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
|(% of Patients Reporting Event)|
|Body as a Whole|
|Application Site Reaction||24||12|
|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)
|IN MALES ONLY|
|IN FEMALES ONLY|
|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.
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)
|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.
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) .
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).