1.  LY 248686

• A. ORAL
  
  • 1. DEPRESSION
    
    • a. The recommended total daily dose of duloxetine is 40 milligrams/day (mg/day)(given as 20 mg twice daily) to 60 mg/day (given either once a day or as 30 mg twice a day) without regard to meals. There is no evidence that doses greater than 60 mg/day confer any added benefits (Prod Info Cymbalta(R), 2004).
    • b. At least 14 days should elapse between discontinuation of a monoamine oxidase inhibitor and initiation of therapy with duloxetine. At least 5 days should elapse after stopping duloxetine before starting treatment with a monoamine oxidase inhibitor (Prod Info Cymbalta(R), 2004).
    • c. Abrupt discontinuation of duloxetine has lead to symptoms such as dizziness, nausea, headache, paresthesia, vomiting, irritability, and nightmare. Gradual reduction of the dose, rather than abrupt discontinuation, is recommended. If intolerable symptoms occur following a decrease in dose, resuming the previously prescribed dose may be considered, followed by smaller decreases (Prod Info Cymbalta(R), 2004).
  • 1. DIABETIC NEUROPATHIC PAIN
    
    • a. The recommended dose of duloxetine for the treatment of neuropathic pain associated with diabetic peripheral neuropathy is 60 milligrams (mg) once daily without regard to meals. There is no evidence that doses higher than 60 mg/day provide additional significant benefit. A lower starting dose may be considered for patients in whom tolerability is a concern (Prod Info Cymbalta(R), 2004).

• A. In renally impaired patients, duloxetine should be initiated at a lower dose and then increased gradually. Duloxetine is not recommended for patients with end- stage renal disease (requiring dialysis) or severe renal impairment (creatinine clearance less than 30 milliliters/minute) (Prod Info Cymbalta(R), 2004).

• A. Duloxetine is not recommended for use in patients with any hepatic insufficiency (Prod Info Cymbalta(R), 2004).

• A. INITIAL RESPONSE :
  
  • 1. DEPRESSION, ORAL : within 3 weeks (Berk et al, 1997).
    • a. Time to significant improvement of Hamilton Depression Rating Scale (HAMD) scores with 20 mg daily (open study).
• B. PEAK RESPONSE :
  
  • 1. PLATELET SEROTONIN UPTAKE INHIBITION, ORAL : 4 to 6 hours (Kasahara et al, 1996; Ishigooka et al, 1994).
    • a. Represents time to maximal or near-maximal inhibition in platelets from healthy subjects treated with 20 mg daily. This pharmacodynamic parameter may correlate with CNS activity (Ishigooka et al, 1997; Kasahara et al, 1996), although its usefulness for clinical monitoring has not been determined.

• A. MULTIPLE DOSE :
  
  • 1. PLATELET SEROTONIN UPTAKE INHIBITION, ORAL : at least 7 days (Kasahara et al, 1996; Ishigooka et al, 1994).
    • a. Represents duration of inhibition after the last dose of a regimen of 20 mg daily for one week. Effects persisted after plasma levels of duloxetine were no longer detectable.

• A. THERAPEUTIC DRUG CONCENTRATION :
  
  • 1. DEPRESSION, not established.
    • a. Studies attempting to define plasma levels that are associated with clinical improvement of depression have not been published.
    • b. Significant inhibition of serotonin uptake in platelets from healthy subjects receiving 20 mg daily has occurred with trough plasma concentrations exceeding 5 ng/mL (Ishigooka et al, 1997). This pharmacodynamic parameter may correlate with CNS activity (Ishigooka et al, 1997; Kasahara et al, 1996), although its usefulness for clinical monitoring has not been established.
• B. TIME TO PEAK CONCENTRATION :
  
  • 1. ORAL, TABLET : 6 to 10 hours (Artigas, 1995; Johnson et al, 1995).
    • a. Values represent times to peak levels over the range of 10 to 40 mg once daily, with a tendency toward prolonged times with higher doses. Duloxetine exhibits linear pharmacokinetics (Sharma et al, 2000).
    • b. Following single oral doses of 20 mg, a mean peak duloxetine plasma level of 13 ng/mL was reported; plasma levels of the desmethyl metabolite (active) were less than 2 ng/mL (Johnson et al, 1995).
    • c. Steady-State
      
