<dt>o</dt>\n<dd>high blood pressure</dd>\n<dt>o</dt>\n<dd>chest pain</dd>\n<dt>o</dt>\n<dd>sweating</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>fainting</dd>\n<dt>o</dt>\n<dd>agitated</dd>\n<dt>o</dt>\n<dd>stiff jaw</dd>\n<dt>o</dt>\n<dd>coma</dd>\n<dt>o</dt>\n<dd>low blood pressure</dd>\n<dt>o</dt>\n<dd>trouble breathing</dd>\n<dt>o</dt>\n<dd>cool, clammy skin</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>If you have any of these symptoms of EMSAM overdosage, remove your patch right away and call your healthcare provider or go to the nearest hospital emergency room right away. It may take up to 12 hours before you have these symptoms, and they may be worse 24 to 48 hours after you apply your EMSAM patch.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What should I avoid while using EMSAM?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>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.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Do not </span>eat foods or drink beverages that contain high amounts of tyramine while using EMSAM 9 mg or EMSAM 12 mg <span class=\"Bold\">or</span> for 2 weeks after you stop using EMSAM 9 mg or EMSAM 12 mg. Continue to avoid tyramine-rich foods or beverages for 2 weeks after a dose reduction to EMSAM 6 mg.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">If you start and continue EMSAM 6 mg you do not need to make any diet changes.</span>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">The table below lists foods and drinks you should avoid while you use EMSAM 9 mg and EMSAM 12 mg.</span>\n</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Type of Food and Drink</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Foods and drinks you should avoid that contain Tyramine</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Meat, Poultry, and Fish</p>\n</td><td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>air dried, aged and fermented meats, sausages and salamis</dd>\n<dt>•</dt>\n<dd>pickled herring</dd>\n<dt>•</dt>\n<dd>any spoiled or improperly stored meat, poultry, and fish. These are foods that have a change in color, odor, or become moldy.</dd>\n<dt>•</dt>\n<dd>spoiled or improperly stored animal livers</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Vegetables</p>\n</td><td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>broad bean pods (fava bean pods)</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Dairy (milk products)</p>\n</td><td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>aged cheeses</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Drinks</p>\n</td><td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>all tap beers and other beers that have not been pasteurized</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Other</p>\n</td><td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>concentrated yeast extract (such as Marmite)</dd>\n<dt>•</dt>\n<dd>sauerkraut</dd>\n<dt>•</dt>\n<dd>most soybean products (including soy sauce and tofu) </dd>\n<dt>•</dt>\n<dd>over-the-counter supplements containing tyramine</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>All foods you eat must be fresh or properly frozen.</dd>\n<dt>•</dt>\n<dd>Avoid foods when you do not know how those foods should be stored.</dd>\n<dt>•</dt>\n<dd>Ask your healthcare provider if you are not sure if certain foods and drinks contain tyramine.</dd>\n<dt>•</dt>\n<dd>Do not drive, operate heavy machinery or do other dangerous activities until you know how EMSAM affects you. </dd>\n<dt>•</dt>\n<dd>You should not drink alcohol while using EMSAM.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of EMSAM?</span>\n</p>\n<p>\n<span class=\"Bold\">EMSAM may cause serious side effects, including:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">See “What is the most important information I should know about EMSAM?”</span>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">serotonin syndrome.</span> A potentially life-threatening problem called serotonin syndrome can happen when you use EMSAM while you take certain medicines called MAOIs. Symptoms of serotonin syndrome include: </dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>agitation</dd>\n<dt>o</dt>\n<dd>coma</dd>\n<dt>o</dt>\n<dd>dizziness</dd>\n<dt>o</dt>\n<dd>fever</dd>\n<dt>o</dt>\n<dd>stiff muscles</dd>\n<dt>o</dt>\n<dd>nausea</dd>\n</dl>\n</td><td valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>seeing things that are not there (hallucinations)</dd>\n<dt>o</dt>\n<dd>rapid pulse</dd>\n<dt>o</dt>\n<dd>sweating</dd>\n<dt>o</dt>\n<dd>seizures</dd>\n<dt>o</dt>\n<dd>muscle twitching</dd>\n<dt>o</dt>\n<dd>vomiting</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>confusion</dd>\n<dt>o</dt>\n<dd>low blood pressure</dd>\n<dt>o</dt>\n<dd>flushing</dd>\n<dt>o</dt>\n<dd>tremors</dd>\n<dt>o</dt>\n<dd>become unstable</dd>\n<dt>o</dt>\n<dd>diarrhea</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">If you suddenly have these symptoms, stop using EMSAM immediately by removing the patch and go to the nearest hospital emergency room right away.</p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">a sudden, severe increase in blood pressure (hypertensive crisis). A hypertensive crisis can happen when you eat certain foods and drink certain beverages while you use EMSAM. </span>A hypertensive crisis can lead to stroke and death. <br/>See<span class=\"Bold\"> “What should I avoid while using EMSAM?” </span>\n<br/>\n<span class=\"Bold\">A hypertensive crisis can also happen if you use EMSAM with certain other medicines. See “Who should not use EMSAM?”</span>\n<br/>Symptoms of a hypertensive crisis include:</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>sudden, severe headache</dd>\n<dt>o</dt>\n<dd>vomiting</dd>\n<dt>o</dt>\n<dd>a fast heartbeat (palpitations) or a change in the way your heart beats </dd>\n<dt>o</dt>\n<dd>the pupils in your eyes increase in size</dd>\n<dt>o</dt>\n<dd>fast or slow heart beat with chest pain</dd>\n</dl>\n</td><td class=\"Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>nausea</dd>\n<dt>o</dt>\n<dd>stiff or sore neck</dd>\n<dt>o</dt>\n<dd>excessive sweating, sometimes with fever or cold clammy skin</dd>\n<dt>o</dt>\n<dd>light bothers your eyes</dd>\n<dt>o</dt>\n<dd>bleeding in your brain</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>If you suddenly have these symptoms, go to the nearest hospital emergency room right away.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">mania or hypomania</span> (manic episodes) in people who have a history of mania. Symptoms of manic episodes include:</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>greatly increased energy</dd>\n<dt>o</dt>\n<dd>severe problems sleeping</dd>\n<dt>o</dt>\n<dd>racing thoughts</dd>\n</dl>\n</td><td valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>reckless behavior</dd>\n<dt>o</dt>\n<dd>unusually grand ideas</dd>\n<dt>o</dt>\n<dd>excessive happiness or irritability</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>talking more or faster than usual</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">The most common side effects of EMSAM include:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>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 healthcare provider.</dd>\n<dt>•</dt>\n<dd>headache</dd>\n<dt>•</dt>\n<dd>trouble sleeping (insomnia)</dd>\n<dt>•</dt>\n<dd>diarrhea</dd>\n<dt>•</dt>\n<dd>dry mouth</dd>\n<dt>•</dt>\n<dd>indigestion</dd>\n<dt>•</dt>\n<dd>rash</dd>\n<dt>•</dt>\n<dd>sore throat</dd>\n<dt>•</dt>\n<dd>sinus infection</dd>\n</dl>\n<p>These are not all the possible side effects of EMSAM. <span class=\"Bold\">Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store EMSAM?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Store EMSAM at room temperature between 68°F to 77°F (20°C to 25°C).</dd>\n<dt>•</dt>\n<dd>Store EMSAM in the sealed pouch it comes in until you are ready to use it.</dd>\n<dt>•</dt>\n<dd>Keep EMSAM and all medicines out of the reach of children.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of EMSAM.</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use EMSAM for a condition for which it was not prescribed. Do not give EMSAM to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about EMSAM that is written for health professionals.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in EMSAM?</span>\n</p>\n<p>\n<span class=\"Bold\">Active Ingredient:</span> selegiline</p>\n<p>\n<span class=\"Bold\">Inactive Ingredients:</span> acrylic adhesive, ethylene vinyl acetate, polyethylene, polyester, polyurethane, and silicone coated polyester</p>\n<p>Distributed by: <span class=\"Bold\">Mylan Specialty L.P., </span>Morgantown, WV 26505 U.S.A.</p>\n<p>Manufactured for:<br/>\n<span class=\"Bold\">Somerset Pharmaceuticals, Inc.</span>\n<br/>Morgantown, WV 26505 U.S.A.</p>\n<p>For more information, go to <span class=\"Underline\">www.EMSAM.com</span> or call 1-800-395-3376.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Medication Guide has been approved by the U.S. Food and Drug AdministrationIssued: 5/2020

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EMSAM® [EM sam] (selegiline transdermal system)

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Step 1. Where to apply EMSAM

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Step 2. Before you apply EMSAM

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Step 3. How to apply EMSAM

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Step 4. Removing and disposing of your patch

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This Instructions for Use has been approved by the U.S. Food and Drug Administration.

