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CYMBALTA®
(duloxetine hydrochloride)
Delayed–release Capsules
WARNING
Suicidality and Antidepressant Drugs — Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Cymbalta or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Cymbalta is not approved for use in pediatric patients. (See WARNINGS, Clinical Worsening and Suicide Risk, PRECAUTIONS, Information for Patients, PRECAUTIONS, Pediatric Use.)
DESCRIPTION
Cymbalta® (duloxetine hydrochloride) is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. Its chemical designation is (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride. The empirical formula is C18H19NOS•HCl, which corresponds to a molecular weight of 333.88. The structural formula is:
Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water.
Each capsule contains enteric–coated pellets of 22.4, 33.7, or 67.3 mg of duloxetine hydrochloride equivalent to 20, 30, or 60 mg of duloxetine, respectively. These enteric–coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach. Inactive ingredients include FD&C Blue No. 2, gelatin, hypromellose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, and triethyl citrate. The 20 and 60 mg capsules also contain iron oxide yellow.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase (MAO). Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.
Pharmacokinetics
Special Populations
Drug-Drug Interactions (also see PRECAUTIONS, Drug Interactions)
Potential for Other Drugs to Affect Duloxetine
Potential for Duloxetine to Affect Other Drugs
CLINICAL STUDIES
Major Depressive Disorder
The efficacy of Cymbalta as a treatment for depression was established in 4 randomized, double–blind, placebo–controlled, fixed–dose studies in adult outpatients (18 to 83 years) meeting DSM–IV criteria for major depression. In 2 studies, patients were randomized to Cymbalta 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks; in the third study, patients were randomized to Cymbalta 20 or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks; in the fourth study, patients were randomized to Cymbalta 40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks. There is no evidence that doses greater than 60 mg/day confer any additional benefit.
In all 4 studies, Cymbalta demonstrated superiority over placebo as measured by improvement in the 17–li Hamilton Depression Rating Scale (HAMD–17) total score.
Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.
Diabetic Peripheral Neuropathic Pain
The efficacy of Cymbalta for the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN) was established in 2 randomized, 12–week, double–blind, placebo–controlled, fixed–dose studies in adult patients having diabetic peripheral neuropathy for at least 6 months. Study 1 and 2 enrolled a total of 791 patients of whom 592 (75%) completed the studies. Patients enrolled had Type I or II diabetes mellitus with a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months. The patients had a baseline pain score of ≥4 on an 11–point scale ranging from 0 (no pain) to 10 (worst possible pain). Patients were permitted up to 4 g of acetaminophen per day as needed for pain, in addition to Cymbalta. Patients recorded their pain daily in a diary.
Both studies compared Cymbalta 60 mg once daily or 60 mg twice daily with placebo. Study 1 additionally compared Cymbalta 20 mg with placebo. A total of 457 patients (342 Cymbalta, 115 placebo) were enrolled in Study 1 and a total of 334 patients (226 Cymbalta, 108 placebo) were enrolled in Study 2. Treatment with Cymbalta 60 mg one or two times a day statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain score from baseline. For various degrees of improvement in pain from baseline to study endpoint, Figures 1 and 2 show the fraction of patients achieving that degree of improvement. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
Generalized Anxiety Disorder
The efficacy of Cymbalta in the treatment of generalized anxiety disorder (GAD) was established in 1 fixed–dose randomized, double–blind, placebo–controlled trial and 2 flexible–dose randomized, double–blind, placebo–controlled trials in adult outpatients between 18 and 83 years of age meeting the DSM–IV criteria for GAD.
In 1 flexible–dose study and in the fixed–dose study, the starting dose was 60 mg once daily where down titration to 30 mg once daily was allowed for tolerability reasons before increasing it to 60 mg once daily. Fifteen percent of patients were down titrated. One flexible–dose study had a starting dose of 30 mg once daily for 1 week before increasing it to 60 mg once daily.
The 2 flexible–dose studies involved dose titration with Cymbalta doses ranging from 60 mg once daily to 120 mg once daily (N=168 and N=162) compared to placebo (N=159 and N=161) over a 10–week treatment period. The mean dose for completers at endpoint in the flexible–dose studies was 104.75 mg/day. The fixed–dose study evaluated Cymbalta doses of 60 mg once daily (N=168) and 120 mg once daily (N=170) compared to placebo (N=175) over a 9–week treatment period. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit.