      • (1) Steady-state has been reached in 3 to 5 days with 20 to 40 mg twice-daily, and after 7 days with 20 mg once daily in healthy subjects; with the latter regimen, the mean peak plasma level at steady-state was 21 ng/mL (15 to 32 ng/mL) (Artigas, 1995).
      • (2) During oral administration of 20 and 30 mg twice daily in healthy subjects, mean steady-state trough plasma levels were approximately 15 ng/mL and 20 ng/mL, respectively, in one study (Sharma et al, 2000).
• C. AREA UNDER THE CURVE (AUC)
  
  • 1. After a single 60-milligram dose of duloxetine, patients with end stage renal disease receiving chronic intermittent hemodialysis had Cmax and AUC values approximately 100% greater than those of patients with normal renal function. The AUCs of the major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5- hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7- to 9-fold higher and would be expected to increase further with multiple dosing (Prod Info Cymbalta(R), 2004).
  • 2. After a single 20-milligram dose of duloxetine, 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B) showed a 5-fold increase in AUC compared to non-cirrhotic patients (Prod Info Cymbalta(R), 2004).

• A. BIOAVAILABILITY (F) :
  
  • 1. ORAL, TABLET :
    
    • a. Absolute (intravenous versus oral) data are unavailable. Based on urinary excretion, oral bioavailability appears to exceed 70% (Artigas, 1995).
    • b. There is a median 2-hour lag until absorption begins (Prod Info Cymbalta(R), 2004).
    • c. With an evening dose, there is a 3-hour delay in absorption and a 30% increase in apparent clearance, compared to a morning dose (Prod Info Cymbalta(R), 2004).
• B. EFFECTS OF FOOD : slows absorption
  • 1. Food does not affect Cmax but delays time to peak concentration from 6 to 10 hours and reduces extent of absorption by 10% (Prod Info Cymbalta(R), 2004).

• 2.3.2.1 DISTRIBUTION SITES
  • A. TOTAL PROTEIN BINDING : at least 95% (Johnson et al, 1995).
  • B. OTHER DISTRIBUTION SITES :
    
    • 1. SALIVA, 0% (Johnson et al, 1995).
• 2.3.2.2 DISTRIBUTION KINETICS
  • A. VOLUME OF DISTRIBUTION : 1640 L (Prod Info Cymbalta(R), 2004).

• 2.3.3.1 METABOLISM SITES AND KINETICS
  • A. LIVER, extensive (Sharma et al, 2000; Artigas, 1995).
    • 1. The major metabolic pathways involve oxidation of the naphthyl ring followed by conjugation and further oxidation involving 2 P450 isozymes, CYP2D6 and CYP1A2. (Prod Info Cymbalta(R), 2004).
• 2.3.3.2 METABOLITES
  • A. Desmethyl duloxetine (active) (Johnson et al, 1995; Artigas, 1995).
    • 1. Preclinical data suggest potency similar to the parent compound for inhibition of serotonin reuptake, but less activity at the norepinephrine transporter (Goodnick, 1999; Artigas, 1995).
  • B. Hydroxylated metabolite (active) (Artigas, 1995; Goodnick, 1999).
    • 1. Preclinical data suggest potency similar to the parent compound for inhibition of serotonin reuptake (Goodnick, 1999; Artigas, 1995).

• 2.3.4.1 BREAST MILK
  • A. BREASTFEEDING : unknown.
• 2.3.4.2 KIDNEY
  • A. RENAL EXCRETION : 77% total (Johnson et al, 1995; Artigas, 1995).
  • B. Excreted mainly as metabolites; only trace amounts of unchanged drug (Johnson et al, 1995).
• 2.3.4.3 OTHER
  • A. TOTAL BODY CLEARANCE : 114 L/hr (Sharma et al, 2000).
    • 1. Value after oral doses in healthy subjects.
    • 2. Cirrhotic (Child-Pugh Class B) patients (n=6) had a clearance of 15% that of age- and gender-matched healthy subjects after a 20-milligram dose of duloxetine (Prod Info Cymbalta(R), 2004).
  • B. OTHER EXCRETION :
    
    • 1. FECES, 15% (Johnson et al, 1995; Artigas, 1995).
      • a. It is unclear from available data if this represents unabsorbed drug or biliary excretion.