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DISTRIBUTED BY: Mylan Specialty L.P. Morgantown, WV 26505 U.S.A.

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MANUFACTURED FOR: Somerset Pharmaceuticals, Inc. Morgantown, WV 26505 U.S.A.

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Revised: 5/2020 EMSAM:PIR15/EMSAM:PLR15

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NDC-49502-900-30

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EACH UNIT DOSE PACKAGE IS NOT CHILD RESISTANT Rx only

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EMSAM® (selegiline transdermal system) 6 mg/24 h

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FOR TRANSDERMAL USE ONLY

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Patient: Read enclosed Medication Guide.

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Pharmacist: Dispense with enclosed Medication Guide.

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30 TRANSDERMAL SYSTEMS

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INSTRUCTIONS FOR APPLICATION

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1. Select and prepare an appropriate site on the upper chest or back (below the neck and above the waist), the upper thigh, or the outer surface of the upper arm, as directed in the enclosed Medication Guide.

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2. Bend both sides of the clear peelable liner. Peel off one strip only of the clear liner. Avoid touching the sticky side of the transdermal system.

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3. Apply sticky side of the transdermal system to the chosen skin site. Remove remaining strip, gently roll remaining part onto skin, and press transdermal system firmly in place with the tips of your fingers.

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For more detailed instructions, read enclosed Medication Guide.

{ "type": "p", "children": [], "text": "\nFor more detailed instructions, read enclosed Medication Guide.\n" }

Dosage: Apply one (1) transdermal system every 24 hours.  Read enclosed Medication Guide.

{ "type": "p", "children": [], "text": "\nDosage: Apply one (1) transdermal system every 24 hours.  Read enclosed Medication Guide. \n" }

Each transdermal system has a release rate of 6 mg selegiline per 24 hour period.  Wear only one transdermal system at a time.

{ "type": "p", "children": [], "text": "\nEach transdermal system has a release rate of 6 mg selegiline per 24 hour period.  Wear only one transdermal system at a time.\n" }

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]" }

Dist. by Mylan Specialty L.P. Morgantown, WV 26505 U.S.A.

{ "type": "p", "children": [], "text": "Dist. by\nMylan Specialty L.P.\nMorgantown, WV 26505 U.S.A." }

Mfd. for Somerset Pharmaceuticals, Inc. Morgantown, WV 26505 U.S.A.

{ "type": "p", "children": [], "text": "Mfd. for\nSomerset Pharmaceuticals, Inc.\nMorgantown, WV 26505 U.S.A." }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

S033:93:30C:R10

{ "type": "p", "children": [], "text": "\nS033:93:30C:R10\n" }

NDC-49502-901-30

{ "type": "p", "children": [], "text": "\nNDC-49502-901-30\n" }

EACH UNIT DOSE PACKAGE IS NOT CHILD RESISTANT Rx only

{ "type": "p", "children": [], "text": "\nEACH UNIT DOSE PACKAGE IS NOT CHILD RESISTANT\n\nRx only\n" }

EMSAM® (selegiline transdermal system) 9 mg/24 h

{ "type": "p", "children": [], "text": "\nEMSAM®\n\n(selegiline transdermal system)\n\n9 mg/24 h\n" }

Important: Do not eat certain foods. Read enclosed Medication Guide.

{ "type": "p", "children": [], "text": "\nImportant: Do not eat certain foods.\n\nRead enclosed Medication Guide.\n" }

FOR TRANSDERMAL USE ONLY

{ "type": "p", "children": [], "text": "\nFOR TRANSDERMAL USE ONLY\n" }

Pharmacist: Dispense with enclosed Medication Guide.

{ "type": "p", "children": [], "text": "\nPharmacist: Dispense with enclosed \n\nMedication Guide.\n" }

30 TRANSDERMAL SYSTEMS

{ "type": "p", "children": [], "text": "\n30 TRANSDERMAL\n\nSYSTEMS\n" }

INSTRUCTIONS FOR APPLICATION

{ "type": "p", "children": [], "text": "\nINSTRUCTIONS FOR APPLICATION\n" }

1. Select and prepare an appropriate site on the upper chest or back (below the neck and above the waist), the upper thigh, or the outer surface of the upper arm, as directed in the enclosed Medication Guide.

{ "type": "p", "children": [], "text": "\n1. Select and prepare an appropriate site on the upper chest or back (below the neck and above the waist), the upper thigh, or the outer surface of the upper arm, as directed in the enclosed Medication Guide." }

2. Bend both sides of the clear peelable liner. Peel off one strip only of the clear liner. Avoid touching the sticky side of the transdermal system.

{ "type": "p", "children": [], "text": "\n2. Bend both sides of the clear peelable liner. Peel off one strip only of the clear liner. Avoid touching the sticky side of the transdermal system." }

3. Apply sticky side of the transdermal system to the chosen skin site. Remove remaining strip, gently roll remaining part onto skin, and press transdermal system firmly in place with the tips of your fingers.

{ "type": "p", "children": [], "text": "\n3. Apply sticky side of the transdermal system to the chosen skin site. Remove remaining strip, gently roll remaining part onto skin, and press transdermal system firmly in place with the tips of your fingers." }

For more detailed instructions, read enclosed Medication Guide.

{ "type": "p", "children": [], "text": "\nFor more detailed instructions, read enclosed Medication Guide.\n" }

Dosage: Apply one (1) transdermal system every 24 hours.  Read enclosed Medication Guide.

{ "type": "p", "children": [], "text": "\nDosage: Apply one (1) transdermal system every 24 hours.  Read enclosed Medication Guide. \n" }

Each transdermal system has a release rate of 9 mg selegiline per 24 hour period.  Wear only one transdermal system at a time.

{ "type": "p", "children": [], "text": "\nEach transdermal system has a release rate of 9 mg selegiline per 24 hour period.  Wear only one transdermal system at a time.\n" }

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]" }

Dist. by Mylan Specialty L.P. Morgantown, WV 26505 U.S.A.

{ "type": "p", "children": [], "text": "Dist. by\nMylan Specialty L.P.\nMorgantown, WV 26505 U.S.A." }

Mfd. for Somerset Pharmaceuticals, Inc. Morgantown, WV 26505 U.S.A.

{ "type": "p", "children": [], "text": "Mfd. for\nSomerset Pharmaceuticals, Inc.\nMorgantown, WV 26505 U.S.A." }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

S044:93:30C:R10

{ "type": "p", "children": [], "text": "\nS044:93:30C:R10\n" }

NDC-49502-902-30

{ "type": "p", "children": [], "text": "\nNDC-49502-902-30\n" }

EACH UNIT DOSE PACKAGE IS NOT CHILD RESISTANT Rx only

{ "type": "p", "children": [], "text": "\nEACH UNIT DOSE PACKAGE IS NOT CHILD RESISTANT\n\nRx only\n" }

EMSAM® (selegiline transdermal system) 12 mg/24 h

{ "type": "p", "children": [], "text": "\nEMSAM®\n\n(selegiline transdermal system)\n\n12 mg/24 h\n" }

Important: Do not eat certain foods. Read enclosed Medication Guide.

