section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Duloxetine hydrochloride, a selective serotonin- and norepinephrine-reuptake inhibitor (SNRI), is an antidepressant and anxiolytic agent.1,2,29,30,31

Uses ⬆ ⬇

[Section Outline]

Major Depressive Disorder !!navigator!!

Duloxetine hydrochloride is used for the acute and maintenance treatment of major depressive disorder in adults.1,34,44,45

Clinical Experience

Efficacy of duloxetine for the acute treatment of major depression has been established in 4 double-blind, placebo-controlled studies of 8-9 weeks' duration in outpatient settings in adults.1 In these studies, patients receiving duloxetine (40-120 mg daily) had greater improvements in the 17-item Hamilton depression rating scale (HAMD-17) total score than did patients receiving placebo.1 No age-, race-, or gender-related differences in efficacy were noted in these studies.1

Efficacy of duloxetine for the maintenance treatment of major depressive disorder has been established in a randomized, placebo-controlled, relapse prevention study in which 533 adult outpatients who met DSM-IV criteria for major depressive disorder initially received duloxetine 60 mg once daily in a 12-week, open-label, acute phase.1,34,44 Patients who responded to treatment during the acute phase were then randomized to continue receiving duloxetine at the same dosage or to receive placebo for 26 weeks in the continuation phase.1,34,44 The duloxetine-treated patients experienced a longer time to relapse of depression compared with the placebo recipients.1,34,44 In addition, more placebo recipients relapsed compared with patients receiving duloxetine (approximately 29% and 17%, respectively).34,44

Clinical Perspective

Treatment options for major depressive disorder include pharmacologic and nonpharmacologic (e.g., psychotherapy) approaches.498,499,500,501 Several classes of antidepressant drugs are available for the treatment of major depressive disorder.498,499,500,501 In general, these drugs have shown similar effectiveness; therefore, treatment is guided by specific patient and drug-related factors.498,499,501

A legacy practice guideline from the American Psychiatric Association (APA) published in 2010 states that the effectiveness of antidepressants in the treatment of major depressive disorder is generally comparable between and within classes of medications, including selective serotonin reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and other antidepressants (e.g., bupropion, mirtazapine, trazodone).501 Therefore, the initial selection of an antidepressant can be based mainly on the following factors: patient preference; nature of prior response to medication; safety, tolerability, and anticipated adverse effects; concurrent psychiatric and medical conditions; specific properties of the medication (e.g., half-life, cytochrome P-450 [CYP] interactions, other drug interactions); and cost.501

The Department of Veterans Affairs and Department of Defense developed more current guidelines for management of major depressive disorder.500 These guidelines state that treatment of uncomplicated major depressive disorder can be initiated with either psychotherapy (e.g., cognitive behavioral therapy) or pharmacotherapy, depending on patient preference; for patients with severe, persistent, or recurrent major depressive disorder, a combination of pharmacotherapy and psychotherapy is suggested.500 When pharmacotherapy is used as initial therapy, either bupropion, mirtazapine, a SSRI, SNRI, trazodone, vilazodone, or vortioxetine is suggested.500 No evidence is available to suggest superiority of one agent over another.500 The guidelines recommend against using esketamine, ketamine, MAOIs, nefazodone, or TCAs as initial therapy.500 For patients not responding to initial therapy, recommendations include switching to another antidepressant (including MAOIs or TCAs), switching to or augmenting with psychotherapy, or augmenting with a second-generation antipsychotic.500

Generalized Anxiety Disorder !!navigator!!

Duloxetine hydrochloride is used for the acute management of generalized anxiety disorder in adults and pediatric patients ≥7 years of age.1,29,30,31

The manufacturer states that the anxiolytic efficacy of duloxetine for long-term use (i.e., exceeding 10 weeks) has not been established by controlled studies to date.1 If duloxetine is used for extended periods, the need for continued therapy should be reassessed periodically.1

Clinical Experience

Efficacy of duloxetine for the treatment of generalized anxiety disorder in adults has been established in 3 placebo-controlled trials of 9-10 weeks' duration in outpatient settings in adults who met DSM-IV criteria for generalized anxiety disorder.1,29,30,31 In these studies, patients receiving duloxetine (60-120 mg daily) had greater improvements in the Hamilton anxiety scale (HAM-A) total score and the Sheehan Disability Scale (SDS) global functional impairment score than did patients receiving placebo.1,29,30,31 No age- or gender-related differences in efficacy were noted in these studies.1

Another trial, which included a 26-week, open-label, flexible-dose (up to 120 mg daily) acute treatment phase followed by a 26-week, double-blind, placebo-controlled, continuation phase, evaluated the efficacy of duloxetine for prevention of relapse in patients with generalized anxiety disorder.1,502 Patients responding to acute treatment (≥50% reduction in HAM-A score and Clinical Global Impressions of Improvement (CGI-I) rating of much or very much improved) with duloxetine were randomly re-assigned to treatment with either duloxetine at the same dosage or placebo.1,502 Of 887 patients in the acute phase, 429 entered the double-blind phase.1 Relapse was defined as an increase of ≥2 points in the Clinical Global Impressions of Improvement-Severity (CGI-S) score to ≥4 and a Mini-International Neuropsychiatric Interview diagnosis of generalized anxiety disorder or discontinuation of treatment due to lack of efficacy.1 The relapse rate was 13.7 or 41.8% for duloxetine- or placebo-treated patients, respectively.502 Time to relapse was also longer with duloxetine as compared to placebo.502

Efficacy of duloxetine for the treatment of generalized anxiety disorder was also evaluated in geriatric patients (≥65 years of age) in a randomized, double-blind, placebo-controlled, phase 4 trial.1,503 A total of 288 patients were treated with either duloxetine (30 mg with increases up to 120 mg per day) or placebo for 10 weeks, followed by a 2-week taper-off period.1,503 Response to treatment was assessed by a ≥50% reduction from baseline in HAM-A total score; remission was a HAM-A total score of ≤7.503 Improvement in HAM-A scores from baseline was substantially greater with duloxetine compared to placebo (-15.9 or -11.7 for duloxetine or placebo, respectively).503 Response and remission rates for duloxetine were 71.3 and 44.8%, respectively, compared to 45.5 and 29.5%, respectively, for placebo.503

Efficacy of duloxetine for the treatment of generalized anxiety disorder in pediatric patients was evaluated in a flexible dose, randomized, double-blind, placebo controlled study.1,504 A total of 272 patients 7-17 years of age with generalized anxiety disorder were randomized to treatment with duloxetine (30 mg with increases up to 120 mg once daily) or placebo for 10 weeks.1,504 After the acute treatment phase, all patients were treated with duloxetine (30-120 mg once daily) in an 18-week extension phase.504 At 10 weeks, duloxetine treatment resulted in greater improvement in the Pediatric Anxiety Rating Scale (PARS) for anxiety severity compared to placebo.1,504 At 28 weeks, duloxetine also resulted in improvements in CGI-S scores, anxiety symptom severity, and Children's Global Assessment Scale (CGAS) scores.504

Clinical Perspective

First-line treatments for generalized anxiety disorder in adults include cognitive behavioral therapy, pharmacotherapy (SSRIs or SNRIs), or a combination of both.505 Pregabalin and buspirone are considered second-line or add-on therapies.505 SSRIs approved for use in generalized anxiety disorder include paroxetine, sertraline, and escitalopram; approved SNRIs include venlafaxine and duloxetine.506

Among children and adolescents, anxiety disorders have a lifetime prevalence of 20-30% in the US.507 Similar to treatment for adults, guidelines from the American Academy of Child and Adolescent Psychiatry (AACAP) recommend cognitive behavioral therapy or an SSRI for patients 6-18 years of age with generalized anxiety.507 The guidelines suggest that combination treatment (cognitive behavioral therapy plus an SSRI) could be offered preferentially to either therapy alone.507 SNRIs can also be considered.507

Neuropathic Pain !!navigator!!

