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 practice.
The stated frequencies of adverse reactions represent the proportion of patients who experienced, at least once, one 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.
Adverse Reactions in Adults
Adult Clinical Trial Database
The data described below reflect exposure to duloxetine delayed-release capsules in placebo-controlled adult trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1294). The age range in this pooled population was 17 to 89 years of age. In this pooled population, 66%, 61%, 61%, 43%, and 94% of adult patients were female; and 82%, 73%, 85%, 74%, and 86% of adult patients were Caucasian in the MDD, GAD, OA and CLBP, DPNP, and FM populations, respectively. Most patients received duloxetine delayed-release capsules dosages of a total of 60 to 120 mg per day [see Clinical Studies (14)]. The data below do not include results of the trial that evaluated the efficacy of duloxetine delayed-release capsules for the treatment of GAD in patients ≥65 years old (Study GAD-5) [see Clinical Studies (14.3)]; however, the adverse reactions observed in this geriatric population were generally similar to adverse reactions in the overall adult population.
Adverse Reactions Leading to Treatment Discontinuation in Adult Placebo-Controlled Trials
Major Depressive Disorder
Approximately 8.4% (319/3779) of duloxetine delayed-release capsules-treated patients in placebo-controlled adult trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of placebo-treated patients. Nausea (duloxetine delayed-release capsules 1.1%, placebo 0.4%) was the only adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetine delayed-release capsules-treated patients and at a rate of at least twice that of placebo-treated patients).
Generalized Anxiety Disorder
Approximately 13.7% (139/1018) of the duloxetine delayed-release capsules-treated patients in placebo-controlled adult trials for GAD discontinued treatment due to an adverse reaction, compared with 5% (38/767) for placebo-treated patients. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 3.3%, placebo 0.4%), and dizziness (duloxetine delayed-release capsules 1.3%, placebo 0.4%).
Diabetic Peripheral Neuropathic Pain
Approximately 12.9% (117/906) of the duloxetine delayed-release capsules-treated patients in placebo-controlled adult trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo-treated patients. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 3.5%, placebo 0.7%), dizziness (duloxetine delayed-release capsules 1.2%, placebo 0.4%), and somnolence (duloxetine delayed-release capsules 1.1%, placebo 0%).
Fibromyalgia
Approximately 17.5% (227/1294) of the duloxetine delayed-release capsules-treated patients in 3- to 6-month placebo-controlled adult trials for FM discontinued treatment due to an adverse reaction, compared with 10.1% (96/955) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 2.0%, placebo 0.5%), headache (duloxetine delayed-release capsules 1.2%, placebo 0.3%), somnolence (duloxetine delayed-release capsules 1.1%, placebo 0%), and fatigue (duloxetine delayed-release capsules 1.1%, placebo 0.1%).
Chronic Pain due to Osteoarthritis
Approximately 15.7% (79/503) of the duloxetine delayed-release capsules-treated patients in 13-week, placebo-controlled adult trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 2.2%, placebo 1%).
Chronic Low Back Pain
Approximately 16.5% (99/600) of the duloxetine delayed-release capsules-treated patients in 13-week, placebo-controlled adult trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 3%, placebo 0.7%), and somnolence (duloxetine delayed-release capsules 1%, placebo 0%).
Most Common Adverse Reactions in Adult Trials
The most commonly observed adverse reactions in duloxetine delayed-release capsules-treated patients (as defined above) were:
The most commonly observed adverse reactions in duloxetine delayed-release capsules-treated patients in all the pooled adult populations (i.e., MDD, GAD, DPNP, FM, OA, and CLBP) (incidence of at least 5% and at least twice the incidence in placebo-treated patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis.
Table 2 displays the incidence of adverse reactions in placebo-controlled trials for approved adult populations (i.e., MDD, GAD, DPNP, FM, OA, and CLBP) that occurred in 5% or more of duloxetine delayed-release capsules-treated patients and with an incidence greater than placebo-treated patients.
Adverse Reactions in Pooled MDD and GAD Trials in Adults
Table 3 displays the incidence of adverse reactions in MDD and GAD placebo-controlled adult trials that occurred in 2% or more of duloxetine delayed-release capsules-treated patients and with an incidence greater than placebo-treated patients.
Adverse Reactions in the DPNP, FM, OA, and CLBP Adult Trials
Table 4 displays the incidence of adverse reactions that occurred in 2% or more of duloxetine delayed-release capsules-treated patients (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled adult trials and with an incidence greater than placebo-treated patients.
Effects on Male and Female Sexual Function in Adults with MDD
Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual adverse reactions, was used prospectively in 4 MDD placebo-controlled adult trials (Studies MDD-1, MDD-2, MDD-3, and MDD-4) [see Clinical Studies (14.2)]. The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction. Positive numbers signify a worsening of sexual function from baseline. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients.
In these trials, duloxetine delayed-release capsules-treated male patients experienced significantly more sexual dysfunction, as measured by the total score on the ASEX and the ability to reach orgasm, than placebo-treated male patients (see Table 5). Duloxetine delayed-release capsules-treated female patients did not experience more sexual dysfunction than placebo-treated female patients as measured by ASEX total score. Healthcare providers should routinely inquire about possible sexual adverse reactions in duloxetine delayed-release capsules-treated patients.
Vital Sign Changes in Adults
In placebo-controlled clinical trials across approved adult populations for change from baseline to endpoint, duloxetine delayed-release capsules-treated patients had mean increases of 0.23 mm Hg in systolic blood pressure (SBP) and 0.73 mm Hg in diastolic blood pressure (DBP) compared to mean decreases of 1.09 mm Hg in SBP and 0.55 mm Hg in DBP in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see Warnings and Precautions (5.3, 5.11)].