In all 3 studies, Cymbalta demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM–A) total score and by the Sheehan Disability Scale (SDS) global functional impairment score. The SDS is a widely used and well–validated scale that measures the extent emotional symptoms disrupt patient functioning in 3 life domains: work/school, social life/leisure activities and family life/home responsibilities.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.
INDICATIONS AND USAGE
Major Depressive Disorder
Cymbalta is indicated for the treatment of major depressive disorder (MDD).
The efficacy of Cymbalta has been established in 8– and 9–week placebo–controlled trials of outpatients who met DSM–IV diagnostic criteria for major depressive disorder (see CLINICAL STUDIES).
A major depressive episode (DSM–IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or a suicide attempt or suicidal ideation.
The effectiveness of Cymbalta in hospitalized patients with major depressive disorder has not been studied.
The effectiveness of Cymbalta in long–term use for major depressive disorder, that is, for more than 9 weeks, has not been systematically evaluated in controlled trials. The physician who elects to use Cymbalta for extended periods should periodically evaluate the long–term usefulness of the drug for the individual patient.
Diabetic Peripheral Neuropathic Pain
Cymbalta is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy (see CLINICAL STUDIES).
Generalized Anxiety Disorder
Cymbalta is indicated for the treatment of generalized anxiety disorder (GAD).
The efficacy of Cymbalta has been established in three 9– or 10–week placebo–controlled trials of outpatients who met DSM–IV diagnostic criteria for generalized anxiety disorder (see CLINICAL STUDIES).
Generalized anxiety disorder is defined by the DSM–IV as excessive anxiety and worry, present more days than not, for at least 6 months. The excessive anxiety and worry must be difficult to control and must cause significant distress or impairment in normal functioning. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and/or sleep disturbance.
The effectiveness of Cymbalta in long–term use for GAD, that is, for more than 10 weeks, has not been systematically evaluated in controlled trials. The physician who elects to use Cymbalta for extended periods should periodically evaluate the long–term usefulness of the drug for the individual patient.
CONTRAINDICATIONS
Hypersensitivity
Cymbalta is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.
Monoamine Oxidase Inhibitors
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS).
Uncontrolled Narrow-Angle Glaucoma
In clinical trials, Cymbalta use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow–angle glaucoma.
WARNINGS
PRECAUTIONS
General
Information for Patients
Laboratory Tests
Drug Interactions (also see CLINICAL PHARMACOLOGY, Drug-Drug Interactions)
Potential for Other Drugs to Affect Cymbalta
Potential for Duloxetine to Affect Other Drugs
Cymbalta May Have a Clinically Important Interaction with the Following Other Drugs:
Carcinogenesis, Mutagenesis, Impairment of Fertility
Pregnancy
Labor and Delivery
The effect of duloxetine on labor and delivery in humans is unknown. Duloxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Duloxetine is excreted into the milk of lactating women. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose. Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of Cymbalta in a child or adolescent must balance the potential risks with the clinical need.
Geriatric Use
Of the 2418 patients in premarketing clinical studies of Cymbalta for MDD, 5.9% (143) were 65 years of age or over. Of the 1074 patients in the DPN premarketing studies, 33% (357) were 65 years of age or over. Premarketing clinical studies of GAD did not include sufficient numbers of subjects age 65 or over to determine whether they respond differently from younger subjects. In the MDD and DPN studies, no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. As with other antidepressants, Cymbalta has been associated with cases of clinically significant hyponatremia (see Hyponatremia, under PRECAUTIONS).
ADVERSE REACTIONS
Cymbalta has been evaluated for safety in 2418 patients diagnosed with major depressive disorder who participated in multiple–dose premarketing trials, representing 1099 patient–years of exposure. Among these 2418 Cymbalta–treated patients, 1139 patients participated in eight 8– or 9–week, placebo–controlled trials at doses ranging from 40 to 120 mg/day, while the remaining 1279 patients were followed for up to 1 year in an open–label safety study using flexible doses from 80 to 120 mg/day. Two placebo–controlled studies with doses of 80 and 120 mg/day had 6–month maintenance extensions. Of these 2418 patients, 993 Cymbalta–treated patients were exposed for at least 180 days and 445 Cymbalta–treated patients were exposed for at least 1 year.