Duloxetine hydrochloride is used for the management of neuropathic pain associated with diabetic peripheral neuropathy in adults.1,48,49

Clinical Experience

Efficacy of duloxetine for the management of diabetic peripheral neuropathy has been established in 2 randomized, controlled, 12-week studies in adults with type 1 or 2 diabetes mellitus and a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months.1,48,49 Patients were excluded from the studies if they met DSM-IV-TR criteria for major depressive disorder and dysthymia.48,49 Patients were randomized to receive duloxetine 60 mg once daily, 60 mg twice daily, or placebo in study 1 and to duloxetine 20 or 60 mg once daily, 60 mg twice daily, or placebo in study 2.1,48,49 In both studies, the primary outcome was the reduction in weekly mean pain scores.48,49 A total of 791 patients were enrolled.1 Duloxetine 60 mg once or twice daily resulted in greater improvement in mean pain scores and a greater percentage of patients achieving a ≥50% reduction in pain scores from baseline over placebo (26-27% for placebo versus 41-53% for duloxetine).48,49 Some patients in the study experienced a decrease in pain as early as week 1, which persisted throughout the study.1,48,49

Clinical Perspective

The American Diabetes Association (ADA) standards of care on diabetic neuropathy stress the importance of optimal glucose, serum lipid, and blood pressure control along with lifestyle changes to help prevent or delay the development of diabetic neuropathies.508 However, no treatment is currently available to reverse the underlying nerve damage resulting from the neuropathy.508 Symptoms of diabetic neuropathy can vary, depending on the sensory fibers affected, but most commonly include pain (burning or stabbing), numbness, and tingling.509 For pain, the ADA pharmacologic recommendations include gabapentinoids, SNRIs, sodium channel blockers, and tricyclic antidepressants.508 The guidelines do not state a preference for one agent over another.508 The use of opioid agents for chronic neuropathic pain is not recommended.508

Fibromyalgia !!navigator!!

Duloxetine hydrochloride is used for the management of fibromyalgia in adults and pediatric patients ≥13 years of age.1,46,47,65

Clinical Experience

Efficacy of duloxetine for the management of fibromyalgia in adults has been established in 2 randomized, double-blind, placebo-controlled, fixed-dose studies; the studies included patients with a diagnosis of fibromyalgia based on the American College of Rheumatology (ACR) criteria (i.e., history of widespread pain for 3 months and pain present in 11 or more of the 18 specific tender point sites).1,46,47 The first study (FM-1) was 3 months in duration and enrolled female patients only,1,47 while the second study (FM-2) was 6 months in duration and enrolled both male and female patients.1,46 Approximately 25% of the patients had concurrent major depressive disorder.1,47 Both of these studies compared duloxetine 60 mg once daily or 120 mg daily (given in divided doses in FM-1 and as a single daily dose in FM-2) with placebo.1,46,47 In addition, FM-2 compared duloxetine 20 mg daily with placebo during the initial 3 months of the 6-month study; after 3 months, the duloxetine dosage was titrated up to 60 mg once daily for the remainder of the study.1,46 In these studies, duloxetine therapy in dosages of 60 or 120 mg daily significantly improved the endpoint mean pain scores from baseline and increased the number of patients who had at least a 50% reduction in pain score compared with baseline.1,46,47 Although pain reduction was observed in patients both with and without major depressive disorder,1,46,47 the degree of pain reduction may be greater in patients with major depressive disorder.1 Some patients experienced a reduction in pain as early as week 1, which persisted throughout the study.1,46,47 Improvement also was noted on measures of function as well as on the Patient Global Impression of Improvement (PGI) scale.1,46,47 Neither study demonstrated an additional therapeutic benefit with a dosage of 120 mg daily compared with 60 mg daily, and the higher dosage was associated with more frequent adverse effects and early discontinuance of therapy.1,46,47

The efficacy of duloxetine in the treatment of fibromyalgia in pediatric patients 13-17 years of age was evaluated in a 13-week, placebo-controlled trial in 184 patients.1,510 Patients with a diagnosis of juvenile-onset fibromyalgia and a baseline score of ≥4 on the Brief Pain Inventory (BPI)-Modified Short Form were randomized to treatment with duloxetine (initial dosage of 30 mg once daily for 1 week then 60 mg daily) or placebo.1 Patients with rheumatologic disorders (e.g., arthritis or an autoimmune disorder) were excluded.510 The primary outcome was mean change from baseline in pain severity based on BPI ratings.510 Baseline BPI pain severity was 5.7.1 At 13 weeks, greater improvement was seen in BPI pain severity from baseline with duloxetine compared to placebo; however, the difference was not statistically different (-1.62 versus -0.97).1,510

Clinical Perspective

The Centers for Disease Control and Prevention (CDC) guidelines on the use of opioids address treatment approaches to chronic pain, including pain resulting from fibromyalgia.516 Nonpharmacologic therapies (e.g., exercise, cognitive behavioral therapy, massage) are initially recommended to manage chronic pain.516 Nonopioid analgesics can be used if nonpharmacologic approaches are not sufficient for pain relief; opioids should not be considered first-line treatments for chronic pain conditions in most situations.516 In patients with fibromyalgia, the CDC guidelines state that tricyclic and SNRI antidepressants (including duloxetine), NSAIAs, and the gabapentinoids are used to improve pain, function, and quality of life.516 Selection of an appropriate regimen should be individualized.516

Chronic Musculoskeletal Pain !!navigator!!

Duloxetine hydrochloride is used for the treatment of chronic musculoskeletal pain in adults.1

Clinical Experience

Efficacy of duloxetine for the management of chronic musculoskeletal pain has been established in several randomized, double-blind, placebo-controlled studies in adults with chronic low back pain or chronic pain from osteoarthritis.1

Three double-blind, placebo-controlled studies enrolled adult patients with chronic low back pain who were randomized to treatment with duloxetine 20, 60, or 120 mg daily or placebo.1 Two studies (CLBP-1 and CLPB-2) treated patients for 13 weeks; the third study (CLBP-3) was 12 weeks in duration.1,511,512,513

Study CLBP-1 enrolled 236 adult patients with chronic low back pain who were randomized to treatment with either duloxetine 60 mg or placebo for 13 weeks.1,511 In patients not responding to duloxetine 60 mg (<30% reduction in pain at 7 weeks), dosage was increased to 120 mg daily in a double-blind fashion.1 The primary outcome was reduction in pain intensity (PI) as measured by the BPI 24-hour average pain ratings.511 Baseline mean pain rating was 6 on a scale of 0-10.1 Patients treated with duloxetine experienced greater pain reduction than placebo; at 13 weeks, the mean change from baseline in pain rating was -2.32 or -1.50 for duloxetine or placebo, respectively.1,511