{ "type": "p", "children": [], "text": "\nImportant: Do not eat certain foods.\n\nRead enclosed Medication Guide.\n" }

FOR TRANSDERMAL USE ONLY

{ "type": "p", "children": [], "text": "\nFOR TRANSDERMAL USE ONLY\n" }

Pharmacist: Dispense with enclosed Medication Guide.

{ "type": "p", "children": [], "text": "\nPharmacist: Dispense with enclosed \n\nMedication Guide.\n" }

30 TRANSDERMAL SYSTEMS

{ "type": "p", "children": [], "text": "\n30 TRANSDERMAL\n\nSYSTEMS\n" }

INSTRUCTIONS FOR APPLICATION

{ "type": "p", "children": [], "text": "\nINSTRUCTIONS FOR APPLICATION\n" }

1. Select and prepare an appropriate site on the upper chest or back (below the neck and above the waist), the upper thigh, or the outer surface of the upper arm, as directed in the enclosed Medication Guide.

{ "type": "p", "children": [], "text": "\n1. Select and prepare an appropriate site on the upper chest or back (below the neck and above the waist), the upper thigh, or the outer surface of the upper arm, as directed in the enclosed Medication Guide." }

2. Bend both sides of the clear peelable liner. Peel off one strip only of the clear liner. Avoid touching the sticky side of the transdermal system.

{ "type": "p", "children": [], "text": "\n2. Bend both sides of the clear peelable liner. Peel off one strip only of the clear liner. Avoid touching the sticky side of the transdermal system." }

3. Apply sticky side of the transdermal system to the chosen skin site. Remove remaining strip, gently roll remaining part onto skin, and press transdermal system firmly in place with the tips of your fingers.

{ "type": "p", "children": [], "text": "\n3. Apply sticky side of the transdermal system to the chosen skin site. Remove remaining strip, gently roll remaining part onto skin, and press transdermal system firmly in place with the tips of your fingers." }

For more detailed instructions, read enclosed Medication Guide.

{ "type": "p", "children": [], "text": "\nFor more detailed instructions, read enclosed Medication Guide.\n" }

Dosage: Apply one (1) transdermal system every 24 hours.  Read enclosed Medication Guide.

{ "type": "p", "children": [], "text": "\nDosage: Apply one (1) transdermal system every 24 hours.  Read enclosed Medication Guide. \n" }

Each transdermal system has a release rate of 12 mg selegiline per 24 hour period.  Wear only one transdermal system at a time.

{ "type": "p", "children": [], "text": "\nEach transdermal system has a release rate of 12 mg selegiline per 24 hour period.  Wear only one transdermal system at a time.\n" }

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]" }

Dist. by Mylan Specialty L.P. Morgantown, WV 26505 U.S.A.

{ "type": "p", "children": [], "text": "Dist. by \nMylan Specialty L.P.\nMorgantown, WV 26505 U.S.A." }

Mfd. for Somerset Pharmaceuticals, Inc. Morgantown, WV 26505 U.S.A.

{ "type": "p", "children": [], "text": "Mfd. for\nSomerset Pharmaceuticals, Inc.\nMorgantown, WV 26505 U.S.A." }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

S055:93:30C:R10

{ "type": "p", "children": [], "text": "\nS055:93:30C:R10\n" }

ZELAPAR is indicated as an adjunct in the management of patients with Parkinson’s disease being treated with levodopa/carbidopa who exhibit deterioration in the quality of their response to this therapy. There is no evidence from controlled studies that ZELAPAR has any beneficial effect in the absence of concurrent levodopa therapy [see Clinical Studies (14)].

{ "type": "p", "children": [], "text": "ZELAPAR is indicated as an adjunct in the management of patients with Parkinson’s disease being treated with levodopa/carbidopa who exhibit deterioration in the quality of their response to this therapy. There is no evidence from controlled studies that ZELAPAR has any beneficial effect in the absence of concurrent levodopa therapy [see Clinical Studies (14)]." }

Initiate treatment with 1.25 mg given once a day for at least 6 weeks. After 6 weeks, the dose may be increased to 2.5 mg given once a day if a desired benefit has not been achieved and the patient is tolerating ZELAPAR. There is no evidence that doses greater than 2.5 mg a day provide additional benefit, and they should ordinarily be avoided because of the potential increased risk of adverse events.

Take ZELAPAR in the morning before breakfast and without liquid. Patients should avoid ingesting food or liquids for 5 minutes before and after taking ZELAPAR.

Patients should not attempt to push ZELAPAR through the foil backing. Patients should PEEL BACK the backing of one or two blisters (as prescribed) with dry hands, and GENTLY remove the tablet(s). Patients should IMMEDIATELY place the ZELAPAR tablet(s) on top of the tongue where it will disintegrate in seconds.

In patients with mild to moderate hepatic disease (Child-Pugh score 5 to 9), the daily dose of ZELAPAR should be reduced (from 2.5 to 1.25 mg daily), depending on the clinical response. ZELAPAR is not recommended in patients with severe hepatic impairment (Child-Pugh score greater than 9) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

No dose adjustment of ZELAPAR is required in patients with mild to moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min). The maintenance dose of ZELAPAR (1.25 mg or 2.5 mg) is determined by the individual clinical response. ZELAPAR is not recommended in patients with severe renal impairment and patients with end-stage renal disease [ESRD] (creatinine clearance [CLcr] <30 mL/min) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

ZELAPAR Orally Disintegrating Tablets are pale yellow, imprinted with a stylized “V”, and contain 1.25 mg selegiline hydrochloride.

{ "type": "p", "children": [], "text": "ZELAPAR Orally Disintegrating Tablets are pale yellow, imprinted with a stylized “V”, and contain 1.25 mg selegiline hydrochloride. " }

ZELAPAR is contraindicated in patients with:

{ "type": "p", "children": [], "text": "ZELAPAR is contraindicated in patients with:" }

{ "type": "", "children": [], "text": "" }

ZELAPAR should not be used at daily doses exceeding those recommended (2.5 mg/day) because of the risks associated with non-selective inhibition of MAO [see Drug Interactions (7.3) and Clinical Pharmacology (12.2)].

The selectivity of ZELAPAR for MAO-B may not be absolute even at the recommended daily dose of 2.5 mg daily. The selectivity of MAO-B inhibitors typically decreases, and it is ultimately lost as the dose is increased beyond recommended doses. Hypertensive reactions associated with ingestion of tyramine-containing foods have been reported even in patients taking the recommended daily dose of swallowed selegiline, a dose which is generally believed to be selective for MAO-B. Selectivity for MAO-B inhibition is gradually lost with increasing daily doses. An increase in tyramine sensitivity for blood pressure responses appears to begin at a dose of 5 mg ZELAPAR daily [see Drug Interactions (7.5)]. However, the precise dose at which ZELAPAR becomes a non-selective inhibitor of all MAO enzymes in individual patients is unknown.

Reports of hypertensive reactions have occurred in patients who ingested tyramine-containing consumables (i.e., food or drink) while receiving swallowed selegiline at the recommended dose (a dose believed to be relatively selective for MAO-B).

The safe use of ZELAPAR at doses above 2.5 mg daily without dietary tyramine restrictions has not been established.

A pharmacodynamic study showed increased tyramine sensitivity for increasing blood pressure and decreased selectivity for MAO-B with dosing above the recommended level (2.5 mg daily) [see Clinical Pharmacology (12.2)].

Uncontrolled hypertension has been reported when taking the recommended dose of swallowed selegiline and a sympathomimetic medication (ephedrine).

After starting ZELAPAR, monitor patients for new onset hypertension or exacerbation of hypertension that is not adequately controlled.