Cymbalta has also been evaluated for safety in 1074 patients with diabetic peripheral neuropathy representing 472 patient–years of exposure. Among these 1074 Cymbalta–treated patients, 568 patients participated in two 12– to 13–week, placebo–controlled trials at doses ranging from 20 to 120 mg/day. An additional 449 patients were enrolled in an open–label safety study using 120 mg/day for a duration of 6 months. Another 57 patients, originally treated with placebo, were exposed to Cymbalta for up to 12 months at 60 mg twice daily in an extension phase. Among these 1074 patients, 484 had 6 months of exposure to Cymbalta, and 220 had 12 months of exposure.
Cymbalta has also been evaluated for safety in 668 patients with generalized anxiety disorder representing 95 patient–years of exposure.These 668 patients participated in 9– or 10–week placebo–controlled trials at doses ranging from 60 mg once daily to 120 mg once daily. Of these 668 patients, 449 were exposed for at least 2 months to Cymbalta.
In the full cohort of placebo–controlled clinical trials for any indication, safety has been evaluated in 8504 patients treated with duloxetine and 6123 patients treated with placebo. In clinical trials, a total of 23,983 patients have been exposed to duloxetine. In duloxetine clinical trials, adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.
Clinical investigators recorded adverse events using descriptive terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing adverse events, grouping similar types of events into a smaller number of standardized event categories is necessary. In the tables and tabulations that follow, MedDRA 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 uled. An event was considered treatment–emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Events reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality.
The cited figures provide the prescriber with some basis for estimating the relative contribution of drug and non–drug factors to the adverse event incidence rate in the population studied. The prescriber should be aware that the figures in the tables and tabulations 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.
Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials
Major Depressive Disorder
Approximately 10% of the 1139 patients who received Cymbalta in the MDD placebo–controlled trials discontinued treatment due to an adverse event, compared with 4% of the 777 patients receiving placebo. Nausea (Cymbalta 1.4%, placebo 0.1%) was the only common adverse event reported as reason for discontinuation and considered to be drug–related (i.e., discontinuation occurring in at least 1% of the Cymbalta–treated patients and at a rate of at least twice that of placebo).
Diabetic Peripheral Neuropathic Pain
Approximately 14% of the 568 patients who received Cymbalta in the DPN placebo–controlled trials discontinued treatment due to an adverse event, compared with 7% of the 223 patients receiving placebo. Nausea (Cymbalta 3.5%, placebo 0.4%), dizziness (Cymbalta 1.6%, placebo 0.4%), somnolence (Cymbalta 1.6%, placebo 0%) and fatigue (Cymbalta 1.1%, placebo 0%) were the common adverse events reported as reasons for discontinuation and considered to be drug–related (i.e., discontinuation occurring in at least 1% of the Cymbalta–treated patients and at a rate of at least twice that of placebo).
Generalized Anxiety Disorder
Approximately 16% of the 668 patients who received Cymbalta in the GAD placebo–controlled trials discontinued treatment due to an adverse event, compared with 4% of the 495 patients receiving placebo. Nausea (Cymbalta 3.7%, placebo 0.2%), vomiting (Cymbalta 1.4%, placebo 0%) and dizziness (Cymbalta 1.2%, placebo 0.2%) were the common adverse events reported as reasons for discontinuation and considered to be drug–related (i.e., discontinuation occurring in at least 1% of the Cymbalta–treated patients and at a rate of at least twice that of placebo).
Adverse Events Occurring at an Incidence of 2% or More Among Cymbalta-Treated Patients in Placebo-Controlled Trials
Major Depressive Disorder
Table 2 gives the incidence of treatment–emergent adverse events that occurred in 2% or more of patients treated with Cymbalta in the premarketing acute phase of MDD placebo–controlled trials and with an incidence greater than placebo. The most commonly observed adverse events in Cymbalta–treated MDD patients (incidence of 5% or greater and at least twice the incidence in placebo patients) were: nausea; dry mouth; constipation; decreased appetite; fatigue; somnolence; and increased sweating (see Table 2).