• 2.3.5.1 PARENT COMPOUND
  • A. ELIMINATION HALF-LIFE : 11 to 16 hours (Johnson et al, 1995; Sharma et al, 2000; Artigas, 1995).
    • 1. Values after oral dosing; no clear evidence of dose-dependency.

• A. HEMATOLOGIC EFFECTS
  
  • 1. Anemia, leukopenia, increased white blood cell count, lymphadenopathy, and thrombocytopenia have occurred, albeit infrequently, with use of duloxetine (Prod Info Cymbalta(R), 2004).

• A. CARDIOVASCULAR EFFECTS
  
  • 1. A placebo-controlled trial with daily doses of 40 to 120 milligrams (mg) for 8 weeks caused a mean blood pressure increase of 2 millimeters of mercury (mm Hg) systolic and 0.5 mm Hg diastolic (Prod Info Cymbalta(R), 2004).
  • 2. In a large cohort study including 481,744 persons and 1487 cases of SUDDEN CARDIAC DEATH occurring in a community setting, the use of selective serotonin reuptake inhibitors was not associated with an increased risk of sudden cardiac death (rate ratio, 0.95; 95% CI, 0.42 to 2.15). In contrast, users of tricyclic antidepressants in doses of 100 mg or higher (amitriptyline or its equivalent) had a 41% increased rate of sudden cardiac death (rate ratio, 1.41; 95% CI, 1.02 to 1.95) (Ray et al, 2004).
  • 3. Small increases in systolic/diastolic blood pressure and decreases in heart rate compared to placebo have been observed with twice-daily dosing in recumbent healthy subjects; no significant effects on blood pressure or heart rate were seen in the standing position (Sharma et al, 2000).

• A. CENTRAL NERVOUS SYSTEM EFFECTS
  
  • 1. INSOMNIA (up to 20% of patients), HEADACHE (up to 16%), and SOMNOLENCE (up to 9%) have been the most common adverse effects in open studies involving patients with depression; other less frequent CNS effects included DIZZINESS, TREMOR, and AGITATION (Goodnick, 1999; Berk et al, 1997; Ishigooka et al, 1996). However, in the absence of a control group, these data are essentially meaningless. A high incidence of adverse effects is usually seen with any kind of treatment (drug or placebo) in depressed patients.
  • 2. Some evidence of SOMNOLENCE was seen in placebo-controlled study in healthy subjects (Sharma et al, 2000).

• A. METABOLIC EFFECTS
  
  • 1. Patients treated with duloxetine for 9 weeks in clinical trials showed an average WEIGHT LOSS of 0.5 kilogram (kg), while placebo-treated patients showed a weight gain of 0.2 kg (Prod Info Cymbalto(R), 2004).

• A. GASTROINTESTINAL EFFECTS
  
  • 1. NAUSEA (up to 20% of patients), DIARRHEA (8%) or CONSTIPATION (11%), and DRY MOUTH (15%) have been relatively common adverse effects in the treatment of depression in open studies; less frequently, ANOREXIA and TASTE CHANGES have been described (Johnson et al, 1995; Berk et al, 1997; Ishigooka et al, 1996; Goodnick, 1999). In the absence of control groups, the true incidence of these effects is unknown.

• A. GENITOURINARY EFFECTS
  
  • 1. Urinary hesitation may be attributable to duloxetine treatment (Prod Info Cymbalta(R), 2004).
  • 2. DYSURIA was reported in some depressed patients during therapy in an open study (Ishigooka et al, 1995). Causality is uncertain.
• B. SEXUAL DYSFUNCTION
  
  • 1. Duloxetine caused more sexual dysfunction in males, such as ejaculatory dysfunction, decreased libido, erectile dysfunction, delayed ejaculation, and particularly the ability to reach orgasm, than did placebo. Female sexual function was not affected by duloxetine (Prod Info Cymbalta(R), 2004).

• A. OCULAR EFFECTS
  
  • 1. Blurred vision was reported in 4% of patients treated with duloxetine (Prod Info Cymbalta(R), 2004).