Study CLBP-2 randomized 404 adult patients with chronic low back pain to treatment with either a fixed-dose of duloxetine (20, 60, or 120 mg daily) or placebo for 13 weeks.1,512 The primary outcome was reduction in PI, defined as the weekly mean of the 24-h average pain ratings.512 At baseline, weekly mean PI pain ratings ranged from 6.1-6.4 on a scale of 0-10.512 At 13 weeks, no difference in pain reduction was seen between duloxetine and placebo.1

Study CLBP-3 enrolled 401 adult patients with chronic low back pain who were randomized to receive either duloxetine 60 mg or placebo daily for 12 weeks.1,513 The primary outcome was reduction in pain intensity as measured by the BPI 24-hour average pain ratings at week 12.513 Baseline pain intensity was 6 on a scale of 0-10 for both groups.1,513 At 12 weeks, 48.7 or 34.7% of patients treated with duloxetine or placebo had a 50% reduction in BPI average pain score from baseline.513 Duloxetine was also associated with a greater reduction in average pain ratings compared to placebo (-2.25 versus -1.65).1,513

Two double-blind, 13-week clinical trials (OA-1 and OA-2) evaluated the efficacy of duloxetine in adults for treatment of chronic pain due to osteoarthritis of the knee.1,514,515 Patients were randomly assigned to treatment with either duloxetine (60 or 120 mg once daily) or placebo.1,514,515 In Study OA-1, duloxetine was initiated at 30 mg daily for 1 week, then increased to 60 mg daily; for patients with <30% pain reduction at week 7, dosage of duloxetine was increased to 120 mg daily for the remainder of the study.1,514 In Study OA-2, duloxetine was started at 30 mg daily for 1 week, then increased to 60 mg daily for 7 weeks; patients were then re-randomized to either duloxetine 60 or 120 mg daily.1,515 Study OA-1 enrolled 256 patients, and Study OA-2 enrolled 231 patients.1,514,515 The primary outcome assessed was reduction from baseline in weekly 24-hour average pain severity.514,515 At baseline, patients in both studies had a mean pain rating of 6 on a scale of 0-10.1,514,515

In Study OA-1, duloxetine resulted in a greater reduction in pain rating compared with placebo (-2.32 versus -1.73, respectively).1,514 A 50% reduction in pain was reported by 37.9 or 22.2% of patients treated with duloxetine (60 or 120 mg) or placebo, respectively.514 In study OA-2, duloxetine did not provide greater pain relief than placebo.1

Clinical Perspective

The Centers for Disease Control and Prevention (CDC) guidelines on the use of opioids address treatment approaches to chronic pain, including pain resulting from osteoarthritis or low back pain.516 Nonpharmacologic therapies (e.g., exercise, weight loss) are initially recommended to manage chronic pain.516 Nonopioid analgesics can be used if nonpharmacologic approaches are not sufficient for pain relief; opioids should not be considered as first-line treatment for chronic pain conditions in most situations.516 In patients with osteoarthritis or chronic low back pain who have an insufficient response to nonpharmacologic interventions, CDC guidelines state that topical NSAIAs, systemic NSAIAs, or duloxetine may be considered.516 Selection of an appropriate regimen should be individualized.516

Stress Urinary Incontinence !!navigator!!

Duloxetine has been used for the management of moderate to severe stress urinary incontinence (SUI)† in women.20,21,22,23,24,25,26,33,35,36,37,38,39,40,41,42,43 In a number of placebo-controlled clinical trials involving women with predominantly SUI receiving duloxetine or placebo for up to 12 weeks, duloxetine was significantly better than placebo in reducing the frequency of incontinence episodes (which were reduced by approximately 50% in patients receiving duloxetine) and improving patients' quality of life (as assessed by Incontinence Quality of Life questionnaire scores).20,21,22,23,24,25,26,35,36,39,41,43 Therapy with the drug generally was well tolerated in these studies, with nausea being the most commonly reported adverse effect.22,23,24,26,35,36,37,38,39,41,43

Data from one subsequent analysis suggest that the beneficial effects of duloxetine in women with SUI are maintained for up to 30 months.33 In addition, some data suggest that combining duloxetine and pelvic floor muscle training exercises may be more effective than either treatment alone.36,39 The potential role of duloxetine therapy relative to other forms of treatment (including pelvic floor muscle training, management of fluid intake and voiding, weight loss, devices, and surgery) remains to be established and requires additional study.20,21,35,36

Chemotherapy-induced Peripheral Neuropathy !!navigator!!

Duloxetine has been used for the management of chemotherapy-induced peripheral neuropathy†.518 Guidelines from the American Society of Clinical Oncology (ASCO) recommend that clinicians assess and discuss with patients the appropriateness of dosage reduction, dosage delay, or use of an alternate chemotherapy in patients who develop intolerable neuropathy during administration of neurotoxic chemotherapy.518 Duloxetine may be offered to patients with painful chemotherapy-induced peripheral neuropathy who have completed neurotoxic chemotherapy.518 This recommendation is based on the results of clinical trials evaluating duloxetine versus venlafaxine, pregabalin, or vitamin B12.518

Dosage and Administration ⬆ ⬇

[Section Outline]

General !!navigator!!

Pretreatment Screening

Patient Monitoring

Other General Considerations

Administration !!navigator!!

Duloxetine hydrochloride is administered orally without regard to meals.1 The delayed-release capsules should be swallowed whole and not chewed or crushed; the contents should not be sprinkled on food or mixed with liquids.1

If a dose is missed, take the missed dose as soon as it is remembered.1 If it is almost time for the next scheduled dose, skip the missed dose and resume regular dosing.1 Do not take 2 doses of duloxetine at the same time.1

Store duloxetine capsules at 25°C; excursions are permitted to 15—30°C.1

Dosage !!navigator!!

Dosage of duloxetine hydrochloride is expressed in terms of duloxetine.1

Because withdrawal effects may occur, abrupt discontinuance of duloxetine should be avoided.1 When duloxetine therapy is discontinued, dosage should be tapered gradually and the patient carefully monitored to reduce the risk of withdrawal symptoms.1 If intolerable symptoms occur following dosage reduction or upon discontinuance of treatment, duloxetine therapy may be reinstituted at the previously prescribed dosage until such symptoms abate.1 Clinicians may resume dosage reductions at that time but at a more gradual rate.1

Pediatric Dosage

Generalized Anxiety Disorder

For the management of generalized anxiety disorder in pediatric patients ≥7 years of age, the recommended initial dosage of duloxetine is 30 mg once daily.1 After 2 weeks, the dosage may be increased to 60 mg once daily.1 The manufacturer states the recommended dosage range is 30-60 mg once daily; however, some patients may benefit from dosages higher than 60 mg once daily.1 If the decision is made to increase the dosage beyond 60 mg once daily, increase dosage in increments of 30 mg once daily (up to a maximum dosage of 120 mg daily).