Serotonin syndrome and hyperpyrexia have been reported with the combined treatment of an antidepressant (e.g., selective serotonin reuptake inhibitors-SSRIs, serotonin-norepinephrine reuptake inhibitors-SNRIs, tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants) and a non-selective MAOI (e.g., phenelzine, tranylcypromine) or selective MAO-B inhibitors, such as selegiline (ELDEPRYL), rasagiline (AZILECT), and olanzapine (Zydis) selegiline (ZELAPAR).

Serotonin syndrome is a potentially serious condition, which can result in death. Typical clinical signs and symptoms include behavioral and cognitive/mental status changes (e.g., confusion, hypomania, hallucinations, agitation, delirium, headache, and coma), autonomic effects (e.g., syncope, shivering, sweating, high fever/hyperthermia, hypertension, hypotension, tachycardia, nausea, diarrhea), and somatic effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifested by clonus, and tremor).

In the post-marketing period, fatal and non-fatal cases of serotonin syndrome have been reported in patients treated with antidepressants concomitantly with ZELAPAR [see Contraindications (4) and Drug Interactions (7.1, 7.2, 7.3)].

Clinical studies of ZELAPAR did not allow concomitant use of any selective serotonin re-uptake inhibitor (e.g., fluoxetine-Prozac, fluvoxamine-Luvox, paroxetine-Paxil, sertraline, venlafaxine-Effexor, or nefazodone-Serzone) or any non-selective serotonin reuptake inhibiting antidepressant drug (except when taken at a low dose and only at night for the purpose of effective sleep) with ZELAPAR.

Because the mechanisms responsible for these reactions are not fully understood, avoid the combination of ZELAPAR with any antidepressant. At least 14 days should elapse between discontinuation of ZELAPAR and initiation of treatment with a SSRI, SNRI, tricyclic, tetracyclic, or triazolopyridine antidepressant. In patients taking antidepressants with a long half-life (e.g., fluoxetine and its active metabolite), allow at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) to elapse between discontinuation of fluoxetine and initiation of ZELAPAR [see Drug Interactions (7.6)].

Patients with Parkinson’s disease treated with ZELAPAR or other drugs increasing dopaminergic tone have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence, some did not perceive warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported as late as one year after initiation of treatment.

It has been reported that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment.

Somnolence may occur in patients receiving ZELAPAR. There was an increased risk for somnolence in geriatric patients (≥65 years) vs. non-geriatric patients treated with ZELAPAR. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients should be advised to exercise caution while driving, operating machines, or working at heights during treatment with ZELAPAR. Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities during treatment with ZELAPAR.

Before initiating treatment with ZELAPAR, advise patients about the potential to develop drowsiness and specifically ask about factors that may increase this risk, such as concomitant sedating medications and the presence of sleep disorders. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), ZELAPAR should ordinarily be discontinued. If a decision is made to continue ZELAPAR, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Assessments of orthostatic (supine and standing) blood pressures at different times throughout the 12 week study period in two controlled trials showed that the frequency of orthostatic hypotension (>20 mm Hg decrease in systolic blood pressure and/or >10 mm Hg decrease in diastolic blood pressure) was greater with ZELAPAR treatment than with placebo treatment. Patients taking ZELAPAR were most likely to experience a decline in systolic and diastolic blood pressure at 8 weeks (2 weeks after initiating 2.5 mg ZELAPAR). At that time, the incidence of systolic orthostatic hypotension was about 21% in ZELAPAR-treated patients and 9% in placebo-treated patients. The incidence of diastolic orthostatic hypotension was about 12% in ZELAPAR-treated patients and about 4% in placebo-treated patients. Thus, it appears that there may be an increased risk for orthostatic hypotension in the period after increasing the daily dose of ZELAPAR from 1.25 to 2.5 mg.

The incidence of orthostatic hypotension was higher in geriatric patients (≥65 years) than in non-geriatric patients. In the geriatric patients, orthostatic hypotension occurred in about 3% of ZELAPAR-treated patients compared to 0% of placebo-treated patients.

ZELAPAR may potentiate dopaminergic side effects of levodopa and may cause dyskinesia or exacerbate preexisting dyskinesia. In controlled trials, the incidence of dyskinesia was 6% in ZELAPAR-treated patients and 3% in placebo-treated patients. Decreasing the dose of levodopa may lessen dyskinesia. The incidence of dyskinesia causing study discontinuation was greater on ZELAPAR than on placebo.

In controlled trials, hallucination was reported by 4% of ZELAPAR-treated patients and 2% in placebo-treated patients. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in about 1% of ZELAPAR-treated patients, compared to no patient on placebo.

Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during ZELAPAR treatment or after starting or increasing the dose of ZELAPAR. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.

Patients with a major psychotic disorder should ordinarily not be treated with ZELAPAR because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of ZELAPAR [see Drug Interactions (7.8)].

Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including ZELAPAR, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge eating, or other urges while being treated with ZELAPAR. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ZELAPAR.

Although not reported with ZELAPAR in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.

In the controlled clinical trials, periodic examinations of the tongue and oral mucosa were performed. At the end of the study, the frequency of mild oropharyngeal abnormality (e.g., swallowing pain, mouth pain, discrete areas of focal reddening, multiple foci of reddening, edema, and/or ulceration) in patients without similar abnormality at baseline was 10% in ZELAPAR-treated patients compared to 3% in placebo-treated patients.

Phenylalanine can be harmful to patients with phenylketonuria (PKU). ZELAPAR contains phenylalanine, a component of aspartame. Each ZELAPAR 1.25 mg tablet contains 1.25 mg phenylalanine. Patients taking the 2.5 mg dose of ZELAPAR will receive 2.5 mg phenylalanine. Before prescribing ZELAPAR to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including ZELAPAR.

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction per total number of patients treated) 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 incidence of adverse reactions observed in clinical practice.

Because the controlled trials performed during premarketing development both used a titration design (1.25 mg per day for 6 weeks, followed by 2.5 mg per day for 6 weeks), with a resultant confounding of time and dose, it was impossible to adequately evaluate the effects of dose on the incidence of adverse reactions.

The most common adverse reactions (treatment difference incidence at least 3% greater than placebo incidence) reported in the double-blind, placebo-controlled trials during ZELAPAR treatment were constipation, skin disorders, vomiting, dizziness, dyskinesia, insomnia, dyspnea, myalgia, and rash (see Table 1).

Of the 194 patients treated with ZELAPAR in the double-blind, placebo-controlled trials, 5% discontinued due to adverse reactions compared to 1% of the 98 patients who received placebo. Most common adverse reactions causing discontinuation of treatment included dizziness, chest pain, accidental injury, and myasthenia.

Incidence in Controlled Clinical Trials

Table 1 lists the adverse reactions reported in the placebo-controlled trials after at least one dose of ZELAPAR (incidence 2% or greater).