Percentage of Patients Reporting Event | ||
System Organ Class / Adverse Event | Cymbalta | Placebo |
Gastrointestinal Disorders | ||
Nausea | 20 | 7 |
Dry mouth | 15 | 6 |
Constipation | 11 | 4 |
Diarrhea | 8 | 6 |
Vomiting | 5 | 3 |
Metabolism and Nutrition Disorders | ||
Appetite decreased | 8 | 2 |
Investigations | ||
Weight decreased | 2 | 1 |
General Disorders and Administration Site | ||
Fatigue | 8 | 4 |
Nervous System Disorders | ||
Dizziness | 9 | 5 |
Somnolence | 7 | 3 |
Tremor | 3 | 1 |
Skin and Subcutaneous Tissue Disorders | ||
Sweating increased | 6 | 2 |
Vascular Disorders | ||
Hot flushes | 2 | 1 |
Eye Disorders | ||
Vision blurred | 4 | 1 |
Psychiatric Disorders | ||
Insomnia | 11 | 6 |
Anxiety | 3 | 2 |
Libido decreased | 3 | 1 |
Orgasm abnormal | 3 | 1 |
Reproductive System and Breast Disorders | ||
Erectile dysfunction | 4 | 1 |
Ejaculation delayed | 3 | 1 |
Ejaculatory dysfunction | 3 | 1 |
Diabetic Peripheral Neuropathic Pain
Table 3 gives the incidence of treatment–emergent adverse events that occurred in 2% or more of patients treated with Cymbalta in the premarketing acute phase of DPN placebo–controlled trials (doses of 20 to 120 mg/day) and with an incidence greater than placebo. The most commonly observed adverse events in Cymbalta–treated DPN patients (incidence of 5% or greater and at least twice the incidence in placebo patients) were: nausea; somnolence; dizziness; constipation; dry mouth; hyperhidrosis; decreased appetite; and asthenia (see Table 3).
Percentage of Patients Reporting Event | ||||
System Organ Class / | Cymbalta | Cymbalta | Cymbalta | Placebo |
Gastrointestinal Disorders | ||||
Nausea | 30 | 22 | 14 | 9 |
Constipation | 15 | 11 | 5 | 3 |
Diarrhea | 7 | 11 | 13 | 6 |
Dry mouth | 12 | 7 | 5 | 4 |
Vomiting | 5 | 5 | 6 | 4 |
Dyspepsia | 4 | 4 | 4 | 3 |
Loose stools | 2 | 3 | 2 | 1 |
General Disorders and Administration | ||||
Fatigue | 12 | 10 | 2 | 5 |
Asthenia | 8 | 4 | 2 | 1 |
Pyrexia | 3 | 1 | 2 | 1 |
Infections and Infestations | ||||
Nasopharyngitis | 9 | 7 | 9 | 5 |
Metabolism and Nutrition Disorders | ||||
Decreased appetite | 11 | 4 | 3 | <1 |
Anorexia | 5 | 3 | 3 | <1 |
Musculoskeletal and Connective Tissue | ||||
Muscle cramp | 4 | 4 | 5 | 3 |
Myalgia | 4 | 1 | 3 | <1 |
Nervous System Disorders | ||||
Somnolence | 21 | 15 | 7 | 5 |
Headache | 15 | 13 | 13 | 10 |
Dizziness | 17 | 14 | 6 | 6 |
Tremor | 5 | 1 | 0 | 0 |
Psychiatric Disorders | ||||
Insomnia | 13 | 8 | 9 | 7 |
Renal and Urinary Disorders | ||||
Pollakiuria | 5 | 1 | 3 | 2 |
Reproductive System and Breast Disorders | ||||
Erectile dysfunction | 4 | 1 | 0 | 0 |
Respiratory, Thoracic and Mediastinal | ||||
Cough | 5 | 3 | 6 | 4 |
Pharyngolaryngeal pain | 6 | 1 | 3 | 1 |
Skin and Subcutaneous | ||||
Hyperhidrosis | 8 | 6 | 6 | 2 |
Generalized Anxiety Disorder
Table 4 gives the incidence of treatment–emergent adverse events that occurred in 2% or more of patients treated with Cymbalta in the premarketing acute phase of GAD placebo–controlled trials (doses of 60 to 120 mg once daily) and with an incidence greater than placebo. The most commonly observed adverse events in Cymbalta–treated GAD patients (incidence of 5% or greater and at least twice the incidence in placebo patients) were: nausea; fatigue; dry mouth; somnolence; constipation; insomnia; appetite decreased; hyperhidrosis; libido decreased; vomiting; ejaculation delayed; and erectile dysfunction (see Table 4).