Fibromyalgia

For the management of fibromyalgia in pediatric patients ≥13 years of age, the recommended initial dosage of duloxetine is 30 mg once daily.1 Based on response and tolerability, the manufacturer states that dosage may be increased up to 60 mg once daily.1

Adult Dosage

Major Depressive Disorder

For the management of major depressive disorder, the recommended initial dosage of duloxetine in adults is 40 mg daily (given as 20 mg twice daily) to 60 mg daily (given either as 60 mg once daily or 30 mg twice daily).1 In some patients, it may be desirable to initiate therapy with a dosage of 30 mg once daily for 1 week to allow patients to adjust to duloxetine before increasing to 60 mg once daily.1

The manufacturer recommends a maintenance duloxetine dosage of 60 mg once daily in adults.1,34 Although duloxetine dosages of 120 mg daily have been effective, there is no evidence that dosages exceeding 60 mg daily provide additional therapeutic benefit.1 The usefulness of duloxetine therapy and the appropriate dosage should be reevaluated periodically in patients receiving long-term therapy.1

Generalized Anxiety Disorder

For the management of generalized anxiety disorder in adults <65 years of age, the recommended initial dosage of duloxetine is 60 mg once daily.1 In some patients, it may be desirable to initiate therapy with a dosage of 30 mg once daily for 1 week to allow patients to adjust to duloxetine before increasing to 60 mg once daily.1 Dosage may be increased in increments of 30 mg once daily (up to a maximum dosage of 120 mg once daily).1 However, no additional benefit has been demonstrated from duloxetine dosages exceeding 60 mg once daily.1 The usefulness of duloxetine therapy and the appropriate dosage should be reevaluated periodically in patients receiving prolonged therapy.1

For the management of generalized anxiety disorder in adults ≥65 years of age, the recommended initial dosage of duloxetine is 30 mg once daily.1 Dosage may be increased after 2 weeks to a target dosage of 60 mg once daily.1 If the decision is made to increase above 60 mg once daily, increase dosage in increments of 30 mg once daily (up to a maximum dosage of 120 mg once daily).1

Neuropathic Pain

For the management of neuropathic pain associated with diabetic peripheral neuropathy, the recommended adult dosage of duloxetine is 60 mg once daily.1 Duloxetine dosages exceeding 60 mg daily do not appear to provide substantially greater therapeutic benefit and are less well tolerated.1 For patients in whom tolerability is a concern, a lower initial dosage may be considered.1 Because renal disease is often present in patients with diabetes, consider initiating duloxetine at a reduced starting dosage and then gradually increasing the dosage.1

Fibromyalgia

For the management of fibromyalgia, the recommended adult dosage of duloxetine is 60 mg once daily.1 The manufacturer states that treatment should be initiated at 30 mg once daily for 1 week to allow patients to adjust to the drug before increasing the dosage to 60 mg once daily.1 Some patients may respond to the initial dosage of 30 mg once daily.1 Duloxetine dosages exceeding 60 mg daily do not appear to provide greater therapeutic benefit, even in patients not responding to a dosage of 60 mg daily, and are associated with a higher incidence of adverse effects.1

Chronic Musculoskeletal Pain

For the management of chronic musculoskeletal pain, the recommended adult dosage of duloxetine is 60 mg once daily.1 The manufacturer states that treatment should be initiated at 30 mg once daily for 1 week to allow patients to adjust to the drug before increasing the dosage to 60 mg once daily.1 Duloxetine dosages exceeding 60 mg daily do not appear to provide greater therapeutic benefit, even in patients not responding to a dosage of 60 mg daily, and are associated with a higher incidence of adverse effects.1

Stress Urinary Incontinence

Although the optimum dosage and duration of duloxetine therapy for the treatment of stress urinary incontinence† in women remain to be established, the most commonly used dosage in controlled trials has been 80 mg daily, usually given as 40 mg twice daily (dosage range: 20-120 mg daily).20,21,22,23,24,25,26,36,38,41,43 Some patients may benefit (i.e., reduced risk of nausea and dizziness) from initiating therapy with a duloxetine dosage of 20 mg twice daily for 2 weeks before increasing to the usual dosage of 40 mg twice daily.38,39 If adverse effects are bothersome during the first few weeks of therapy at the usual dosage, the dosage may be reduced to 20 mg twice daily.36 The safety of higher dosages (i.e., 120 mg daily), which have been used in a limited number of women with more severe cases of stress urinary incontinence, requires additional study.20,21,25,36

Special Populations !!navigator!!

Hepatic Impairment

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1 Use of duloxetine should be avoided in patients with chronic liver disease or cirrhosis.1

Renal Impairment

The manufacturer makes no specific dosage recommendations for patients with mild or moderate renal impairment.1 Use of duloxetine should be avoided in patients with severe renal impairment (creatinine clearance <30 mL/minute).1

Geriatric Patients

The manufacturer recommends initiating duloxetine therapy at a dosage of 30 mg once daily for 2 weeks before considering a dosage increase when treating generalized anxiety disorder in geriatric patients ≥65 years of age.1

Consider dosage reduction or discontinuation if symptomatic orthostatic hypotension, falls, or syncope occur.1 Geriatric patients typically have a greater fall risk due to the use of multiple medications and increased presence of comorbid conditions and gait disturbances.1

Cautions ⬆ ⬇

[Section Outline]

Contraindications !!navigator!!

Warnings/Precautions !!navigator!!

Warnings

Suicidal Thoughts and Behaviors

A boxed warning is included in the prescribing information for duloxetine about the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants.1 Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants.1 This risk may persist until clinically important remission occurs.1 Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.1 However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.1 Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors [SSRIs] and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.1 An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age and a reduced risk was observed in adults 65 years of age or older.1

All patients being treated with antidepressants for any indication should be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1 Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.1

Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.1 Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms.1 It is also recommended that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.1

Because bipolar disorder may initially present as a major depressive episode, screen patients with depressive symptoms to determine the risk of bipolar disorder prior to initiating duloxetine.1 Screening should include taking a detailed psychiatric history (including family history of suicide, bipolar disorder, and depression).1 Although not established in controlled clinical studies, treatment of bipolar disorder with an antidepressant alone may precipitate the development of a mixed/manic episode in patients at risk for bipolar disorder.1 Duloxetine is not indicated for use in the treatment of bipolar disorder.1

Other Warnings and Precautions

Hepatotoxicity

Hepatic failure, sometimes fatal, has been reported in duloxetine-treated patients.1 The cases presented as hepatitis accompanied by abdominal pain, hepatomegaly, and markedly elevated serum transaminase concentrations (more than 20 times the upper limit of normal [ULN]) with or without jaundice, reflecting a mixed or hepatocellular pattern of hepatic injury.1 Duloxetine should be discontinued in any patient who develops jaundice or other evidence of clinically important hepatic dysfunction; therapy should not be resumed unless another cause for the hepatic dysfunction can be established.1

Cases of cholestatic jaundice with minimal elevation of serum transaminase concentrations also have been reported.1 Postmarketing reports indicate that elevated serum transaminase, bilirubin, and alkaline phosphatase concentrations have occurred in duloxetine-treated patients with chronic hepatic disease or cirrhosis.1

Duloxetine has been shown to increase the risk of serum transaminase elevations in clinical trials; such elevations resulted in discontinuance of the drug in 0.3% of patients.1 The median time to detection of the transaminase elevation was about 2 months.1 In placebo-controlled trials, elevations in serum ALT concentrations to more than 3 times the ULN occurred in 1.25% of duloxetine-treated patients compared with 0.45% of those receiving placebo.1 There was evidence of a dose-response relationship for ALT and AST elevations.1

