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Emsam

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Emsam

Emsam

SIDE EFFECTS

The premarketing development program for EMSAM (selegiline transdermal system) included selegiline exposures in patients and/or normal subjects from two different groups of studies:702 healthy subjects in clinical pharmacology/pharmacokinetics studies and 2036 exposures from patients in controlled and uncontrolled major depressive disorder clinical trials. The conditions and duration of treatment with EMSAM (selegiline transdermal system) varied and included double-blind, open-label, fixed-dose, and dose titration studies of short-term and longer-term exposures. Safety was assessed by monitoring adverse events,physical examinations, vital signs,body weights, laboratory analyses,and ECGs.

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

Adverse Findings Observed in Short-Term Placebo-Controlled Trials

Adverse Events Associated with Discontinuation of Treatment

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

Adverse Events Occurring at an Incidence of 2% or More Among EMSAM (selegiline transdermal system) -Treated Patients

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

Only one adverse event was associated with a reporting of at least 5% in the EMSAM (selegiline transdermal system) 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 (selegiline transdermal system) than that in the entire study pool, the following events met these criteria: application site reactions,insomnia,diarrhea,and pharyngitis.

These figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators.The cited figures, however, do provide the prescribing physicians with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.

Table 2. Treatment-Emergent Adverse Events: Incidence in Placebo-Controlled Clinical Trials for Major Depressive Disorder With EMSAM (selegiline transdermal system) 1

Body System/ Preferred Term EMSAM
(N=817)
Placebo
(N=668)
  (% of Patients Reporting Event)
Body as a Whole
  Headache 18 17
Digestive
  Diarrhea 9 7
  Dyspepsia 4 3
Nervous
  Insomnia 12 7
  Dry Mouth 8 6
Respiratory
  Pharyngitis 3 2
  Sinusitis 3 1
Skin
  Application Site Reaction 24 12
  Rash 4 2
1Events reported by at least 2% of patients treated with EMSAM are included,except the following events,which had an incidence on placebo treatment ≥ EMSAM: infection, nausea, dizziness, pain, abdominal pain, nervousness, back pain, asthenia, anxiety, flu syndrome, accidental injury, somnolence, rhinitis, and palpitations.

Application Site Reactions

In the pool of short-term, placebo-controlled major depressive disorder studies, application site reactions (ASRs) were reported in 24% of EMSAM (selegiline transdermal system) -treated patients and 12% of placebo-treated patients.Most ASRs were mild or moderate in severity. None were considered serious. ASRs led to dropout in 2% of EMSAM (selegiline transdermal system) -treated patients and no placebo-treated patients.

In one such study which utilized higher mean doses of EMSAM (selegiline transdermal system) ,ASRs were reported in 40% of EMSAM (selegiline transdermal system) -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.

Male and Female Sexual Dysfunction with MAO Inhibitors

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

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

Table 3. Incidence of Sexual Side Effects in Placebo-Controlled Clinical Trials With EMSAM (selegiline transdermal system)

Adverse Event EMSAM Placebo
IN MALES ONLY
(N=304) (N=256)
Abnormal Ejaculation 1.0% 0.0%
Decreased Libido 0.7% 0.0%
Impotence 0.7% 0.4%
Anorgasmia 0.2% 0.0%
  IN FEMALES ONLY
(N=513) (N=412)
Decreased Libido 0.0% 0.2%
There are no adequately designed studies examining sexual dysfunction with EMSAM treatment.

Vital Sign Changes

EMSAM (selegiline transdermal system) 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 (selegiline transdermal system) -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 (selegiline transdermal system) ,6.2% of EMSAM (selegiline transdermal system) -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 (selegiline transdermal system) -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.

Weight Changes

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

Table 4. Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials With EMSAM (selegiline transdermal system)

Weight Change EMSAM Placebo
(N=757) (N=614)
Gained ≥ 5% 2.1% 2.4%
Lost ≥ 5% 5.0% 2.8%

In these trials, the mean change in body weight among EMSAM (selegiline transdermal system) -treated patients was -1.2 lbs compared to +0.3 lbs in placebo-treated patients.

Laboratory Changes

EMSAM (selegiline transdermal system) 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 (selegiline transdermal system) .

ECG Changes

Electrocardiograms (ECGs) from EMSAM (selegiline transdermal system) (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.