Percentage of Patients Reporting Event | ||
System Organ Class / Adverse Event | Cymbalta | Placebo |
Eye Disorders | ||
Vision blurred | 4 | 2 |
Gastrointestinal Disorders | ||
Nausea | 38 | 10 |
Dry mouth | 12 | 4 |
Constipation | 10 | 3 |
Diarrhea | 8 | 6 |
Vomiting | 5 | 2 |
Abdominal pain | 4 | 3 |
Dyspepsia | 4 | 3 |
General Disorders and Administration Site | ||
Fatigue | 13 | 5 |
Metabolism and Nutrition Disorders | ||
Appetite decreased | 8 | 3 |
Nervous System Disorders | ||
Dizziness | 15 | 8 |
Somnolence | 12 | 3 |
Tremor | 4 | 1 |
Paraesthesia | 2 | 1 |
Psychiatric Disorders | ||
Insomnia | 9 | 4 |
Libido decreased | 7 | 2 |
Agitation | 4 | 2 |
Orgasm abnormal | 3 | 0 |
Reproductive System and Breast Disorders | ||
Ejaculation delayed | 5 | 1 |
Erectile dysfunction | 5 | 1 |
Respiratory, Thoracic and Mediastinal | ||
Yawning | 3 | 0 |
Skin and Subcutaneous Tissue Disorders | ||
Hyperhidrosis | 7 | 2 |
Vascular Disorders | ||
Hot flushes | 3 | 1 |
Adverse events seen in men and women were generally similar except for effects on sexual function (described below). Clinical studies of Cymbalta did not suggest a difference in adverse event rates in people over or under 65 years of age. There were too few non–Caucasian patients studied to determine if these patients responded differently from Caucasian patients.
Effects on Male and Female Sexual Function
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, 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 displays the incidence of sexual side effects spontaneously reported by at least 2% of either male or female patients taking Cymbalta in MDD placebo–controlled trials.
Percentage of
Patients Reporting Event | ||||
% Male Patients | % Female Patients | |||
Adverse Event | Cymbalta | Placebo | Cymbalta | Placebo |
Orgasm abnormal | 4 | 1 | 2 | 0 |
Ejaculatory dysfunction | 3 | 1 | NA | NA |
Libido decreased | 6 | 2 | 1 | 0 |
Erectile dysfunction | 4 | 1 | NA | NA |
Ejaculation delayed | 3 | 1 | NA | NA |
Because adverse sexual events are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo–controlled trials. In these trials, as shown in Table 6 below, patients treated with Cymbalta experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with Cymbalta experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on Cymbalta than on placebo as measured by ASEX total score. These studies did not, however, include an active control drug with known effects on female sexual dysfunction, so that there is no evidence that its effects differ from other antidepressants. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. Physicians should routinely inquire about possible sexual side effects.
Male Patients | Female Patients | |||
Cymbalta | Placebo | Cymbalta | Placebo | |
ASEX Total (Items 1–5) | 0.56 | -1.07 | -1.15 | -1.07 |
Item 1 — Sex drive | -0.07 | -0.12 | -0.32 | -0.24 |
Item 2 — Arousal | 0.01 | -0.26 | -0.21 | -0.18 |
Item 3 — Ability to achieve
erection | 0.03 | -0.25 | -0.17 | -0.18 |
Item 4 — Ease of reaching orgasm | 0.40 | -0.24 | -0.09 | -0.13 |
Item 5 — Orgasm satisfaction | 0.09 | -0.13 | -0.11 | -0.17 |
Urinary Hesitation
Cymbalta is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Cymbalta, consideration should be given to the possibility that they might be drug–related.
Laboratory Changes
Cymbalta treatment, for up to 9–weeks in MDD, 9–10 weeks in GAD or 13–weeks in DPN placebo–controlled clinical trials, 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 Cymbalta–treated patients when compared with placebo–treated patients (see PRECAUTIONS).
Vital Sign Changes
In clinical trials across indications, relative to placebo, duloxetine treatment was associated with mean increases of up to 2.1 mm Hg in systolic blood pressure and up to 2.3 mm Hg in diastolic blood pressure, averaging up to 2 mm Hg. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure (see PRECAUTIONS).