Because of the possibility that duloxetine and alcohol may interact to cause hepatic injury or that duloxetine may aggravate preexisting hepatic disease, duloxetine should not be prescribed to patients with substantial alcohol consumption or evidence of chronic hepatic disease.1

Orthostatic Hypotension, Falls, and Syncope

Orthostatic hypotension and syncope have been reported with therapeutic dosages of duloxetine; although these effects tend to occur within the first week of therapy, they may occur at any time, particularly following increases in dosage.1 Falls resulting in serious injury also have been reported in patients receiving duloxetine.1 The degree of orthostatic decrease in blood pressure appears related to the risk of falling, as well as other factors that may increase the underlying fall risk.1 A higher rate of falls was reported in clinical trials with duloxetine compared to placebo.1 The risk of decreased blood pressure may be greater in patients receiving concomitant treatment with other drugs that produce orthostatic hypotension (such as antihypertensive agents); in patients receiving potent inhibitors of the cytochrome P-450 (CYP) 1A2 isoenzyme; or in those receiving duloxetine dosages exceeding 60 mg daily.1 Dosage reduction or discontinuance of duloxetine should be considered in patients experiencing symptomatic orthostatic hypotension and/or syncope during therapy.1

Fall risk appears to be proportional to a patient's underlying fall risk, and appears to increase with increasing age.1 Geriatric patients typically have a greater underlying fall risk due to the increased prevalence of multiple medications and the increased presence of comorbid conditions and gait disturbances.1

Serotonin Syndrome

Potentially life-threatening serotonin syndrome has been reported with selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs alone), including duloxetine, but particularly with concurrent administration of other serotonergic drugs (e.g., serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists [“triptans”]), tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John's Wort [ Hypericum perforatum ]) and drugs that impair serotonin metabolism (e.g., MAO inhibitors).1 Signs and symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1

Concurrent therapy with MAO inhibitors used for treatment of depression is contraindicated.1 Duloxetine should not be initiated in patients receiving MAO inhibitors such as linezolid or IV methylene blue.1 If an MAO inhibitor such as linezolid or IV methylene blue is necessary in a patient receiving duloxetine, discontinue duloxetine before initiating the MAO inhibitor.1

Monitor all patients receiving duloxetine for serotonin syndrome.1 If serotonin syndrome occurs, immediately discontinue treatment with duloxetine and any concurrently administered serotonergic agents and initiate supportive symptomatic treatment.1

Bleeding

Drugs that inhibit serotonin reuptake, including duloxetine, may increase the risk of bleeding events.1 Concurrent administration of aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), warfarin, and other anticoagulants may add to this risk.1 Case reports and epidemiologic studies have demonstrated an association between the use of drugs that interfere with serotonin reuptake and the occurrence of GI bleeding.1 A postmarketing study found an increased incidence of postpartum hemorrhage in mothers receiving duloxetine.1 Bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.1 Advise patients of the risk of bleeding associated with concomitant use of duloxetine and aspirin or other NSAIAs, warfarin, or other drugs that affect coagulation.1

Severe Skin Reactions

Severe skin reactions such as erythema multiforme and Stevens-Johnson Syndrome (SJS) can occur with duloxetine.1 The rate of reported cases of SJS associated with duloxetine is greater than the incidence reported in the general population (1 to 2 cases per million person-years).1 Discontinue duloxetine at the first appearance of blisters, peeling rash, mucosal erosions, or other signs of hypersensitivity if not attributed to another condition.1

Discontinuation Syndrome

Because withdrawal effects (e.g., dysphoric mood, irritability, agitation, nausea/vomiting, dizziness, sensory disturbances, anxiety, confusion, headache, lethargy, emotional lability, insomnia, nightmares, hypomania, tinnitus, seizures) may occur, abrupt discontinuance of duloxetine should be avoided.1 Gradually reduce dosage when discontinuing therapy.1

If intolerable symptoms occur following dosage reduction or discontinuance, reinstitute previously prescribed dosage until symptoms abate, then resume more gradual dosage reductions.1

Activation of Mania/Hypomania

Activation of mania and hypomania has occurred in patients with major depressive disorder receiving duloxetine.1 Use the drug with caution in patients with a history of mania.1

Angle-closure Glaucoma

Antidepressant drugs such as duloxetine may cause pupillary dilation, which can trigger an angle closure attack in patients without a patent iridectomy with anatomically narrow angles.1

Seizures

Use of duloxetine has not been systematically evaluated in patients with seizures, but seizures have been reported in patients receiving the drug; therefore, duloxetine should be used with caution in patients with a history of seizures.1

Elevated Blood Pressure

Duloxetine may increase blood pressure.1 Monitor blood pressure prior to and periodically during duloxetine therapy.1

Clinically Important Drug Interactions

Because cytochrome P-450 (CYP)1A2 and CYP2D6 are responsible for duloxetine metabolism, the potential exists for clinically important drug interactions when duloxetine is used concomitantly with CYP1A2 inhibitors, CYP2D6 inhibitors, and CYP2D6 substrates.1

Concurrent therapy with MAO inhibitors used for the treatment of depression is contraindicated.1

Because of the possibility that duloxetine and alcohol may interact to cause hepatic injury, duloxetine should not be prescribed to patients with a history of substantial alcohol use.1

Caution is advised when duloxetine is given with or substituted for other centrally acting drugs, including those with a similar mechanism of action.1

Hyponatremia

Treatment with SSRIs and SNRIs, including duloxetine, may result in hyponatremia.1,64 In many cases, hyponatremia appears to be due to the syndrome of inappropriate antidiuretic hormone (SIADH).1,64 Cases with serum sodium concentrations lower than 110 mmol/L have been reported and hyponatremia appeared reversible when duloxetine was discontinued.1,64 Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia.1,64 Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls; more severe and/or acute cases have been associated with hallucinations, syncope, seizures, coma, respiratory arrest, and death.1,64 Initiate appropriate medical intervention and consider drug discontinuance in patients with symptomatic hyponatremia.1,64

Use in Patients with Concomitant Illnesses

Experience with duloxetine in patients with concomitant diseases is limited.1

Because alterations in gastric motility may affect the stability of the enteric coating of the pellets contained in duloxetine capsules, the drug should be used with caution in patients with conditions that may slow gastric emptying (e.g., in some patients with diabetes mellitus).1

Duloxetine has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease; such patients were generally excluded from clinical studies.1

Duloxetine worsens glycemic control in some patients with diabetes.1 In the 12-week acute treatment phase of 3 clinical studies in patients with diabetic peripheral neuropathy, small increases in fasting blood glucose were observed in duloxetine-treated patients compared with those receiving placebo.1 In the extension phase of these studies, which lasted up to 52 weeks, fasting blood glucose increased by 12 mg/dL in duloxetine-treated patients and decreased by 11.5 mg/dL in the routine care group; increases in glycosylated hemoglobin (hemoglobin A1c) were observed in both groups of patients although the average increase was 0.3% greater in the duloxetine-treated patients compared with those receiving routine care.1

Urinary Hesitation and Retention

Duloxetine belongs to a class of drugs known to affect urethral resistance.1 If symptoms of urinary hesitation develop during therapy, consider possibility that they may be drug-related.1

Cases of urinary retention have been reported during postmarketing experience; in some of these cases, hospitalization and/or catheterization has been necessary.1,38