• A. SKIN AND SUBCUTANEOUS EFFECTS
  
  • 1. Increased sweating (6%) has been reported with duloxetine treatment (Prod Info Cymbalta(R), 2004).
  • 2. Night sweats, pruritus, and rash have occurred with high frequency with duloxetine treatment. Acne, alopecia, cold sweat, ecchymosis, eczema, erythema, face edema, increased tendency to bruise, and photosensitivity reaction have been reported with lower frequency (Prod Info Cymbalta(R), 2004).

• A. WITHDRAWAL SYMPTOMS
  
  • 1. Small increases in heart rate and sleep disturbances (insomnia, abnormal dreams) have occurred following abrupt discontinuation of multiple-dose administration in healthy subjects (Sharma et al, 2000). However, doses in this study were relatively high (20 to 40 mg twice daily). Withdrawal data following once-daily doses of 20 mg in healthy subjects or depressed patients are unavailable.
• B. OVERDOSE
  

• 1. U.S. Food and Drug Administration's Pregnancy Category C, by the manufacturer (Prod Info Cymbalta(R), 2004).
• 2. Neonates exposed to selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine uptake inhibitors (SNRIs) late in the third trimester have developed serious complications, sometimes requiring prolonged hospitalization, respiratory support, and tube feeding. Respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor jitteriness, irritability, and constant crying have been observed. This clinical picture is consistent with a toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome (Prod Info Cymbalta(R), 2004).

• 1. Neonates exposed to serotonin and norepinephrine reuptake inhibitors (SNRIs) late in the third trimester have required prolonged hospitalization, respiratory support, and tube feeding. Clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These signs and symptoms are consistent with a direct toxic effect of SNRIs or with a drug discontinuation syndrome (Prod Info Cymbalta(R), 2004).

• A. CHLORDIAZEPOXIDE/AMITRIPTYLINE
  
• B. CIPROFLOXACIN
  
• C. CLASS I-C ANTIARRHYTHMIC AGENTS
  
• D. ENOXACIN
  
• E. FLUOXETINE
  
• F. FLUVOXAMINE
  
• G. MONOAMINE OXIDASE INHIBITORS
  
• H. PAROXETINE
  
• I. PERPHENAZINE/AMITRIPTYLINE
  
• J. PHENOTHIAZINES
  
• K. QUINIDINE
  
• L. THIORIDAZINE
  
• M. TRICYCLIC ANTIDEPRESSANTS
  

• A. PHYSICAL EXAMINATION
  
  • 1. Symptoms of depression (improvement)

• A. PHYSICAL EXAMINATION
  
  • 1. Blood pressure and pulse in patients prior to initiating treatment and periodically throughout
  • 2. Signs of toxicity (eg, somnolence, sleep disturbances, persistent GI symptoms)

• A. Similar to milnacipran and venlafaxine, duloxetine is a serotonin/norepinephrine reuptake inhibitor (SNRI). These agents are claimed to be at least as effective as tricyclics but with lower toxicity, and more efficacious than selective serotonin reuptake inhibitors (SSRIs). The primary role of SNRIs is as an alternative in patients with major depressive disorder who have responded poorly to other agents (eg, tricyclics or SSRIs).
• B. At present, duloxetine is not recommended over other available SNRIs in poorly-responsive patients.
• C. Published data are too limited to assess the role of duloxetine in urinary incontinence.

• A. MECHANISM OF ACTION
  
  • 1. Duloxetine is a dual-selective serotonin (5HT) and norepinephrine reuptake inhibitor (Wong et al, 1993). Although structurally unrelated, the mechanism and pharmacodynamic characteristics of duloxetine are generally like those of venlafaxine and milnacipran (Artigas, 1995; Pinder, 1997; Sharma et al, 2000). Duloxetine is the (+)-isomer of the racemic compound (Wong et al, 1993). It bears structural similarity to fluoxetine and tomoxetine.
  • 2. Duloxetine is a secondary amine, whereas venlafaxine and milnacipran are tertiary amines. All three agents have been demonstrated to inhibit norepinephrine and 5HT uptake in preclinical studies; both duloxetine and venlafaxine were more potent inhibitors of 5HT than norepinephrine reuptake, whereas milnacipran was a more potent inhibitor of norepinephrine uptake (Goodnick, 1999; Artigas, 1995). Duloxetine has exhibited higher potency at both reuptake sites than milnacipran or venlafaxine (Artigas, 1995; Beique et al, 1998; Goodnick, 1999). In vitro, duloxetine has not shown significant affinity for histamine H1, dopamine D2, cholinergic, alpha-1 adrenergic, 5HT-1A, 5HT-1B, 5HT-1D, 5HT-2A, 5HT-2C, or opioid receptors (Artigas, 1995; Goodnick, 1999; Wong et al, 1993).
  • 3. The in vitro activity of antidepressants has not always been predictive of in vivo/clinical effects. Thus, the greater in vitro activity of duloxetine compared to venlafaxine may not imply greater clinical efficacy. Some in vivo data have suggested the similar potency of duloxetine in inhibiting 5HT and norepinephrine reuptake (Wong et al, 1993), which contrasts in vitro findings. Clinical comparisons of the serotonin/norepinephrine reuptake inhibitors (SNRIs) are essential to determine relevant differences.
  • 4. Duloxetine has increased neural sphincter activity and bladder capacity in animal studies (Voelker, 1998; Andersson et al, 1999), and has been investigated in urinary incontinence.
• B. REVIEW ARTICLES
  