Duloxetine treatment, for up to 13–weeks in placebo–controlled trials typically caused a small increase in heart rate compared to placebo of up to 3 beats per minute.
Weight Changes
In placebo–controlled clinical trials, MDD and GAD patients treated with Cymbalta for up to 10–weeks experienced a mean weight loss of approximately 0.5 kg, compared with a mean weight gain of approximately 0.2 kg in placebo–treated patients. In DPN placebo–controlled clinical trials, patients treated with Cymbalta for up to 13–weeks experienced a mean weight loss of approximately 1.1 kg, compared with a mean weight gain of approximately 0.2 kg in placebo–treated patients.
Electrocardiogram Changes
Electrocardiograms were obtained from duloxetine–treated patients and placebo–treated patients in clinical trials lasting up to 13–weeks. No clinically significant differences were observed for QTc, QT, PR, and QRS intervals between duloxetine–treated and placebo–treated patients. There were no differences in clinically meaningful QTcF elevations between duloxetine and placebo. In a positive–controlled study in healthy volunteers using duloxetine up to 200 mg BID, no prolongation of the corrected QT interval was observed.
Other Adverse Events Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine
Following is a ul of MedDRA terms that reflect treatment–emergent adverse events as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with duloxetine at multiple doses throughout the dose range studied during any phase of a clinical trial within the premarketing and postmarketing database (23,983 patients, 10,649.5 patient–years of exposure). The events included are those not already uled in Tables 2 through 4 and not considered in the WARNINGS and PRECAUTIONS sections. The events were reported by more than one patient, are not common as background events and/or were considered possibly drug related (e.g., because of the drug’s pharmacology) or potentially important.
It is important to emphasize that, although the events reported occurred during treatment with Cymbalta, they were not necessarily caused by it. Events are further categorized by body system and uled in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Blood and Lymphatic System Disorders — Infrequent: anemia and lymphadenopathy; Rare: leukopenia and thrombocytopenia.
Cardiac Disorders — Frequent: palpitations; Infrequent: atrial fibrillation, coronary artery disease, myocardial infarction, and tachycardia; Rare: bundle branch block right, cardiac failure, and cardiac failure congestive.
Ear and Labyrinth Disorders — Frequent: vertigo; Infrequent: ear pain and tinnitus.
Eye Disorders — Frequent: vision blurred; Infrequent: conjunctivitis, diplopia, and visual disturbance; Rare: glaucoma, macular degeneration, maculopathy, photopsia, and retinal detachment.
Gastrointestinal Disorders — Frequent: abdominal pain and flatulence; Infrequent: dysphagia, eructation, gastritis, halitosis, irritable bowel syndrome, and stomatitis; Rare: aphthous stomatitis, colitis, esophageal stenosis, gastric ulcer, gingivitis, hematochezia, impaired gastric emptying, and melena.
General Disorders and Administration Site Conditions — Frequent: chills/rigors; Infrequent: edema, edema peripheral, feeling abnormal, feeling hot and/or cold, influenza–like illness, malaise, and thirst; Rare: face edema, gait disturbance, and sluggishness.
Hepato–biliary Disorders — Rare: hepatic steatosis.
Infections and Infestations — Infrequent: gastroenteritis and laryngitis; Rare: diverticulitis.
Investigations — Frequent: weight decreased and weight increased; Infrequent: blood cholesterol increased; Rare: blood creatinine increased, urine output decreased, and white blood cell count increased.
Metabolism and Nutrition Disorders — Infrequent: dehydration, hypercholesterolemia, hyperlipidemia, hypoglycemia, and increased appetite; Rare: dyslipidemia and hypertriglyceridemia.
Musculoskeletal and Connective Tissue Disorders — Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching; Rare: muscular weakness.
Nervous System Disorders — Frequent: dysgeusia, lethargy, and parasthesia/hypoesthesia; Infrequent: coordination abnormal, disturbance in attention, dyskinesia, hypersomnia, myoclonus, and poor quality sleep; Rare: dysarthria.
Psychiatric Disorders — Frequent: agitation, anxiety, libido decreased, nervousness, nightmare/abnormal dreams, and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, restlessness, suicide attempt, and tension; Rare: completed suicide, mania, and pressure of speech.