<div class="scrollingtable"><table width="90.04%"> <caption> <span>Table 1: Adverse Reactions<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> in Double-Blind, Placebo-Controlled Trials with an Incidence ≥2% of Patients Treated with ZELAPAR and More Frequent than the Placebo Group</span> </caption> <col width="38%"/> <col width="24%"/> <col width="38%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold"><span class="Underline">Body System/</span></span> <br/> <span class="Bold"><span class="Underline">Adverse Event</span></span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold"><span class="Underline">ZELAPAR</span></span> <br/> <span class="Bold"><span class="Underline">1.25/2.5 mg</span></span> <br/> <span class="Bold"><span class="Underline">N=194</span></span> <br/> <span class="Bold"><span class="Underline">%</span></span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold"><span class="Underline">Placebo</span></span> <br/> <span class="Bold"><span class="Underline">N=98</span></span> <br/> <span class="Bold"><span class="Underline">%</span></span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Patients may have reported multiple adverse experiences during the study or at discontinuation; thus patients may be included in more than one category.</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Skin disorders represent any new skin abnormality that would not be characterized as rash or neoplastic lesion. These include events such as skin ulcer, fungal dermatitis, skin hypertrophy, contact dermatitis, herpes simplex, dry skin, sweating, urticaria, and pruritus.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Body as a Whole</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="bottom"></td><td class="Botrule Lrule Rrule Toprule" valign="bottom"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Back Pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Chest Pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Cardiovascular System</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypertension</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Digestive System</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Stomatitis</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dyspepsia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Constipation</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dysphagia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Flatulence</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Tooth Disorder</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Hemic and Lymphatic System</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Ecchymosis</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Metabolic and Nutritional Disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypokalemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal System</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Leg Cramps</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Myalgia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Nervous System</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dizziness</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Insomnia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dyskinesia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dry Mouth</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hallucinations</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Somnolence </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Tremor</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Ataxia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Depression</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Respiratory System</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pharyngitis</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rhinitis</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dyspnea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Skin and Appendages</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rash</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Skin Disorders<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> </tbody> </table></div>

Certain adverse reactions were reported at a higher frequency by patients ≥65 years of age compared to patients <65 years [see Use in Specific Populations (8.5)].

No consistent differences in the incidences of adverse reactions were observed between male and female patients.

There were insufficient data to assess the impact of race on the incidence of adverse reactions.

Because serious, sometimes fatal reactions have been precipitated with concomitant use of opioid drugs (e.g., meperidine and its derivatives, methadone, or tramadol) and MAOIs, including selective MAO-B inhibitors, concomitant use of these drugs with ZELAPAR is contraindicated [see Contraindications (4) and Warnings and Precautions (5.2)]. At least 14 days should elapse between discontinuation of ZELAPAR and initiation of treatment with these drugs.

The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. Therefore, in view of ZELAPAR’s MAO inhibitory activity, dextromethorphan should not be used concomitantly with ZELAPAR [see Contraindications (4)].

ZELAPAR is contraindicated for concomitant use with other drugs in the MAOI class or other drugs that are potent inhibitors of monoamine oxidase (including linezolid, an oxazolidinone antibacterial, which also has reversible nonselective MAO inhibition activity) because of the increased risk for hypertensive crisis [see Contraindications (4) and Warnings and Precautions (5.1)]. At least 14 days should elapse between discontinuation of ZELAPAR and initiation of treatment with other MAOIs.

Uncontrolled hypertension, including hypertensive crisis, has been reported when taking the recommended dose of swallowed selegiline and a sympathomimetic medication (ephedrine).

The enzyme, monoamine oxidase (MAO) (primarily type A), in the gastrointestinal tract and liver provides protection from ingested amines (e.g., tyramine) that, if absorbed, have the capacity to cause uncontrolled hypertension (tyramine reaction). If MAO is inhibited in the gastrointestinal tract and liver, ingestion of exogenous amines contained in some foods such as fermented cheese, herring, or over-the-counter cough/cold medicines may be absorbed systemically causing release of norepinephrine and a rise in systemic blood pressure with the potential for uncontrolled hypertension. Selective MAO-B inhibitors lose their selectivity for MAO-B when taken in doses higher than recommended. Non-selective MAO-A inhibitors or MAO-B inhibitors in higher than recommended doses may result in MAO-A inhibition in the gastrointestinal tract and liver.

Results of a tyramine challenge study indicate that ZELAPAR is relatively selective for MAO-B at the recommended dose. In most cases, there is no need for dietary tyramine restriction in patients prescribed ZELAPAR [see Clinical Pharmacology (12.2)] at the recommended dose. Because the selectivity for inhibiting MAO-B diminishes as the dose of ZELAPAR is increased above the recommended daily dose, patients should not take more than 2.5 mg of ZELAPAR daily.

Reports of hypertensive reactions have occurred in patients who ingested tyramine-containing consumables (i.e., food or drink) while receiving swallowed selegiline at the recommended dose (a dose believed to be relatively selective for MAO-B). Hypertensive crisis has also been reported with ZELAPAR use that was not above the recommended dosing.

Uncontrolled hypertension has been reported when taking the recommended dose of swallowed selegiline and a sympathomimetic medication (ephedrine).

Severe toxicity has also been reported in patients receiving the combination of tricyclic antidepressants and swallowed selegiline, or selective serotonin reuptake inhibitors and swallowed selegiline [see Warnings and Precautions (5.2)].

Adequate studies have not been done investigating the effect of CYP3A4 inducers on selegiline. Drugs that induce CYP3A4 (e.g., phenytoin, carbamazepine, nafcillin, phenobarbital, and rifampin) should be used with caution.

It is possible that dopamine antagonists, such as antipsychotics or metoclopramide, could diminish the effectiveness of ZELAPAR.

Risk Summary

There are no adequate data on the developmental risk associated with the use of ZELAPAR in pregnant women. In animal studies, administration of selegiline during pregnancy was associated with developmental toxicity (decreased embryofetal and postnatal offspring growth and survival) at doses greater than those used clinically.

In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage in the indicated population is unknown.

Data

Animal Data

In rats administered selegiline orally (5, 10, and 40 mg/kg/day) throughout the period of organogenesis, a decrease in fetal body weight was observed at the mid and high doses. The no-effect dose for embryofetal developmental toxicity in rats (5 mg/kg/day) is approximately 20 times the maximum recommended human dose (MRHD) of 2.5 mg/day on a mg/m2 basis.

In rabbits administered selegiline orally (5, 30, and 60 mg/kg/day) throughout the period of organogenesis, embryolethality was observed at the highest dose tested and reduced fetal body weight was observed at the mid and high doses. The no-effect dose for embryofetal developmental toxicity in rabbits (5 mg/kg/day) is approximately 40 times the MRHD on a mg/m2 basis.

In rats administered selegiline orally (0.3, 1, and 10 mg/kg/day) during gestation and lactation, decreases in offspring survival and body weights were observed at the highest dose tested. The no-effect dose for pre- and postnatal developmental toxicity (1 mg/kg/day) is approximately 4 times the MRHD on a mg/m2 basis.

Risk Summary

There are no data on the presence of selegiline or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Selegiline and metabolites were detected in rat milk at levels higher than those in maternal plasma.

Because of the potential for serious adverse reactions in breastfed infants from ZELAPAR, including the potential for hypertensive reactions, advise a woman that breastfeeding is not recommended during treatment with ZELAPAR and for 7 days after the final dose.

Safety and effectiveness in pediatric patients have not been established.

The overall incidence of adverse reactions was increased in geriatric patients (≥65 years) compared to non-geriatric patients (<65 years). Clinical studies did not include a sufficient number of geriatric subjects older than 75 years to determine whether they respond differently to ZELAPAR.

Analysis of adverse reaction incidence in each group was conducted to calculate and compare relative risk (ZELAPAR % / Placebo %) for each treatment. The relative risk was ≥2 fold higher for ZELAPAR treatment in the geriatric patients compared to the non-geriatric patients for hypertension, orthostatic/postural hypotension [see Warnings and Precautions (5.4)]. The incidence of orthostatic hypotension by measurement of blood pressure was also higher in geriatric patients than in non-geriatric patients. In the geriatric patients, the treatment difference for incidence of orthostatic hypotension determined by supine and standing blood measurements was 3%.

Patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9) may require a dose reduction of ZELAPAR (from 2.5 to 1.25 mg daily) depending on the clinical response. ZELAPAR is not recommended in patients with severe hepatic impairment (Child-Pugh score >9) [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

No dose adjustment of ZELAPAR is required in patients with mild to moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min). ZELAPAR is not recommended in patients with severe renal impairment and patients with end-stage renal disease [ESRD] (CLcr <30 mL/min) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Experience gained during development of the 5 mg swallowed dosage form reveals that some individuals exposed to doses of 600 mg of d,l-selegiline suffered severe hypotension and psychomotor agitation. Small increments in serum BUN and creatinine have been observed in patients who received ZELAPAR 10 mg daily (4 times the recommended dose).