Duloxetine delayed-release capsules treatment, for up to 26 weeks in placebo-controlled trials across approved adult populations, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.37 beats per minute (increase of 1.20 beats per minute in duloxetine delayed-release capsules-treated patients, decrease of 0.17 beats per minute in placebo-treated patients).
Laboratory Changes in Adults
Duloxetine delayed-release capsules treatment in placebo-controlled clinical trials across approved adult populations, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in duloxetine delayed-release capsules-treated patients when compared with placebo-treated patients [see Warnings and Precautions (5.2)]. High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in duloxetine delayed-release capsules-treated patients compared to placebo-treated patients.
Other Adverse Reactions Observed During the Clinical Trial Evaluation of Duloxetine Delayed-Release Capsules in Adults
Following is a list of adverse reactions reported by patients treated with duloxetine delayed-release capsules in clinical adult trials. In clinical trials of all approved adult populations, 34,756 patients were treated with duloxetine delayed-release capsules. Of these, 27% (9337) took duloxetine delayed-release capsules for at least 6 months, and 12% (4317) took duloxetine delayed-release capsules for at least one year. The following listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause 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.
Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.
Adverse Reactions Observed in Placebo-Controlled Clinical Trials in Pediatric Patients
Pediatric Clinical Trial Database
The data described below reflect exposure to duloxetine delayed-release capsules (N=567) in pediatric patients aged 7 to 18 years of age from two 10-week, placebo-controlled trials in patients with MDD (N=341) (Studies MDD-6 and MDD-7), one 10-week placebo-controlled trial in GAD (N=135) (Study GAD-6), and a 13-week trial in fibromyalgia (N=91). Duloxetine delayed-release capsules is not approved for the treatment of MDD in pediatric patients [see Use in Specific Populations (8.4)] . Of the duloxetine delayed-release capsules -treated patients in these studies, 36% were 7 to 11 years of age (64% were between 12 to 18 years old), 55% were female, and 69% were Caucasian. Patients received 30 to 120 mg of duloxetine delayed-release capsules per day during placebo-controlled acute treatment studies. In the pediatric MDD, GAD, and fibromyalgia trials up to 40 weeks long, there were 988 duloxetine delayed-release capsules-treated pediatric patients aged 7 to 17 years of age (most patients received 30 to 120 mg per day) - 35% were 7 to 11 years of age (65% were 12 to 17 years old) and 56% were female.
Most Common Adverse Reactions in Pediatric Trials
The most common adverse reactions (≥5% in duloxetine delayed-release capsules-treated patients and at least twice the incidence of placebo-treated patients) in all pooled pediatric populations (MDD, GAD, and fibromyalgia) were decreased weight, decreased appetite, nausea, vomiting, fatigue, and diarrhea.
Adverse Reactions in Pediatric Patients Aged 7 to 17 Years Old with MDD and GAD
The adverse reaction profile observed in clinical trials in pediatric patients aged 7 to 18 years old with MDD and GAD was consistent with the adverse reaction profile observed in adult clinical trials. The most common (≥5% and twice placebo) adverse reactions observed in these pediatric clinical trials included: nausea, diarrhea, decreased weight, and dizziness.
Table 6 provides the incidence of adverse reactions in MDD and GAD pediatric placebo-controlled trials that occurred in greater than 2% of patients treated with duloxetine delayed-release capsules and with an incidence greater than patients treated with placebo. Duloxetine delayed-release capsules are not approved in the treatment of MDD in pediatric patients [see Use in Specific Populations (8.4)].
Other adverse reactions that occurred at an incidence of less than 2% and were reported by more duloxetine delayed-release capsules-treated patients than placebo-treated patients in pediatric MDD and GAD clinical trials included: abnormal dreams (including nightmare), anxiety, flushing (including hot flush), hyperhidrosis, palpitations, pulse increased, and tremor (duloxetine delayed-release capsules are not approved to treat pediatric patients with MDD).
The most commonly reported symptoms following discontinuation of duloxetine delayed-release capsules in pediatric MDD and GAD clinical trials included headache, dizziness, insomnia, and abdominal pain [see Warnings and Precautions (5.7)].
Growth (Height and Weight) in Pediatric Patients 7 to 17 Years Old with GAD and MDD
Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Duloxetine delayed-release capsules-treated pediatric patients in clinical trials experienced a 0.1 kg mean decrease in weight at 10 weeks, compared with a mean weight gain of approximately 0.9 kg in placebo-treated pediatric patients. The proportion of patients who experienced a clinically significant decrease in weight (≥3.5%) was greater in the duloxetine delayed-release capsules group than in the placebo group (16% and 6%, respectively). Subsequently, over the 4- to 6-month uncontrolled extension periods, duloxetine delayed-release capsules-treated patients on average trended toward recovery to their expected baseline weight percentile based on population data from age- and sex-matched peers.
In studies up to 9 months, duloxetine delayed-release capsules-treated pediatric patients experienced an increase in height of 1.7 cm on average (2.2 cm increase in patients 7 to 11 years of age and 1.3 cm increase in patients 12 to 17 years of age). While height increase was observed during these studies, a mean decrease of 1% in height percentile was observed (decrease of 2% in patients 7 to 11 years of age and increase of 0.3% in patients 12 to 17 years of age). Weight and height should be monitored regularly in pediatric patients treated with duloxetine delayed-release capsules [see Use in Specific Populations (8.4)].
Adverse Reactions in Pediatric Patients Aged 13 to 17 Years Old with Fibromyalgia
Table 7 provides the incidence of adverse reactions in a fibromyalgia pediatric placebo-controlled trial (Study FM-4) that occurred in greater than 5% of patients treated with duloxetine delayed-release capsules and with an incidence greater than patients treated with placebo [see Clinical Studies (14.5)] .