Label: ESCITALOPRAM OXALATE tablet

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

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Adults Adverse reactions information for escitalopram 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 reaction information for escitalopram 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 reactions 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 reactions without first grouping similar types of reactions 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 reactions.

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.

Pediatric Patients Adverse reaction information for pediatric patients was collected in double-blind placebo-controlled studies in 576 pediatric patients 6 to 17 years of age, (286 escitalopram, 290 placebo) with major depressive disorder.

The safety and effectiveness of escitalopram have not been established in pediatric patients less than 12 years of age with MDD or less than 7 years of age with GAD.

Adverse Reactions Associated with Discontinuation of Treatment

Major Depressive Disorder

Adults Among the 715 depressed patients who received escitalopram 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 reactions in patients receiving 10 mg/day escitalopram was not significantly different from the rate of discontinuation for adverse reactions in patients receiving placebo. The rate of discontinuation for adverse reactions in patients assigned to a fixed dose of 20 mg/day escitalopram was 10%, which was significantly different from the rate of discontinuation for adverse reactions in patients receiving 10 mg/day escitalopram (4%) and placebo (3%). Adverse reactions that were associated with the discontinuation of at least 1% of patients treated with escitalopram tablets, and for which the rate was at least twice that of placebo, were nausea (2%) and ejaculation disorder (2% of male patients).

Pediatric Patients Adverse reactions in pediatric patients 6 to 17 years of age were associated with discontinuation of 3.5% of 286 patients receiving escitalopram and 1% of 290 patients receiving placebo. The most common adverse reaction (incidence at least 1% for escitalopram and greater than placebo) associated with discontinuation was insomnia (1% escitalopram, 0% placebo).

The safety and effectiveness of escitalopram have not been established in pediatric patients less than 12 years of age with MDD.

Generalized Anxiety Disorder

Adults Among the 429 GAD patients who received escitalopram 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 reactions that were associated with the discontinuation of at least 1% of patients treated with escitalopram, 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

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Adults The most commonly observed adverse reactions in escitalopram 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 adverse reactions that occurred among 715 depressed patients who received escitalopram at doses ranging from 10 to 20 mg/day in placebo-controlled trials. Reactions included are those occurring in 2% or more of patients treated with escitalopram and for which the incidence in patients treated with escitalopram was greater than the incidence in placebo-treated patients.

Pediatric Patients The overall profile of adverse reactions in pediatric patients 6 to 17 years in major depressive disorder 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 and greater than placebo: back pain, urinary tract infection, vomiting, and nasal congestion.

The safety and effectiveness of escitalopram have not been established in pediatric patients less than 12 years of age with MDD.

Generalized Anxiety Disorder

Adults The most commonly observed adverse reactions in escitalopram 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 reactions that occurred among 429 GAD patients who received escitalopram 10 to 20 mg/day in placebo-controlled trials. Reactions included are those occurring in 2% or more of patients treated with escitalopram and for which the incidence in patients treated with escitalopram was greater than the incidence in placebo-treated patients.

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 groups) was examined on the basis of the combined incidence of adverse reactions in two fixed-dose trials. The overall incidence rates of adverse reactions in 10 mg escitalopram-treated patients (66%) was similar to that of the placebo-treated patients (61%), while the incidence rate in 20 mg/day escitalopram-treated patients was greater (86%). Table 4 shows common adverse reactions that occurred in the 20 mg/day escitalopram group with an incidence that was approximately twice that of the 10 mg/day escitalopram group and approximately twice that of the placebo group.

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.

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 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 treatment. In addition, a comparison of supine and standing vital sign measures in subjects receiving escitalopram indicated that escitalopram treatment is not associated with orthostatic changes.

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

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Laboratory Changes Escitalopram 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 treatment.

ECG Changes Electrocardiograms from escitalopram (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 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 and the placebo group. The incidence of bradycardic outliers was 0.5% in the escitalopram 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 Cmax for the dose of 20 mg is 6.6 (7.9) msec. Escitalopram 30 mg given once daily resulted in mean Cmax of 1.7-fold higher than the mean Cmax 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 Tablets Following is a list of treatment-emergent adverse reactions, as defined in the introduction to the ADVERSE REACTIONS section, reported by the 1,428 patients treated with escitalopram tablets 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 reactions already listed in Tables 2 & 3, those reactions for which a drug cause was remote and at a rate less than 1% or lower than placebo, those reactions which were so general as to be uninformative, and those reactions reported only once which did not have a substantial probability of being acutely life threatening. Reactions are categorized by body system. Reactions 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.

Additional pediatric use information is approved for AbbVie Inc.’s LEXAPRO® (escitalopram) tablets. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

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