Since the selective inhibition of MAO-B by ZELAPAR is achieved only at doses in the range recommended for the treatment of Parkinson’s disease (e.g., 2.5 mg/day), overdoses are likely to cause significant inhibition of both MAO-A and MAO-B. Consequently, the signs and symptoms of overdose may resemble those observed with marketed non-selective MAO inhibitors [e.g., tranylcypromine (PARNATE®), isocarboxazid (MARPLAN®), and phenelzine (NARDIL®)]. For this reason, in cases of overdose with selegiline, dietary tyramine restriction should be observed for several weeks to avoid the risk of a hypertensive reaction.

NOTE: The following description of presenting symptoms and clinical course is based upon overdose descriptions of non-selective MAO inhibitors and does not include information from patients who have overdosed on oral selegiline or ZELAPAR.

Characteristically, signs and symptoms of non-selective MAO inhibitor overdose may not appear immediately. Delays of up to 12 hours between ingestion of drug and the appearance of signs may occur. Importantly, the peak intensity of the syndrome may not be reached for upwards of a day following the overdose. Death has been reported following overdosage. Therefore, immediate hospitalization, with continuous patient observation and monitoring for a period of at least two days following the ingestion of such drugs in overdose, is strongly recommended.

The clinical picture of MAO inhibitor overdose varies considerably; its severity may be a function of the amount of drug consumed. The central nervous and cardiovascular systems are prominently involved.

Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin.

Treatment of overdose with non-selective MAO inhibitors is symptomatic and supportive. Induction of emesis or gastric lavage with instillation of charcoal slurry may be helpful in early poisoning, provided the airway has been protected against aspiration. Signs and symptoms of central nervous system stimulation, including convulsions, should be treated with diazepam, given slowly intravenously. Phenothiazine derivatives and central nervous system stimulants should be avoided. Hypotension and vascular collapse should be treated with intravenous fluids and, if necessary, blood pressure titration with an intravenous infusion of a dilute pressor agent. It should be noted that adrenergic agents may produce a markedly increased pressor response.

Support respiration, including management of the airway, use of supplemental oxygen, and mechanical ventilatory assistance, as required.

Body temperature should be monitored closely. Intensive management of hyperpyrexia may be required. Maintenance of fluid and electrolyte balance is essential.

ZELAPAR Orally Disintegrating Tablets contain selegiline hydrochloride, a levorotatory acetylenic derivative of phenethylamine. Selegiline hydrochloride is described chemically as: (-)-(R)-N, α-dimethyl-N-2-propynylphenethylamine hydrochloride and its structural formula is:

{ "type": "p", "children": [], "text": "ZELAPAR Orally Disintegrating Tablets contain selegiline hydrochloride, a levorotatory acetylenic derivative of phenethylamine. Selegiline hydrochloride is described chemically as: (-)-(R)-N, α-dimethyl-N-2-propynylphenethylamine hydrochloride and its structural formula is:" }

Its empirical formula is C13H17N∙HCl, representing a molecular weight of 223.74. Selegiline hydrochloride is a white to almost white crystalline powder that is freely soluble in water and in methanol, slightly soluble in acetone.

{ "type": "p", "children": [], "text": "Its empirical formula is C13H17N∙HCl, representing a molecular weight of 223.74. Selegiline hydrochloride is a white to almost white crystalline powder that is freely soluble in water and in methanol, slightly soluble in acetone." }

ZELAPAR Orally Disintegrating Tablets are available for oral administration (not to be swallowed) in a strength of 1.25 mg. Each lyophilized orally disintegrating tablet contains the following inactive ingredients: aspartame, citric acid, gelatin, glycine, mannitol, opatint yellow, purified water, and grapefruit flavor.

{ "type": "p", "children": [], "text": "ZELAPAR Orally Disintegrating Tablets are available for oral administration (not to be swallowed) in a strength of 1.25 mg. Each lyophilized orally disintegrating tablet contains the following inactive ingredients: aspartame, citric acid, gelatin, glycine, mannitol, opatint yellow, purified water, and grapefruit flavor." }

Selegiline is an irreversible inhibitor of monoamine oxidase (MAO), which regulates the metabolic degradation of catecholamines and serotonin in the central nervous system and peripheral tissues. At recommended doses, selegiline is selective for MAO type B (MAO-B), the major form in the brain. Inhibition of MAO-B activity, by blocking the catabolism of dopamine, may result in increased dopamine levels; however, there is evidence that selegiline may act through other mechanisms to increase dopaminergic activity.

A pharmacodynamic study investigating daily ZELAPAR doses of 2.5 mg, 5 mg, and 10 mg for tyramine sensitivity showed that increased tyramine sensitivity resulting in increased blood pressure (because of MAO-A inhibition and decreased selectivity for MAO-B) occurred with dosing above the recommended level (2.5 mg daily). An increase in tyramine sensitivity for blood pressure responses appears to begin at a dose of 5 mg ZELAPAR daily [see Warnings and Precautions (5.1)].

Absorption

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

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

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

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

Food Effects

When ZELAPAR is taken with food, the Cmax and AUC of selegiline are about 60% of those seen when ZELAPAR is taken in the fasted state. Since ZELAPAR is placed on the tongue and absorbed through the oral mucosa, the intake of food and liquid should be avoided 5 minutes before and after ZELAPAR administration [see Dosage and Administration (2.1)].

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

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

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

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

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

Elimination

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

Specific Populations

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

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

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

Renal Impairment: Following once-daily dosing of ZELAPAR 2.5 mg to selegiline steady-state (10 days) in 6 subjects with mild renal impairment (CLcr >50 to 89 mL/min) and in 6 subjects with moderate renal impairment (CLcr >30 to 50 mL/min), AUC and Cmax of selegiline and desmethylselegiline were not substantially different from healthy subjects; however, methamphetamine and amphetamine exposures were increased by 34-67% in subjects with moderate renal impairment. Following once-daily dosing of ZELAPAR 1.25 mg to steady-state (10 days) in 6 end-stage renal disease patients, off dialysis, selegiline exposure was not substantially different from that in healthy subjects, however methamphetamine and amphetamine exposures were increased approximately 4-fold compared to healthy subjects [see Dosage and Administration (2.3) and Use in Specific Populations (8.7)].

Hepatic Impairment: Subjects with mild hepatic impairment (Child-Pugh score 5 to 6), received once-daily dosing of ZELAPAR 2.5 mg to selegiline until they attained steady-state (10 days). The AUC and Cmax of selegiline were 1.5-fold higher and the AUC and Cmax of the metabolite desmethylselegiline were 1.4-fold and 1.2-fold higher. In subjects with moderate hepatic impairment (Child-Pugh score 7 to 9), the AUC of selegiline and desmethylselegiline increased 1.5-fold and 1.8-fold, respectively, whereas the Cmax of selegiline and desmethylselegiline were comparable to healthy subjects. Patients with severe hepatic impairment (Child-Pugh score >9) had a 4-fold increased AUC of selegiline, 3-fold increased Cmax of selegiline, a 1.25-fold increased AUC of desmethylselegiline and 50% reduced Cmax of desmethylselegiline. Methamphetamine and amphetamine metabolite AUC values were not affected by liver dysfunction [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Drug Interactions

No studies have been conducted to evaluate drug interactions on the pharmacokinetics of ZELAPAR.

Effect of CYP3A inhibitor itraconazole: Itraconazole (200 mg once daily) did not affect the pharmacokinetics of selegiline (single 10 mg oral, swallowed dose).

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

Drug Interaction Studies

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

Carcinogenesis

Carcinogenicity studies of orally administered selegiline are not available for ZELAPAR.