Sexual Dysfunction

Sexual dysfunction, resulting in ejaculatory delay or failure, decreased libido, or erectile dysfunction in males, and decreased libido or absent orgasm in females, can occur with the use of SNRIs, including duloxetine.1

Providers should inquire about sexual function prior to initiation and during treatment with duloxetine, since sexual function may not be spontaneously reported.1 Obtaining a detailed history, including time to symptom onset, is important when evaluating changes in sexual function, since sexual symptoms can have other causes, including the underlying psychiatric disorder.1 Potential management strategies should be discussed to support patients in making informed treatment decisions.1

Specific Populations

Pregnancy

A National Pregnancy Registry for Antidepressants is available that monitors pregnancy outcomes in women exposed to antidepressants, including duloxetine, during pregnancy.1 Clinicians are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-866-961-2388.1

Available evidence has not identified a clear drug-associated risk of major birth defects or adverse developmental outcomes with duloxetine.1 There are risks associated with untreated depression and fibromyalgia and also the exposure to SNRIs or SSRIs during pregnancy.1 A prospective, longitudinal study of 201 euthymic women receiving antidepressants with a history of major depressive disorder showed that the discontinuation of antidepressants during pregnancy or the postpartum period was associated with a greater likelihood of a relapse of major depression.1 The risks of untreated depression when discontinuing or adjusting treatment during pregnancy or during the postpartum period should be considered.1 Fibromyalgia during pregnancy is also associated with an increased risk of adverse maternal and infant outcomes (preterm premature rupture of membranes, preterm birth, small for gestational age, intrauterine growth restriction, placental disruption, venous thrombosis), although it is not known if these outcomes are directly associated with fibromyalgia or other comorbid factors.1

Data from a post-marketing cohort study suggests that duloxetine use in the month before delivery is associated with an increased risk of postpartum hemorrhage.1

Some neonates exposed to SNRIs or SSRIs late in the third trimester of pregnancy have developed complications that have sometimes been severe and required prolonged hospitalization, respiratory support, and tube feeding.1 Such complications can arise immediately upon delivery.1 Clinical findings reported to date in these neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.1 These clinical features appear to be consistent with either a direct toxic effect of the SNRI or SSRI or, possibly, a drug withdrawal syndrome.1 It should be noted that, in some cases, the clinical picture was consistent with serotonin syndrome.1

Lactation

Duloxetine is distributed into human milk.1 Because exposure to duloxetine through breast milk has resulted in cases of sedation, poor feeding, and poor weight gain in breast-fed infants, breast-fed infants exposed to duloxetine should be monitored for these symptoms.1

Following the administration of duloxetine 40 mg once daily in 6 lactating women for 3.5 days, the resulting amount of duloxetine in the breast milk was approximately 7 mcg/day, which is an estimated daily infant dose of approximately 2 mcg/kg/day, less than 1% of the maternal dose.1 Peak concentrations of duloxetine in the breast milk occurred a median of 3 hours after the dose was administered.1 The presence of duloxetine metabolites in the breast milk has not been evaluated.1

It is not known if duloxetine affects milk production.1 Consider the developmental and health benefits of breast-feeding, the mother's clinical need for the drug, and the potential for adverse effects on the nursing infant from exposure to duloxetine or to the untreated underlying maternal condition.1

Pediatric Use

Safety and efficacy of duloxetine have been established in children 7-17 years of age for the treatment of generalized anxiety disorder, and in adolescents 13-17 years of age for the treatment of juvenile fibromyalgia syndrome.1 Safety and efficacy of duloxetine have not been established in pediatric patients with major depressive disorder, diabetic peripheral neuropathic pain, or chronic musculoskeletal pain.1

Use of duloxetine for the treatment of generalized anxiety disorder in children 7-17 years of age is supported by one 10-week, placebo-controlled clinical trial.1 Safety and efficacy of duloxetine for the treatment of generalized anxiety disorder in children <7 years of age have not been established.1

Use of duloxetine for the treatment of fibromyalgia in adolescents 13-17 years of age is supported by one 13-week, placebo-controlled clinical trial.1 Safety and efficacy of duloxetine for the treatment of fibromyalgia in pediatric patients <13 years of age have not been established.1

Safety and efficacy of duloxetine for major depressive disorder have not been established in pediatric patients.1 In two 10-week, placebo-controlled trials, duloxetine failed to establish superiority for major depressive disorder compared to placebo.1

A greater risk of suicidal thinking or behavior (suicidality) occurred during the first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and other antidepressants).1 No suicides occurred in these pediatric trials.1

Monitor all pediatric patients receiving antidepressant therapy for clinical worsening and the development of suicidal thinking or behavior, especially during the first few months of treatment and during dosage changes.1 Decreased appetite and loss of weight have been observed with use of SSRIs and SNRIs.1 Regular monitoring of weight and growth is also recommended in pediatric patients receiving duloxetine.1

Geriatric Use

Approximately 6, 21, 41, 33, and 8% of patients studied in clinical trials of duloxetine for major depressive disorder, chronic low back pain, osteoarthritis, diabetic peripheral neuropathy, and fibromyalgia, respectively, were 65 years of age or older.1 Although no overall differences in efficacy or safety were observed between geriatric and younger adult patients in the major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, osteoarthritis, and chronic low back pain clinical trials, and other clinical experience has not revealed any evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.1

Clinically important hyponatremia has been reported in geriatric patients, who may be at greater risk for this adverse effect.1

In placebo-controlled trials, patients receiving duloxetine reported a higher rate of falls.1 Fall risk appears to be proportional to the patient's underlying fall risk, and appears to increase with increasing age.1 The impact of age itself on fall risk is unknown, as geriatric patients typically have greater underlying fall risk due to the increased prevalence of multiple medications and the increased presence of comorbid conditions and gait disturbances.1 Falls with serious consequences (fractures, hospitalization) have been reported with duloxetine.1

Hepatic Impairment

Because duloxetine can aggravate underlying liver dysfunction and interact with alcohol to cause liver injury, duloxetine should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.1

In 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B), administration of a single 20-mg duloxetine dose resulted in a mean plasma clearance approximately 15% that of age- and gender-matched controls, and mean exposure (based on AUC) was increased 5-fold.1 Although peak plasma concentrations were not changed, the elimination half-life of duloxetine was increased 3-fold.1

Renal Impairment

In patients with end-stage renal disease (requiring dialysis), AUC and peak plasma concentrations of duloxetine and its metabolites are increased.1 Use of duloxetine is not recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/minute).1

Population pharmacokinetic analyses suggest that mild to moderate (estimated creatinine clearance 30-80 mL/minute) renal impairment has no clinically important effect on duloxetine apparent clearance.1

Common Adverse Effects !!navigator!!

Adverse effects reported in 5% or more of adults receiving duloxetine include nausea, dry mouth, somnolence, constipation, decreased appetite, and increased sweating.1

Adverse effects reported in 5% or more of pediatric patients receiving duloxetine include decreased weight, decreased appetite, nausea, vomiting, fatigue, and diarrhea.1

Drug Interactions ⬆ ⬇

[Section Outline]

Duloxetine is metabolized by cytochrome P-450 (CYP) isoenzymes, principally CYP2D6 and CYP1A2.1 Duloxetine is a moderate inhibitor of CYP2D6 and also inhibits CYP1A2.1 In vitro studies indicate that duloxetine does not inhibit CYP2C9, CYP3A, or CYP2C19.1 In vitro studies indicate that duloxetine does not induce CYP1A2 or CYP3A.1

Drugs Metabolized by Hepatic Microsomal Enzymes !!navigator!!