Other Events Observed During the Premarketing Evaluation of EMSAM (selegiline transdermal system)

During the premarketing assessment in major depressive disorder, EMSAM (selegiline transdermal system) was administered to 2036 patients in Phase III studies.The conditions and duration of exposure to EMSAM (selegiline transdermal system) varied and included double-blind and open-label studies.

In the tabulations that follow,reported adverse events were classified using a standard COSTART-based dictionary terminology.All reported adverse events are included except those already listed in Table 2 or elsewhere in labeling, and those events occurring in only one patient.It is important to emphasize that although the events occurred during treatment with EMSAM (selegiline transdermal system) ,they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in less than 1/100 patients but at least 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

Body as a Whole: Frequent: Chest pain, neck pain. Infrequent: Bacterial infection, ever, cyst, fungal infection, chills, viral infection, suicide attempt, neck rigidity, pelvic pain, photosensitivity reaction,face edema, flank pain, hernia, intentional injury, neoplasm, generalized edema, overdose. Rare: Body odor, halitosis, heat stroke, parasitic infection,malaise,moniliasis.

Cardiovascular System: Frequent: Hypertension. Infrequent: Vasodilatation, tachycardia, migraine, syncope, atrial fibrillation, peripheral vascular disorder. Rare: Myocardial infarct.

Digestive System: Frequent: Constipation, flatulence, anorexia, gastroenteritis, vomiting. Infrequent: Increased appetite, thirst, periodontal abscess, eructation, gastritis, colitis, dysphagia, tongue edema, glossitis, increased salivation, abnormal liver function tests, melena, tongue disorder, tooth caries. Rare: GI neoplasia, rectal hemorrhage.

Hemic and Lymphatic System: Frequent: Ecchymosis. Infrequent: Anemia, lymphadenopathy. Rare: Leukocytosis, leukopenia, petechia.

Metabolic and Nutritional: Frequent: Peripheral edema. Infrequent: Hyperglycemia,increased SGPT, edema, hypercholesteremia, increased SGOT, dehydration, alcohol intolerance, hyponatremia, increased lactic dehydrogenase. Rare: Increased alkaline phosphatase, bilirubinemia, hypoglycemic reaction.

Musculoskeletal System: Frequent: Myalgia, pathological fracture. Infrequent: Arthralgia, generalized spasm, arthritis, myasthenia, arthrosis, tenosynovitis. Rare: Osteoporosis.

Nervous System: Frequent: Agitation, paresthesia, thinking abnormal, amnesia. Infrequent: Leg cramps, tremor, vertigo, hypertonia, twitching, emotional lability, confusion, manic reaction, depersonalization, hyperkinesias, hostility,myoclonus, circumoral paresthesia, hyperesthesia, increased libido, euphoria, neurosis,paranoid reaction. Rare: Ataxia.

Respiratory System: Frequent: Cough increased, bronchitis. Infrequent: Dyspnea, asthma, pneumonia, laryngismus. Rare: Epistaxis, laryngitis, yawn.

Skin and Appendages: Frequent: Pruritus, sweating, acne. Infrequent: Dry skin, maculopapular rash, contact dermatitis, urticaria, herpes simplex, alopecia, vesiculobullous rash, herpes zoster, skin hypertrophy, fungal dermatitis,skin benign neoplasm. Rare: Eczema.

Special Senses: Frequent: Taste perversion, tinnitus. Infrequent: Dry eyes, conjunctivitis, ear pain, eye pain, otitis media, parosmia. Rare: Mydriasis,otitis external,visual field defect.

Urogenital System: Frequent: Urinary tract infection, urinary frequency, dysmenorrhea, metrorrhagia. Infrequent: Urinary tract infection (male), vaginitis,cystitis (female), hematuria (female), unintended pregnancy, dysuria (female), urinary urgency (male and female), vaginal moniliasis, menorrhagia, urination impaired (male), breast neoplasm (female), kidney calculus (female), vaginal hemorrhage, amenorrhea, breast pain, polyuria (female).

Drug Abuse And Dependence

Controlled Substance Class

EMSAM (selegiline transdermal system) is not a controlled substance.

Physical and Psychological Dependence

Several animal studies have assessed potential for abuse and/or dependence with chronic selegiline administration.None of these studies demonstrated a potential for selegiline abuse or dependence.

