Escitalopram (Page 4 of 10)

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Clinical Trial Data Sources
Pediatrics (6 to 17 years)
Adverse events were collected in 576 pediatric patients (286 escitalopram oxalate, 290 placebo) with major depressive disorder in double-blind placebo-controlled studies. Safety and effectiveness of escitalopram oxalate in pediatric patients less than 12 years of age has not been established.

Adults
Adverse events information for escitalopram oxalate was collected from 715 patients with major depressive disorder who were exposed to escitalopram and from 592 patients who were exposed to placebo in double-blind, placebo-controlled trials. An additional 284 patients with major depressive disorder were newly exposed to escitalopram in open-label trials. The adverse event information for escitalopram oxalate in patients with GAD was collected from 429 patients exposed to escitalopram and from 427 patients exposed to placebo in double-blind, placebo-controlled trials.

Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard World Health Organization (WHO) terminology has been used to classify reported adverse events.

The stated frequencies of adverse reactions 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 Events Associated with Discontinuation of Treatment
Major Depressive Disorder
Pediatrics (6 to 17 years)
Adverse events were associated with discontinuation of 3.5% of 286 patients receiving escitalopram oxalate and 1% of 290 patients receiving placebo. The most common adverse event (incidence at least 1% for escitalopram oxalate and greater than placebo) associated with discontinuation was insomnia (1% escitalopram oxalate, 0% placebo).

Adults
Among the 715 depressed patients who received escitalopram oxalate in placebo-controlled trials, 6% discontinued treatment due to an adverse event, as compared to 2% of 592 patients receiving placebo. In two fixed-dose studies, the rate of discontinuation for adverse events in patients receiving 10 mg/day escitalopram oxalate was not significantly different from the rate of discontinuation for adverse events in patients receiving placebo. The rate of discontinuation for adverse events in patients assigned to a fixed dose of 20 mg/day escitalopram oxalate was 10%, which was significantly different from the rate of discontinuation for adverse events in patients receiving 10 mg/day escitalopram oxalate (4%) and placebo (3%). Adverse events that were associated with the discontinuation of at least 1% of patients treated with escitalopram oxalate, and for which the rate was at least twice that of placebo, were nausea (2%) and ejaculation disorder (2% of male patients).

Generalized Anxiety Disorder
Adults
Among the 429 GAD patients who received escitalopram oxalate 10 to 20 mg/day in placebo-controlled trials, 8% discontinued treatment due to an adverse event, as compared to 4% of 427 patients receiving placebo. Adverse events that were associated with the discontinuation of at least 1% of patients treated with escitalopram oxalate, and for which the rate was at least twice the placebo rate, were nausea (2%), insomnia (1%), and fatigue (1%).

Incidence of Adverse Reactions in Placebo-Controlled Clinical Trials
Major Depressive Disorder
Pediatrics (6 to 17 years)
The overall profile of adverse reactions in pediatric patients was generally similar to that seen in adult studies, as shown in Table 2. However, the following adverse reactions (excluding those which appear in Table 2 and those for which the coded terms were uninformative or misleading) were reported at an incidence of at least 2% for escitalopram oxalate and greater than placebo: back pain, urinary tract infection, vomiting, and nasal congestion.

Adults The most commonly observed adverse reactions in escitalopram oxalate patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating increased, fatigue, and somnolence.

Table 2 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 715 depressed patients who received escitalopram oxalate at doses ranging from 10 to 20 mg/day in placebo-controlled trials. Events included are those occurring in 2% or more of patients treated with escitalopram oxalate and for which the incidence in patients treated with escitalopram oxalate was greater than the incidence in placebo-treated patients.

TABLE 2 Treatment-Emergent Adverse Reactions observed with a frequency of ≥ 2% and greater than placebo for Major Depressive Disorder
Adverse Reaction Escitalopram oxalate Placebo
(N=715) % (N=592) %
*
Primarily ejaculatory delay.
Denominator used was for males only (N=225 escitalopram oxalate; N=188 placebo).
Denominator used was for females only (N=490 escitalopram oxalate; N=404 placebo).