Substrates of CYP2D6 (e.g., tricyclic antidepressants [TCAs; amitriptyline, desipramine, imipramine, nortriptyline], phenothiazines, class IC antiarrhythmics [flecainide, propafenone]): increased AUC of the substrate is possible.1 Use with caution.1 Consider monitoring plasma TCA concentrations and reducing the TCA dosage if used concomitantly with duloxetine.1

Drugs Affecting Hepatic Microsomal Enzymes !!navigator!!

Potent inhibitors of CYP1A2 (e.g., fluvoxamine, some quinolone anti-infective agents [e.g., ciprofloxacin, enoxacin]): increased plasma duloxetine concentrations are possible.1 Avoid concomitant use.1

Potent inhibitors of CYP2D6 (e.g., fluoxetine, paroxetine, quinidine) isoenzymes: increased plasma duloxetine concentrations are possible.1

Concomitant administration of duloxetine and fluvoxamine, a dual CYP1A2 and CYP2D6 inhibitor, in poor CYP2D6 metabolizers resulted in a sixfold increase in duloxetine AUC and peak plasma concentrations.1

Drugs Affecting Hemostasis !!navigator!!

Altered anticoagulant effects, including increased bleeding, have been reported when selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), including duloxetine, were concurrently administered with warfarin.1 Because of the potential effect of duloxetine on platelets, the manufacturer recommends careful monitoring of patients receiving warfarin during initiation and discontinuance of duloxetine therapy.1

Concomitant administration of duloxetine (60 or 120 mg once daily) and warfarin (2-9 mg once daily) in healthy subjects for up to 2 weeks did not result in significant changes in the international normalized ratio (INR) from baseline; the pharmacokinetics of either protein-bound and free drug concentrations of R- and S-warfarin were not affected by concomitant use of duloxetine.1

An increased risk of bleeding is possible when duloxetine is used concomitantly with aspirin or other nonsteroidal anti-inflammatory agents; use with caution.1

Drugs that Affect Gastric Acidity !!navigator!!

The bioavailability of duloxetine may be altered if administered with drugs that increase gastric pH.1 However, no clinically important effect was demonstrated when duloxetine was administered with aluminum- and magnesium-containing antacids or famotidine.1

Whether the concomitant administration of proton-pump inhibitors affects duloxetine absorption is currently unknown.1

Alcohol !!navigator!!

An increased risk of hepatotoxicity is possible when duloxetine is used with alcohol; avoid concomitant use in patients with substantial alcohol use.1

Duloxetine has not been shown to potentiate the impairment of mental and motor skills caused by alcohol.1

Antihypertensive Agents !!navigator!!

An increased risk of hypotension and syncope is possible when duloxetine is used with antihypertensive agents.1

Benzodiazepines !!navigator!!

Lorazepam does not appear to affect the pharmacokinetics of duloxetine.1

Temazepam does not appear to affect the pharmacokinetics of duloxetine.1

CNS-active Drugs !!navigator!!

A potential pharmacologic interaction is possible when duloxetine is given with or substituted for other centrally acting drugs, including those with a similar mechanism of action; use with caution.1

Monoamine Oxidase (MAO) Inhibitors !!navigator!!

Potentially fatal serotonin syndrome may occur if duloxetine is used concomitantly with MAO inhibitors; concomitant use is contraindicated.1 The manufacturer recommends that at least 2 weeks should elapse between discontinuance of an MAO inhibitor and initiation of duloxetine and that at least 5 days elapse between discontinuance of duloxetine therapy and initiation of MAO inhibitor therapy.1

Duloxetine should not be initiated in patients receiving MAO inhibitors such as linezolid or IV methylene blue.1 For those patients who require more urgent psychiatric treatment, consider other interventions such as hospitalization.1

In patients already receiving duloxetine, some situations may require urgent treatment with linezolid or IV methylene blue.1 Duloxetine should be immediately discontinued in patients who are deemed to have no acceptable alternatives to linezolid or IV methylene blue and in whom the benefits of linezolid or IV methylene blue therapy are judged to outweigh the potential risks of serotonin syndrome.1 In these patients, monitor for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or IV methylene blue, whichever occurs earlier.1 Resumption of duloxetine may occur 24 hours after the last dose of linezolid or IV methylene blue.1

The risk of serotonin syndrome with administration of methylene blue via non-IV routes (e.g., oral tablets, local injection) or at IV doses <1 mg/kg in patients receiving duloxetine is unclear; however, the provider should be aware of the potential for emergent symptoms of serotonin syndrome when such agents are used concomitantly.1

Serotonergic Drugs !!navigator!!

Potentially life-threatening serotonin syndrome may occur if duloxetine is used concomitantly with drugs affecting serotonergic neurotransmission, including other SNRIs, SSRIs, triptans, TCAs, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's wort (Hypericum perforatum) ; use with caution.1

Monitor all patients receiving duloxetine for serotonin syndrome, particularly during treatment initiation and with increases in dosage.1 If serotonin syndrome occurs, consider discontinuation of duloxetine and any concurrently administered serotonergic agents.1

Smoking !!navigator!!

Smoking reduces duloxetine bioavailability by about one-third.1 The manufacturer states that routine dosage adjustment is not necessary.1

Theophylline !!navigator!!

Small increases (averaging from 7-20%) in theophylline AUCs have been reported during concurrent administration of theophylline and duloxetine.1

Thioridazine !!navigator!!

Increased plasma thioridazine concentrations have been observed in patients receiving duloxetine, resulting in increased risk of serious ventricular arrhythmias and sudden death; concomitant use is not recommended.1

Other Information ⬆ ⬇

Description

Duloxetine hydrochloride, a selective serotonin- and norepinephrine-reuptake inhibitor (SNRI), is an antidepressant and anxiolytic agent.1,2,29,30,31 The drug also has demonstrated analgesic activity in animal models of chronic and persistent pain and in clinical trials evaluating the drug's activity in conditions associated with chronic pain (e.g., neuropathic pain, fibromyalgia).1,37,46,47,48,49

The exact mechanisms of the antidepressant, anxiolytic, and central pain inhibitory actions of duloxetine have not been fully elucidated, but appear to be associated with the drug's potentiation of serotonergic and noradrenergic activity in the CNS.1,49 Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake.1 Duloxetine does not inhibit monoamine oxidase (MAO) and has not demonstrated significant affinity for dopaminergic, adrenergic, cholinergic, γ-aminobutyric acid (GABA), glutamate, histaminergic, and opiate receptors in vitro.1