Carcinogenicity studies of selegiline have not been conducted using the buccal route.

Mutagenesis

Selegiline was negative in the in vitro bacterial reverse mutation (Ames) assay in and the in vivo micronucleus assay. In the in vitro chromosomal aberration assay in mammalian cells, selegiline was negative in the absence of metabolic activation but was clastogenic in the presence of metabolic activation.

Impairment of Fertility

When selegiline was administered orally to male (5, 10, and 40 mg/kg/day) and female (1, 5, and 25 mg/kg/day) rats prior to and during mating and continuing in females to gestation day 7, a decreased number of implantations was observed at the highest doses tested. In males, a reduction in sperm count and density was observed at the highest dose tested. The no-effect doses for reproductive impairment in rats (10 mg/kg/day in males and 5 mg/kg/day in females) are approximately 40 (males) and 20 (females) times the maximum recommended human dose of 2.5 mg/day on a mg/m2 basis.

No fertility studies have been conducted with selegiline using the buccal route.

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

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

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

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

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

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

Table 2: Mean Percentage Change from Baseline in Daily "Off" Hours at End of Treatment

{ "type": "p", "children": [], "text": "\nTable 2: Mean Percentage Change from Baseline in Daily \"Off\" Hours at End of Treatment \n" }

(Average of Weeks 10 and 12) for Intent-to-Treat Population

{ "type": "p", "children": [], "text": "\n(Average of Weeks 10 and 12) for Intent-to-Treat Population\n" }

<div class="scrollingtable"><table width="100%"> <col width="50%"/> <col width="50%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Treatment</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Change from Baseline</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">- 5%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">ZELAPAR</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">- 13%</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"50%\"/>\n<col width=\"50%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Treatment</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Change from Baseline</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Placebo</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">- 5%</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">ZELAPAR</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">- 13%</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

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

{ "type": "p", "children": [], "text": "Figure 1 shows the mean daily percent “OFF” time during treatment over the whole study period for patients treated with ZELAPAR vs. patients treated with placebo." }

Figure 1: Mean Daily Percent "OFF" Time During Treatment Over the Whole Study Period for Patients Treated with ZELAPAR vs. Patients Treated with Placebo

{ "type": "p", "children": [], "text": "Figure 1: Mean Daily Percent \"OFF\" Time During Treatment Over the Whole Study Period for Patients Treated with ZELAPAR vs. Patients Treated with Placebo " }

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

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

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

{ "type": "p", "children": [], "text": "No difference in effectiveness based on age (patients >66 years old vs. <66 years) was detected. The treatment effect size in males was twice that in females, but, given the size of this single trial, this finding is of doubtful significance. " }

ZELAPAR Orally Disintegrating Tablets are available containing 1.25 mg selegiline hydrochloride in a Zydis® formulation. Each pale yellow tablet is imprinted with a stylized “V”. Ten tablets in a blister card are provided in a sachet pouch. The sachet pouch is stored inside a clear child-resistant outer pouch and is packaged in a carton. The blister card and sachet pouch are not child-resistant. The clear outer pouch is child-resistant.

{ "type": "p", "children": [], "text": "ZELAPAR Orally Disintegrating Tablets are available containing 1.25 mg selegiline hydrochloride in a Zydis® formulation. Each pale yellow tablet is imprinted with a stylized “V”. Ten tablets in a blister card are provided in a sachet pouch. The sachet pouch is stored inside a clear child-resistant outer pouch and is packaged in a carton. The blister card and sachet pouch are not child-resistant. The clear outer pouch is child-resistant." }

ZELAPAR (selegiline hydrochloride) is available as:

{ "type": "p", "children": [], "text": "ZELAPAR (selegiline hydrochloride) is available as:" }

{ "type": "", "children": [], "text": "" }

Store at controlled room temperature, 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Use within 3 months of opening pouch and immediately upon opening individual blister. Store blister tablets in sachet pouch at all times. Keep sachet pouch sealed or closed inside clear child-resistant pouch provided. Potency cannot be guaranteed after 3 months of opening the sachet pouch.

{ "type": "p", "children": [], "text": "Store at controlled room temperature, 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Use within 3 months of opening pouch and immediately upon opening individual blister. Store blister tablets in sachet pouch at all times. Keep sachet pouch sealed or closed inside clear child-resistant pouch provided. Potency cannot be guaranteed after 3 months of opening the sachet pouch.\n" }

Hypertension and Non-selective Inhibition of MAO Above the Recommended Dose

{ "type": "p", "children": [], "text": "\nHypertension and Non-selective Inhibition of MAO Above the Recommended Dose \n" }

Advise patients (or their caregivers) not to exceed the daily recommended dose of 2.5 mg. Explain the risk of using higher daily doses of ZELAPAR and provide a brief description of the hypertensive tyramine reaction provided. Rare hypertensive reactions with oral selegiline at recommended doses associated with dietary influences have been reported.

{ "type": "p", "children": [], "text": "Advise patients (or their caregivers) not to exceed the daily recommended dose of 2.5 mg. Explain the risk of using higher daily doses of ZELAPAR and provide a brief description of the hypertensive tyramine reaction provided. Rare hypertensive reactions with oral selegiline at recommended doses associated with dietary influences have been reported." }

Inform patients (or their caregivers) about the potential for MAOI-induced hypertensive reactions and describe their signs and symptoms. Instruct patients to report, immediately, severe headache or other atypical or unusual symptoms not previously experienced or very high blood pressure.

{ "type": "p", "children": [], "text": "Inform patients (or their caregivers) about the potential for MAOI-induced hypertensive reactions and describe their signs and symptoms. Instruct patients to report, immediately, severe headache or other atypical or unusual symptoms not previously experienced or very high blood pressure." }

The possibility exists that very tyramine-rich foods (e.g., aged cheese such as Stilton) could possibly cause an increase in blood pressure. Patients should be advised to avoid certain foods (e.g., aged cheese) containing a very large amount of tyramine while taking recommended doses of ZELAPAR because of the potential for large increases in blood pressure. If patients eat foods very rich in tyramine and do not feel well soon after eating, they should contact their healthcare provider [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "The possibility exists that very tyramine-rich foods (e.g., aged cheese such as Stilton) could possibly cause an increase in blood pressure. Patients should be advised to avoid certain foods (e.g., aged cheese) containing a very large amount of tyramine while taking recommended doses of ZELAPAR because of the potential for large increases in blood pressure. If patients eat foods very rich in tyramine and do not feel well soon after eating, they should contact their healthcare provider [see Warnings and Precautions (5.1)]." }

Serotonin Syndrome

{ "type": "p", "children": [], "text": "\nSerotonin Syndrome\n" }

Inform patients if they are taking, or planning to take, any prescription or over-the-counter drugs, especially antidepressants and over-the-counter cold medications, because there is a potential for interaction with ZELAPAR. Because patients should not use meperidine or certain other analgesics with ZELAPAR, they should contact their healthcare provider before taking analgesics [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Inform patients if they are taking, or planning to take, any prescription or over-the-counter drugs, especially antidepressants and over-the-counter cold medications, because there is a potential for interaction with ZELAPAR. Because patients should not use meperidine or certain other analgesics with ZELAPAR, they should contact their healthcare provider before taking analgesics [see Warnings and Precautions (5.2)]." }

Falling Asleep During Activities of Daily Living and Somnolence

{ "type": "p", "children": [], "text": "\nFalling Asleep During Activities of Daily Living and Somnolence\n" }

Advise patients about the potential for sedating effects associated with ZELAPAR, including somnolence and particularly to the possibility of falling asleep while engaged in activities of daily living. Because somnolence can be a frequent adverse reaction with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with ZELAPAR to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if they experience increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Advise patients not to drive, operate machinery, or work at heights during treatment if they have previously experienced somnolence and/or have fallen asleep without warning prior to use of ZELAPAR [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Advise patients about the potential for sedating effects associated with ZELAPAR, including somnolence and particularly to the possibility of falling asleep while engaged in activities of daily living. Because somnolence can be a frequent adverse reaction with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with ZELAPAR to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if they experience increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Advise patients not to drive, operate machinery, or work at heights during treatment if they have previously experienced somnolence and/or have fallen asleep without warning prior to use of ZELAPAR [see Warnings and Precautions (5.3)]." }