  • 1. Advances in the treatment of depression, including duloxetine (Leonard, 1996; Pinder, 1997).
  • 2. Mechanisms, pharmacology, pharmacokinetics, and clinical efficacy of the SNRIs (Artigas, 1995).

• A. DEPRESSIVE DISORDER, MAJOR
  FDA Labeled Indication
  
  
  • 1. OVERVIEW :

    
    FDA APPROVAL:  Adult, yes; pediatric, no
    EFFICACY:  Adult, effective
    DOCUMENTATION:  Adult, good
    

  • 2. SUMMARY :

    
     - Duloxetine was more effective than placebo
       in treating depression
    

  • 3. ADULT :
    
    • a. Four randomized, double- blind, placebo-controlled, fixed-dose studies that demonstrated superiority of duloxetine over placebo for the treatment of major depression (as measured by improvement on the 17-item Hamilton Depression Rating Scale total score) in patients aged 18 to 85 years. The dose of duloxetine in 2 studies (n=245 and n=267) was 60 milligrams (mg) once daily for 8 weeks; in one study (n=266), the dose was 20 or 40 mg twice daily for 8 weeks; and in a fourth study (n=281), the dose was 40 or 60 mg twice daily for 8 weeks. There was no evidence that doses greater than 60 mg/day gave any added benefit. Analyses suggested no differential responsiveness due to age, gender, or race (Prod Info Cymbalta(R), 2004).
    • b. Duloxetine was more effective than placebo for treating major depression. In a randomized, double-blind, placebo-controlled trial, patients with nonpsychotic major depressive disorder were given duloxetine (n=66), beginning at 40 milligrams (mg) per day and increasing to 120 mg/day by the third week, or placebo (n=68), for 8 weeks. Changes in scores on the Hamilton Depression scale (HAM-D) were significantly greater for duloxetine than for placebo (-9.7 vs -6.6, p=0.009). Ten percent of duloxetine-treated patients discontinued treatment due to adverse events, compared to 4.3% of placebo-treated patients (p=0.417). Asthenia and insomnia were more common among duloxetine-treated patients than among placebo-treated patients. More placebo-treated than duloxetine-treated patients discontinued for lack of efficacy (p=0.047). During the week after discontinuation of treatment, abnormal dreams were noted for patients taking duloxetine, although the incidence did not differ significantly from that of the placebo group (p=0.056) (Goldstein et al, 2002).
    • c. Uncontrolled short-term (6-week) studies have suggested the efficacy or oral duloxetine 10 to 30 milligrams (mg) daily in patients with major depressive or bipolar disorder (Berk et al, 1997; Ishigooka et al, 1996; Artigas, 1995). Clinical response, defined as 50% reduction of the 17-item Hamilton Depression Rating Scale (HAMD-17), was observed in 75 to 78% of patients treated; remission (decrease in HAMD-17 score to less than 6 or 7) was reported in 36 to 62%.
• B. DIABETIC NEUROPATHIC PAIN
  FDA Labeled Indication
  
  
  • 1. OVERVIEW :

    
    FDA APPROVAL:  Adult, yes; pediatric, no
    EFFICACY:  Adult, effective
    DOCUMENTATION:  Adult, good
    

  • 2. SUMMARY :