Duloxetine is well absorbed following oral administration, with peak plasma concentrations usually attained in 6 hours.1 With evening administration, there is a 3 hour delay in absorption and a 33% increase in clearance of the drug compared to morning administration.1 Food increases the time to peak plasma concentrations from 6 to 10 hours, and marginally decreases the extent (about 10%) of absorption.1 Duloxetine pharmacokinetics are dose-proportional over the therapeutic dosing range (30-120 mg daily).1 Steady state plasma concentrations are attained after 3 days of once daily dosing.1 Mean duloxetine concentrations at steady state are about 30% lower in pediatric patients 7-17 years of age relative to adult patients, and are considered comparable between these age groups.1 Duloxetine is extensively metabolized in the liver, principally via oxidation by the cytochrome P-450 (CYP) 2D6 and 1A2 isoenzymes.1 Major circulating metabolites do not significantly contribute to the pharmacologic activity of duloxetine.1 Duloxetine is a moderate inhibitor of CYP2D6 and a somewhat weak inhibitor of CYP1A2.1 The drug is not an inhibitor of CYP2C9, CYP2C19, or CYP3A, nor is it an inducer of CYP1A2 or CYP3A.1 Duloxetine is highly bound (>90%) to human plasma proteins, which is not affected by renal or hepatic impairment.1 The interaction potential of duloxetine with other highly protein bound drugs has not been fully elucidated.1 Duloxetine is excreted principally in the urine as metabolites (about 70%) and unchanged drug (<1%), and in feces (20%).1 The elimination half-life of duloxetine is approximately 12 hours (range: 8-17 hours).1 The bioavailability of duloxetine is decreased by approximately 33% in smokers.1 Pharmacokinetics of duloxetine are not affected by sex; half-life is similar in men and women.1 The impact of race on duloxetine pharmacokinetics has not been evaluated.1

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

DULoxetine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, delayed-release (containing enteric-coated pellets)

20 mg (of duloxetine)*

Cymbalta®

Lilly

Duloxetine Delayed-release Capsules

30 mg (of duloxetine)*

Cymbalta®

Lilly

Duloxetine Delayed-release Capsules

60 mg (of duloxetine)*

Cymbalta®

Lilly

Duloxetine Delayed-release Capsules

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions October 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

1. Lilly USA. Cymbalta® (duloxetine hydrochloride) delayed-release capsules prescribing information. Indianapolis, IN; 2023 Aug.

2. Wong DT, Bymaster FP. Dual serotonin and noradrenaline uptake inhibitor class of antidepressants potential for greater efficacy or just hype? Prog Drug Res . 2002; 58:169-222. Abstract.

20. Mariappan P, Ballantyne Z, N'Dow JMO et al. Serotonin and noradrenaline reuptake inhibitors (SNRI) for stress urinary incontinence in adults. Cochrane Database of Systematic Reviews . 2005; Issue 3:Article no. CD004742.

21. Mariappan P, Alhasso A, Ballantyne Z et al. Duloxetine, a serotonin and noradrenaline reuptake inhibitor (SNRI) for the treatment of stress urinary incontinence: a systematic review. Eur Urol . 2007; 51:67-74. [PubMed 17014950]

22. van Kerrebroeck P, Abrams P, Lange R et al. Duloxetine versus placebo in the treatment of European and Canadian women with stress urinary incontinence. BJOG . 2004; 111:249-57. [PubMed 14961887]

23. Dmochowski RR, Miklos JR, Norton PA et al. for the Duloxetine Urinary Incontinence Study Group. Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence. J Urol . 2003; 170 (4 Pt 1):1259-63.

24. Norton PA, Zinner NR, Yalcin I et al. for the Duloxetine Urinary Incontinence Study Group. Duloxetine versus placebo in the treatment of stress urinary incontinence. Am J Obstet Gynecol . 2002; 187:40-8. [PubMed 12114886]

25. Cardozo L, Drutz HP, Baygani SK et al. Pharmacologic treatment of women awaiting surgery for stress urinary incontinence. Obstet Gynecol . 2004; 104:511-9. [PubMed 15339761]

26. Millard RJ, Moore K, Rencken R et al. for the Duloxetine UI Study Group. Duloxetine vs placebo in the treatment of stress urinary incontinence: a four-continent randomized clinical trial. BJU Int . 2004; 93:311-8. [PubMed 14764128]

29. Rynn M, Russell J, Erickson J et al. Efficacy and safety of duloxetine in the treatment of generalized anxiety disorder: a flexible-dose, progressive titration, placebo-controlled trial. Depress Anxiety. 2007; 0:1-8 (epub ahead of print).

30. Hartford J, Kornstein S, Liebowitz M et al. Duloxetine as an SNRI treatment for generalized anxiety disorder: results from a placebo and active-controlled study. Int Clin Psychopharmacol . 2007; 22:167-74. [PubMed 17414743]

31. Endicott J, Russell JM, Raskin J et al. Duloxetine treatment for role functioning improvement in generalized anxiety disorder: three independent studies. J Clin Psychiatry . 2007; 68:518-24. [PubMed 17474806]

32. Bridge JA, Iyengar S, Salary CB. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA . 2007; 297:1683-96. [PubMed 17440145]

33. Bump RC, Voss S, Beardsworth A et al. Long-term efficacy of duloxetine in women with stress urinary incontinence. BJU Int . 2008; 102:214-8. [PubMed 18422764]

34. Perahia DG, Gilaberte I, Wang F et al. Duloxetine in the prevention of relapse of major depressive disorder: double-blind placebo-controlled study. Br J Psychiatry . 2006; 188:346-53. [PubMed 16582061]

35. Rogers RG. Urinary stress incontinence in women. N Engl J Med . 2008; 358:1029-36. [PubMed 18322284]

36. McCormack PL, Keating GM. Duloxetine in stress urinary incontinence. Drugs . 2004; 64:2567-73. [PubMed 15516154]

37. Thor KB, Kirby M, Viktrup L. Serotonin and noradrenaline involvement in urinary incontinence, depression and pain: scientific basis for overlapping clinical efficacy from a single drug, duloxetine. Int J Clin Pract . 2007; 61:1349-55. [PubMed 17608681]

38. Oelke M, Roovers JPWR, Michel MC. Safety and tolerability of duloxetine in women with stress urinary incontinence. BJOG . 2006; 113(Suppl 1):22-6. [PubMed 16529566]

39. Cardozo L. Duloxetine in the context of current needs and issues in treatment of women with stress urinary incontinence. BJOG . 2006; 113(Suppl 1):1-4. [PubMed 16529562]

40. Miller KL. Stress urinary incontinence in women: review and update on neurological control. J Women's Health . 2005; 14:595-608.

41. Guay DRP. Duloxetine for management of stress urinary incontinence. Am J Geriatr Pharmacother . 2005; 3:25-38. [PubMed 16089245]

42. Latthe PM, Foon R, Khan K. Nonsurgical treatment of stress urinary incontinence (SUI): grading of evidence in systematic reviews. BJOG . 2008; 115:435-44. [PubMed 18271880]

43. Castro-Diaz D, Amoros MAP. Pharmacotherapy for stress urinary incontinence. Curr Opin Urol . 2005; 15:227-30.

44. Detke M, Gilaberte I, Perahia DG et al. Duloxetine vs. placebo in the prevention of relapse of major depressive disorder. Poster presented at American College of Neuropsychopharmacology Annual Meeting. Puerto Rico: 2003 Dec 7-11.

45. Fava M, Detke MJ, Balestrieri M et al. Management of depression relapse: re-initiation of duloxetine treatment or dose increase. J Psychiatr Res . 2006; 40:328-36. [PubMed 16678205]

46. Russell IJ, Mease PJ, Smith TR et al. Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial. Pain . 2008; 136:432-44. [PubMed 18395345]

47. Arnold LM, Rosen A, Pritchett YL et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain . 2005; 119:5-15. [PubMed 16298061]

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