EMSAM (selegiline transdermal system) has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence.While the clinical trials did not reveal any tendency for any drug-seeking behavior,these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse,and such patients should be observed closely for signs of EMSAM (selegiline transdermal system) misuse or abuse (e.g.,development of tolerance,increases in dose,or drug-seeking behavior).

Read the Emsam (selegiline transdermal system) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

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

Alcohol

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

Alprazolam

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

Carbamazepine

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

Ibuprofen

In subjects who had received EMSAM (selegiline transdermal system) 6 mg/24 hours for 11 days, combined administration with the CYP2C9 substrate ibuprofen (800 mg single dose) did not affect the pharmacokinetics of either selegiline or ibuprofen.

Ketoconazole

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

Levothyroxine

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

Olanzapine

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

Phenylpropanolamine (PPA)

In subjects who had received EMSAM (selegiline transdermal system) 6 mg/24 hours for 9 days,co-administration with PPA (25 mg every 4 hours for 24 hours) did not affect the pharmacokinetics of PPA. There was a higher incidence of significant blood pressure elevations with the co-administration of EMSAM (selegiline transdermal system) and PPA than with PPA alone, suggesting a possible pharmacodynamic interaction.It is prudent to avoid the concomitant use of sympathomimetic agents with EMSAM (selegiline transdermal system) .

Pseudoephedrine

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

Risperidone

In subjects who had received EMSAM (selegiline transdermal system) 6 mg/24 hours for 10 days,co-administration with risperidone (2 mg per day for 7 days),a substrate for CYP2D6,did not affect the pharmacokinetics of either selegiline or risperidone.

Tyramine

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

MAO plays a vital physiological role in terminating the biological activity of both endogenous and exogenous amines. In addition to their role in the catabolism of monoamines in the CNS, MAOs are also important in the catabolism of exogenous amines found in a variety of foods and drugs.MAO in the gastrointestinal tract (primarily type A) provides protection from exogenous amines with vasopressor actions, such as tyramine, which if absorbed intact can cause a hypertensive crisis,the so-called "cheese reaction." If a large amount of tyramine is absorbed systemically, it is taken up by adrenergic neurons and causes norepinephrine release from neuronal storage sites with resultant elevation of blood pressure.While most foods contain negligible amounts or no tyramine, a few food products (see WARNINGS) may contain large amounts of tyramine that represent a potential risk for patients with significant inhibition of intestinal MAO-A resulting from administration of MAOIs. Tyramine-containing nutritional supplements should be avoided by patients taking EMSAM (selegiline transdermal system) .

Animal studies have indicated the transdermal administration of selegiline via EMSAM (selegiline transdermal system) 6 mg/24 hours allows for critical levels of MAO inhibition to be achieved in the brain while avoiding levels of gastrointestinal inhibition. To further define the risk of hypertensive crises with use of EMSAM (selegiline transdermal system) , several Phase I tyramine challenge studies were conducted both with and without food.

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

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

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

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

Tyramine pressor doses were also studied in 11 subjects after extended treatment with EMSAM (selegiline transdermal system) 12 mg/24 hours. At 30, 60, and 90 days, the mean pressor doses (TYR30) of tyramine administered without food were 95 mg, 72 mg,and 88 mg,respectively.The lowest pressor dose without food was 25 mg in 3 subjects at day 30 while on EMSAM (selegiline transdermal system) 12 mg/24 hours. Eight subjects from this study, with a mean tyramine pressor dose of 64 mg at 90 days, were subsequently administered tyramine with food, resulting in a mean pressor dose of 172 mg (2.7 times the mean pressor dose observed without food,p < 0.003).

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

In its entirety, the data for EMSAM (selegiline transdermal system) 6 mg/24 hours support the recommendation that a modified diet is not required at this dose. Due to the more limited data available for EMSAM (selegiline transdermal system) 9 mg/24 hours and 12 mg/24 hours, patients receiving these doses should follow Dietary Modifications Required for Patients Taking EMSAM 9 mg/24 hours and 12 mg/24 hours.(See WARNINGS.)

Warfarin

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

Last reviewed on RxList: 6/2/2008
This monograph has been modified to include the generic and brand name in many instances.

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