    
     - Indicated for the treatment of neuropathic pain
       associated with diabetic neuropathy
    

  • 3. ADULT :
    
    • a. Duloxetine treatment effectively reduced neuropathic pain in patients with DIABETIC NEUROPATHY. In two randomized, double-blind, placebo-controlled studies (n=791), diabetic patients experiencing painful distal symmetrical sensorimotor polyneuropathy for at least 6 months (and with a baseline pain score of at least 4 on an 11-point scale) received duloxetine (60 milligrams (mg) once daily, 60 mg twice daily, or 20 mg once daily) or placebo for 12 weeks. In addition to duloxetine, patients were allowed to take up to 4 grams of acetaminophen per day as needed for pain. Therapy with 60 mg of duloxetine once or twice daily produced statistically significant improvements in the mean endpoint pain scores as compared with baseline, and increased the percentage of patients with at least a 50% reduction in pain score from baseline (Prod Info Cymbalta(R), 2004).
• C. URINARY INCONTINENCE
  
  • 1. OVERVIEW :

    
    FDA APPROVAL:  Adult, no; pediatric, no
    EFFICACY:  Adult, effective
    DOCUMENTATION:  Adult, good
    

  • 2. SUMMARY :

    
     - Duloxetine was effective in the treatment of stress
       urinary incontinence in female patients
    
     - Compared with placebo, duloxetine treatment has 
       been associated with a significantly higher 
       frequency of adverse events resulting in higher
       discontinuation rates
    

  • 3. ADULT :
    
    • a. Incontinence episode frequency (IEF) was reduced following the administration of duloxetine for the treatment of stress urinary incontinence. In a randomized, double-blind, placebo-controlled, multi-continent study (n=458), women with stress urinary incontinence of at least 3 months duration and experiencing at least 7 incontinent episodes per week received duloxetine 40 milligrams twice daily or placebo for 12 weeks. The mean IEF at baseline was 18.4 episodes per week and more than half of patients averaged two or more episodes daily. From baseline to endpoint, greater reductions in IEF were observed in the duloxetine group as compared with the placebo group (percentage change, -53.6% vs -40%, respectively; p=0.05); and this effect was even stronger in patients with a baseline IEF of 14 or greater (percentage change, -54.9% vs -41.7%, respectively; p=0.022). In addition, the average voiding interval increased significantly in patients who received duloxetine as compared with those who received placebo (20.4 vs 8.5 minutes, respectively; p less than 0.001). From baseline to endpoint, patients in the duloxetine group also showed greater improvements in mean total scores on the Incontinence Quality of life questionnaire as compared with patients in the placebo group (mean change, 10.3 vs 6.4; p=0.007). However, adverse events were significantly more frequent with duloxetine treatment than with placebo (76.2% vs 59.3%, respectively; p less than 0.001) and resulted in significantly higher discontinuation rates in the duloxetine group as compared with placebo (17.2% vs 1.7%, respectively; p less than 0.001). In duloxetine-treated patients, the most common adverse events included nausea (25.1%), headache (14.5%), insomnia (13.7%), constipation (12.8%), dry mouth (12.3%), dizziness (11%), fatigue (10.1%), somnolence (8.4%), anorexia (6.6%), vomiting (6.2%), and increased sweating (5.7%) (Millard et al, 2004).
    • b. Duloxetine was effective in the treatment of stress urinary incontinence (SUI) in female patients. In a randomized, double-blind, placebo-controlled, multi-center trial, 683 women 22 to 84 years old with SUI of at least 3 months duration and experiencing 7 or more episodes weekly received duloxetine 80 milligrams daily (in two divided doses) or placebo for 12 weeks. Incontinence episode frequency decreased by 50% to 100% in 51.4% of duloxetine-treated patients as compared with 33.5% of placebo-treated patients (p less than 0.001). Mean improvement in the Incontinence Quality of Life (I-QOL) questionnaire total score was also significantly better for patients in the duloxetine group as compared with the placebo group (11.1 vs 6.8, respectively; p less than 0.001). Adverse events occurred more frequently with duloxetine treatment (discontinuation rate, 24.1% vs 4.1%; p less than 0.001) and included nausea (22.7%), fatigue (14.8%), insomnia (14.2%), dry mouth (12.2%), constipation (9.6%), somnolence (8.7%), dizziness (7.6%), headache (7.3%), and diarrhea (6.1%)(Dmochowski et al, 2003).
    • c. Oral duloxetine was reported effective in the treatment of stress or mixed INCONTINENCE in a placebo-controlled study; improvements in 24-hour pad weight, number of episodes, and quality of life were observed during treatment (Andersson et al, 1999). However, this study has not been published, and details regarding treatment allocation, dose, comparative baseline characteristics, and efficacy-evaluation parameters are unavailable for analysis.