Autonomic Nervous System Disorders

Dry Mouth

6%

5%

Sweating Increased

5%

2%

Central & Peripheral Nervous System Disorders

Dizziness

5%

3%

Gastrointestinal Disorders

Nausea

15%

7%

Diarrhea

8%

5%

Constipation

3%

1%

Indigestion

3%

1%

Abdominal Pain

2%

1%

General

Influenza-like Symptoms

5%

4%

Fatigue

5%

2%

Psychiatric Disorders

Insomnia

9%

4%

Somnolence

6%

2%

Appetite Decreased

3%

1%

Libido Decreased

3%

1%

Respiratory System Disorders

Rhinitis

5%

4%

Sinusitis

3%

2%

Urogenital

Ejaculation Disorder *,

9%

<1%

Impotence

3%

<1%

Anorgasmia

2%

<1%

Generalized Anxiety Disorder
Adults The most commonly observed adverse reactions in escitalopram oxalate patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were nausea, ejaculation disorder (primarily ejaculatory delay), insomnia, fatigue, decreased libido, and anorgasmia.

Table 3 enumerates the incidence, rounded to the nearest percent of treatment-emergent adverse events that occurred among 429 GAD patients who received escitalopram oxalate 10 to 20 mg/day in placebo-controlled trials. Events included are those occurring in 2% or more of patients treated with escitalopram oxalate and for which the incidence in patients treated with escitalopram oxalate was greater than the incidence in placebo-treated patients.

TABLE 3 Treatment-Emergent Adverse Reactions observed with a frequency of ≥ 2% and greater than placebo for Generalized Anxiety Disorder
Adverse Reactions Escitalopram oxalate Placebo
(N=429) % (N=427) %
*
Primarily ejaculatory delay.
Denominator used was for males only (N=182 escitalopram oxalate; N=195 placebo).
Denominator used was for females only (N=247 escitalopram oxalate; N=232 placebo).

Autonomic Nervous System Disorders

Dry Mouth

9%

5%

Sweating Increased

4%

1%

Central & Peripheral Nervous System Disorders

Headache

24%

17%

Paresthesia

2%

1%

Gastrointestinal Disorders

Nausea

18%

8%

Diarrhea

8%

6%

Constipation

5%

4%

Indigestion

3%

2%

Vomiting

3%

1%

Abdominal Pain

2%

1%

Flatulence

2%

1%

Toothache

2%

0%

General

Fatigue

8%

2%

Influenza-like Symptoms

5%

4%

Musculoskeletal System Disorder

Neck/Shoulder Pain

3%

1%

Psychiatric Disorders

Somnolence

13%

7%

Insomnia

12%

6%

Libido Decreased

7%

2%

Dreaming Abnormal

3%

2%

Appetite Decreased

3%

1%

Lethargy

3%

1%

Respiratory System Disorders

Yawning

2%

1%

Urogenital

Ejaculation Disorder *,

14%

2%

Anorgasmia

6%

<1%

Menstrual Disorder

2%

1%

Dose Dependency of Adverse Reactions The potential dose dependency of common adverse reactions (defined as an incidence rate of ≥5% in either the 10 mg or 20 mg escitalopram oxalate groups) was examined on the basis of the combined incidence of adverse reactions in two fixed-dose trials. The overall incidence rates of adverse events in 10 mg escitalopram oxalate-treated patients (66%) was similar to that of the placebo-treated patients (61%), while the incidence rate in 20 mg/day escitalopram oxalate-treated patients was greater (86%). Table 4 shows common adverse reactions that occurred in the 20 mg/day escitalopram oxalate group with an incidence that was approximately twice that of the 10 mg/day escitalopram oxalate group and approximately twice that of the placebo group.

TABLE 4 Incidence of Common Adverse Reactions in Patients with Major Depressive Disorder
Adverse Reaction Placebo 10 mg/day 20 mg/day
Escitalopram oxalate Escitalopram oxalate
(N=311) (N=310) (N=125)

Insomnia

4%

7%

14%

Diarrhea

5%

6%

14%

Dry Mouth

3%

4%

9%

Somnolence

1%

4%

9%

Dizziness

2%

4%

7%

Sweating Increased

<1%

3%

8%

Constipation

1%

3%

6%

Fatigue

2%

2%

6%

Indigestion

1%

2%

6%

Male and Female Sexual Dysfunction with SSRIs 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. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences.

Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, 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 5 Incidence of Sexual Side Effects in Placebo-Controlled Clinical Trials

Adverse Event

Escitalopram oxalate

Placebo

In Males Only

(N=407)

(N=383)

Ejaculation Disorder (primarily ejaculatory delay)

12%

1%

Libido Decreased

6%

2%

Impotence

2%

<1%

In Females Only

(N=737)

(N=636)

Libido Decreased

3%

1%

Anorgasmia

3%

<1%

There are no adequately designed studies examining sexual dysfunction with escitalopram treatment.

Priapism has been reported with all SSRIs.

While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

Vital Sign Changes
Escitalopram oxalate 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. These analyses did not reveal any clinically important changes in vital signs associated with escitalopram oxalate treatment. In addition, a comparison of supine and standing vital sign measures in subjects receiving escitalopram oxalate indicated that escitalopram oxalate treatment is not associated with orthostatic changes.

Weight Changes
Patients treated with escitalopram oxalate in controlled trials did not differ from placebo-treated patients with regard to clinically important change in body weight.

Laboratory Changes
Escitalopram oxalate 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 escitalopram oxalate treatment.

ECG Changes
Electrocardiograms from escitalopram oxalate (N=625) and placebo (N=527) groups were compared with respect to outliers defined as subjects with QTc changes over 60 msec from baseline or absolute values over 500 msec post-dose, and subjects with heart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline (tachycardic or bradycardic outliers, respectively). None of the patients in the escitalopram oxalate group had a QTcF interval >500 msec or a prolongation >60 msec compared to 0.2% of patients in the placebo group. The incidence of tachycardic outliers was 0.2% in the escitalopram oxalate and the placebo group. The incidence of bradycardic outliers was 0.5% in the escitalopram oxalate group and 0.2% in the placebo group.

QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg) controlled cross-over, escalating multiple-dose study in 113 healthy subjects. The maximum mean (95% upper confidence bound) difference from placebo arm were 4.5 (6.4) and 10.7 (12.7) msec for 10 mg and supratherapeutic 30 mg escitalopram given once daily, respectively. Based on the established exposure-response relationship, the predicted QTcF change from placebo arm (95% confidence interval) under the C max for the dose of 20 mg is 6.6 (7.9) msec. Escitalopram 30 mg given once daily resulted in mean C max of 1.7-fold higher than the mean C max for the maximum recommended therapeutic dose at steady state (20 mg). The exposure under supratherapeutic 30 mg dose is similar to the steady state concentrations expected in CYP2C19 poor metabolizers following a therapeutic dose of 20 mg.

Other Reactions Observed During the Premarketing Evaluation of Escitalopram Oxalate
Following is a list of treatment-emergent adverse events, as defined in the introduction to the ADVERSE REACTIONS section, reported by the 1428 patients treated with escitalopram oxalate for periods of up to one year in double-blind or open-label clinical trials during its premarketing evaluation. The listing does not include those events already listed in Tables 2 & 3 , those events for which a drug cause was remote and at a rate less than 1% or lower than placebo, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening. Events are categorized by body system. Events of major clinical importance are described in the Warnings and Precautions section (5).

Cardiovascular – hypertension, palpitation.

Central and Peripheral Nervous System Disorders – light-headed feeling, migraine.

Gastrointestinal Disorders – abdominal cramp, heartburn, gastroenteritis.

General – allergy, chest pain, fever, hot flushes, pain in limb.

Metabolic and Nutritional Disorders – increased weight.

Musculoskeletal System Disorders – arthralgia, myalgia, jaw stiffness.

Psychiatric Disorders – appetite increased, concentration impaired, irritability.

Reproductive Disorders/Female – menstrual cramps, menstrual disorder.

Respiratory System Disorders – bronchitis, coughing, nasal congestion, sinus congestion, sinus headache.

Skin and Appendages Disorders – rash.

Special Senses – vision blurred, tinnitus.

Urinary System Disorders – urinary frequency, urinary tract infection.

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