Hypotension/Orthostatic Hypotension

{ "type": "p", "children": [], "text": "\nHypotension/Orthostatic Hypotension\n" }

Advise patients that they may develop symptomatic (or asymptomatic) hypotension while taking ZELAPAR, especially if they are elderly. Hypotension may occur more frequently during initial therapy. Accordingly, caution patients against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with ZELAPAR [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Advise patients that they may develop symptomatic (or asymptomatic) hypotension while taking ZELAPAR, especially if they are elderly. Hypotension may occur more frequently during initial therapy. Accordingly, caution patients against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with ZELAPAR [see Warnings and Precautions (5.4)]." }

Dyskinesia

{ "type": "p", "children": [], "text": "\nDyskinesia\n" }

Inform patients that ZELAPAR may cause and/or exacerbate pre-existing dyskinesias [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Inform patients that ZELAPAR may cause and/or exacerbate pre-existing dyskinesias [see Warnings and Precautions (5.5)]." }

Hallucinations/Psychotic-Like Behavior

{ "type": "p", "children": [], "text": "\nHallucinations/Psychotic-Like Behavior \n" }

Inform patients that hallucinations and other psychotic-like behavior can occur while taking ZELAPAR and that the elderly are at a higher risk than younger patients with Parkinson's disease. Tell patients to report hallucinations or psychotic-like behavior to their healthcare provider promptly should they develop [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Inform patients that hallucinations and other psychotic-like behavior can occur while taking ZELAPAR and that the elderly are at a higher risk than younger patients with Parkinson's disease. Tell patients to report hallucinations or psychotic-like behavior to their healthcare provider promptly should they develop [see Warnings and Precautions (5.6)]." }

Impulse Control/Compulsive Behaviors

{ "type": "p", "children": [], "text": "\nImpulse Control/Compulsive Behaviors\n" }

Advise patients that they may experience impulse control and/or compulsive behaviors while taking one or more of the medications generally used for the treatment of Parkinson’s disease, including ZELAPAR. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with ZELAPAR. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking ZELAPAR. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ZELAPAR [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Advise patients that they may experience impulse control and/or compulsive behaviors while taking one or more of the medications generally used for the treatment of Parkinson’s disease, including ZELAPAR. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with ZELAPAR. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking ZELAPAR. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ZELAPAR [see Warnings and Precautions (5.7)]." }

Withdrawal Emergent Hyperpyrexia and Confusion

{ "type": "p", "children": [], "text": "\nWithdrawal Emergent Hyperpyrexia and Confusion\n" }

Advise patients to contact their healthcare provider if they wish to discontinue ZELAPAR or decrease the dose of ZELAPAR [see Warnings and Precautions (5.8)].

{ "type": "p", "children": [], "text": "Advise patients to contact their healthcare provider if they wish to discontinue ZELAPAR or decrease the dose of ZELAPAR [see Warnings and Precautions (5.8)]." }

Irritation of the Buccal Mucosa

{ "type": "p", "children": [], "text": "\nIrritation of the Buccal Mucosa\n" }

Inform patients that ZELAPAR may cause irritation of the buccal mucosa including swallowing pain, mouth pain, discrete areas of focal reddening, edema, and/or ulceration [see Warnings and Precautions (5.9)].

{ "type": "p", "children": [], "text": "Inform patients that ZELAPAR may cause irritation of the buccal mucosa including swallowing pain, mouth pain, discrete areas of focal reddening, edema, and/or ulceration [see Warnings and Precautions (5.9)]." }

Risk for Phenylketonuric Patients

{ "type": "p", "children": [], "text": "\nRisk for Phenylketonuric Patients\n" }

Advise patients that ZELAPAR contains aspartame which could cause problems in patients with phenylketonuria [see Warnings and Precautions (5.10)].

{ "type": "p", "children": [], "text": "Advise patients that ZELAPAR contains aspartame which could cause problems in patients with phenylketonuria [see Warnings and Precautions (5.10)]." }

Instructions for Use

{ "type": "p", "children": [], "text": "\nInstructions for Use\n" }

Instruct patients not to remove the blister from the sachet pouch until just prior to dosing. The blister pack should then be peeled open with dry hands and the orally disintegrating tablet placed on the tongue, where the tablet will disintegrate. Patients should also avoid drinking liquids or eating food 5 minutes before and after taking ZELAPAR. Use ZELAPAR within 3 months of opening sachet pouch and immediately upon opening individual blister. Store blister tablets in sachet pouch at all times. Keep sachet pouch inside clear child-resistant pouch provided. Potency cannot be guaranteed after 3 months of opening the pouch.

{ "type": "p", "children": [], "text": "Instruct patients not to remove the blister from the sachet pouch until just prior to dosing. The blister pack should then be peeled open with dry hands and the orally disintegrating tablet placed on the tongue, where the tablet will disintegrate. Patients should also avoid drinking liquids or eating food 5 minutes before and after taking ZELAPAR. Use ZELAPAR within 3 months of opening sachet pouch and immediately upon opening individual blister. Store blister tablets in sachet pouch at all times. Keep sachet pouch inside clear child-resistant pouch provided. Potency cannot be guaranteed after 3 months of opening the pouch.\n" }

How should I store ZELAPAR?

{ "type": "p", "children": [], "text": "\nHow should I store ZELAPAR?\n" }

{ "type": "", "children": [], "text": "" }

BLISTER PACKS AND SACHET POUCHES ARE NOT CHILD-RESISTANT. THE CLEAR OUTER POUCH IS CHILD-RESISTANT.

{ "type": "p", "children": [], "text": "\nBLISTER PACKS AND SACHET POUCHES ARE NOT CHILD-RESISTANT. THE CLEAR OUTER POUCH IS CHILD-RESISTANT.\n" }

Distributed by: Bausch Health US, LLCBridgewater, NJ 08807 USA Manufactured by: Catalent Pharma Solutions LimitedSwindon, Wiltshire, SN5 8RU, UK ZELAPAR is a trademark of Bausch Health Companies Inc. or its affiliates. Zydis is a registered trademark of Catalent Pharma Solutions or its affiliates.All other product/brand names are trademarks of the respective owners. © 2021 Bausch Health Companies Inc. or its affiliates 9603102

{ "type": "p", "children": [], "text": "\nDistributed by:\nBausch Health US, LLCBridgewater, NJ 08807 USA\n\nManufactured by:\nCatalent Pharma Solutions LimitedSwindon, Wiltshire, SN5 8RU, UK\nZELAPAR is a trademark of Bausch Health Companies Inc. or its affiliates.\nZydis is a registered trademark of Catalent Pharma Solutions or its affiliates.All other product/brand names are trademarks of the respective owners.\n© 2021 Bausch Health Companies Inc. or its affiliates\n9603102" }

NDC 0187-0453-02 Rx only Zelapar® (selegiline HCL) Orally Disintegrating Tablets 60 Tablets 1.25 mg Contents: Clear child-resistant pouch containing 6 sachetpouches. Each sachet pouch contains 10 tablets BAUSCH HEALTH

{ "type": "p", "children": [], "text": "\nNDC 0187-0453-02\nRx only\n\n\nZelapar®\n(selegiline HCL)\nOrally Disintegrating Tablets\n\n\n60 Tablets\n\n1.25 mg\n\n\nContents:\n\nClear child-resistant pouch containing 6 sachetpouches.\n\nEach sachet pouch contains 10 tablets\n\n\nBAUSCH HEALTH\n" }