Renal and Urinary Disorders — Infrequent: dysuria, micturition urgency, nocturia, polyuria, urinary hesitation, urinary incontinence, urinary retention, urine flow decreased, and urine odor abnormal; Rare: nephropathy.
Reproductive System and Breast Disorders — Frequent: anorgasmia/orgasm abnormal, ejaculation delayed, and ejaculation disorder; Infrequent: menopausal symptoms and sexual dysfunction.
Respiratory, Thoracic and Mediastinal Disorders — Frequent: yawning; Infrequent: throat tightness; Rare: pharyngeal edema.
Skin and Subcutaneous Tissue Disorders — Frequent: pruritus and rash; Infrequent: acne, alopecia, cold sweat, dermatitis contact, eczema, erythema, increased tendency to bruise, night sweats, photosensitivity reaction, and skin ulcer; Rare: dermatitis exfoliative, ecchymosis, and hyperkeratosis.
Vascular Disorders — Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness; Rare: hypertensive crisis and phlebitis.
Postmarketing Spontaneous Reports
Adverse events reported since market introduction that were temporally related to duloxetine therapy and not mentioned elsewhere in labeling include: anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, erythema multiforme, extrapyramidal disorder, glaucoma, hallucinations, hyperglycemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, Stevens–Johnson Syndrome, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
Duloxetine is not a controlled substance.
Physical and Psychological Dependence
In animal studies, duloxetine did not demonstrate barbiturate–like (depressant) abuse potential. In drug dependence studies, duloxetine did not demonstrate dependence–producing potential in rats.
While Cymbalta has not been systematically studied in humans for its potential for abuse, there was no indication of drug–seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Cymbalta (e.g., development of tolerance, incrementation of dose, drug–seeking behavior).
OVERDOSAGE
Management of Overdose
There is no specific antidote to Cymbalta, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug.
An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large–bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.
Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and Cmax by an average of one–third, although some subjects had a limited effect of activated charcoal. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial.
In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who are taking or have recently taken Cymbalta and might ingest excessive quantities of a TCA. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see PRECAUTIONS, Drug Interactions). The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are uled in the Physicians’ Desk Reference (PDR).
DOSAGE AND ADMINISTRATION
Initial Treatment
Maintenance/Continuation/Extended Treatment
Special Populations
Dosage for Renally Impaired Patients — Cymbalta is not recommended for patients with end–stage renal disease (requiring dialysis) or in severe renal impairment (estimated creatinine clearance <30 mL/min) (see CLINICAL PHARMACOLOGY).
Dosage for Hepatically Impaired Patients — It is recommended that Cymbalta not be administered to patients with any hepatic insufficiency (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
Dosage for Elderly Patients — No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in elderly patients, extra care should be taken when increasing the dose.
Treatment of Pregnant Women During the Third Trimester — Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Cymbalta during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Cymbalta in the third trimester.
Dosage for Nursing Mothers — Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended (see CLINICAL PHARMACOLOGY).
Discontinuing Cymbalta
Symptoms associated with discontinuation of Cymbalta and other SSRIs and SNRIs have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
Switching Patients to or from a Monoamine Oxidase Inhibitor
At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Cymbalta. In addition, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI (see CONTRAINDICATIONS and WARNINGS).
HOW SUPPLIED
Literature revised June 28, 2007
Eli Lilly and Company
Indianapolis, IN 46285, USA
www.Cymbalta.com
Copyright © 2004, 2007, Eli Lilly and Company. All rights reserved.
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Supplement Patient Material Section
Medication
Guide
Antidepressant
Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts
or Actions
Read the Medication Guide that comes with your or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about:
all risks and benefits of treatment with antidepressant medicines
all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?
Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic–depressive illness) or suicidal thoughts or actions.
How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:
thoughts about suicide or dying
attempts to commit suicide
new or worse depression
new or worse anxiety
feeling very agitated or restless
panic attacks
trouble sleeping (insomnia)
new or worse irritability
acting aggressive, being angry, or violent
acting on dangerous impulses
an extreme increase in activity and talking (mania)
other unusual changes in behavior or mood
What else do I need to know about antidepressant medicines?
Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a ul of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information.
Patient Information revised June 21, 2007
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