1. Andersson K-E, Appell R, Cardozo LD et al: The pharmacological treatment of urinary incontinence. BJU Intl 1999; 84:923-947.

2. Artigas F: Selective serotonin/noradrenaline reuptake inhibitors (SNRIs). CNS Drugs 1995; 4(2):79-89.

3. Beique J-C, Lavoie N, de Montigny C et al: Affinities of venlafaxine and various reuptake inhibitors for the serotonin and norepinephrine transporters. Eur J Pharmacol 1998; 349:129-132.

4. Berk M, du Plessis AD, Birkett M et al: An open-label study of duloxetine hydrochloride, a mixed serotonin and noradrenaline reuptake inhibitor, in patients with DSM-III-R major depressive disorder. Int Clin Psychopharmacol 1997; 12:137-140.

5. Dmochowski RR, Miklos JR, Norton PA et al: Duloxetine versus placebo for the treatment of north american women with stress urinary incontinence. J Urol 2003; 170:1259-1263.

6. Goldstein DJ, Mallinckrodt C, Lu Y et al: Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial. J Clin Psychiatry 2002; 63(3):225-231.

7. Goodnick PJ: Psychopharmacology of depression in the next millenium. CNS Spectrums 1999; 4(7):21-35.

8. Ishigooka J et al: Simultaneous monitoring of inhibition of serotonin uptake by platelets and plasma drug concentrations following administration of duloxetine, a new antidepressant candidate, to healthy volunteers. Curr Ther Res Clin Exp 1997; 58:679-692.

9. Ishigooka J, Murasaki M and the LY248686 Study Group: First open study with new antidepressant LY248686 (Duloxetine) for depression in Japan. Eur Neuropsychopharmacol 1996; 6(50):50.

10. Ishigooka J, Nagata E, Takahashi A et al: Serotonin uptake inhibition in platelets of duloxetine-treated subjects. Neuropsychopharmacol 1994; 10(218):218.

11. Johnson JT, DeLong AF, Oldham SW et al: Disposition of 14C duloxetine after oral administration in man. Pharmaceut Res 1995; 12(suppl 387):387.

12. Kasahara T, Ishigooka J, Nagata E et al: Long-lasting inhibition of 5-HT uptake of platelets in subjects treated by duloxetine, a potential antidepressant. Jpn J Psychopharmacol 1996; 16:25-31.

13. Leonard BE: New approaches to the treatment of depression. J Clin Psychiatry 1996; 57(suppl 4):26-33.

14. Millard RJ, Moore K, Rencken R et al: Duloxetine vs placebo in the treatment of stress urinary incontinence: a four-continent randomized clinical trial. BJU Int 2004;93(3):311-318.

15. Pinder RM: Designing a new generation of antidepressant drugs. Acta Psychiatr Scand 1997; 96(suppl 391):7-13.

16. Product Information: Cymbalta(R), duloxetine hydrochloride. Eli Lilly and Co.,Indianapolis, IN (issued 8/3/2004) reviewed 9/2004.

17. Ray WA, Meredith S, Thapa PB et al: Cyclic antidepressants and the risk of sudden cardiac death. Clin Pharmacol Ther 2004; 75(3):234-241.

18. Sharma S, Goldberg MJ & Cerimele BJ: Pharmacokinetics and safety of duloxetine, a dual-serotonin and norepinephrine reuptake inhibitor. J Clin Pharmacol 2000; 40:161-167.

19. Voelker R: International group seeks to dispel incontinence "taboo". JAMA 1998; 280(11):951-953.

20. Wong DT, Bymaster FP, Mayle DA et al: LY248686, a new inhibitor of serotonin and norepinephrine uptake. Neuropsychopharmacology 1993; 8(1):23-33.


7.0 AUTHOR INFORMATION