DULOXETINE Hydrochloride (hcl)

Duloxetine (brand names Cymbalta,Yentreve) is a serotonin-norepinephrine reuptake inhibitor (SNRI) used for major depressive disorder (MDD), generalized anxiety disorder (GAD), pain related to diabetic neuropathy and in some countries for stress urinary incontinence (SUI).

Indications

Moderate to severe stress urinary incontinence in women.

Stress urinary incontinence is involuntary loss of urine when the bladder comes under stress, e.g. from coughing, sneezing or other movements that increase the intra-abdominal pressure. Duloxetine was first reported to improve outcomes in SUI in 1998. Systematic reviews with meta-analysis, conducted in 2005  and 2008 (University of Minnesota), each found ten controlled trials. Both systematic reviews concluded that duloxetine did not lead to cure of stress urinary incontinence in the vast majority of people, but that episodes of incontinence were reduced by about 50%. This was associated with an improvement in quality of life measurements. Mild side effects were common, and about a fifth had to discontinue the medication because of poor tolerance.

Cautions

  • elderly

  • cardiac disease

  • hypertension (avoid if uncontrolled)

  • history of mania history of seizures

  • raised intra-ocular pressure, susceptibility to angle-closure glaucoma

  • bleeding disorders or concomitant use of drugs that increase risk of bleeding

Withdrawal of duloxetine Hydrochloride

Nausea, vomiting, headache, anxiety, dizziness, paraesthesia, sleep disturbances, and tremor are the most common features of abrupt withdrawal or marked reduction of the dose; dose should be reduced over at least 1?2 weeks

Contra-indications

  • hepatic impairment;

  • renal impairment (avoid if creatinine clearance less than 30 mL/minute); pregnancy

  • breast-feeding

Dose of Duloxetine

  • Adult over 18 years, 40 mg twice daily, assess for benefit and tolerability after 2?4 weeks
  • Initial dose of 20 mg twice daily for 2 weeks can minimise side effects

 

side effects of Duloxetine

nausea, vomiting, dyspepsia, constipation, diarrhoea, abdominal pain, weight changes, decreased appetite, flatulence, dry mouth; palpitation, hot flush; insomnia, abnormal dreams, paraesthesia, drowsiness, anxiety, headache, dizziness, fatigue, weakness, tremor, nervousness, anorexia; sexual dysfunction; visual disturbances; sweating, pruritus;less commonly gastritis, halitosis, hepatitis, bruxism, tachycardia, hypertension, postural hypotension, syncope, raised cholesterol, vertigo, taste disturbance, cold extremities, impaired temperature regulation, impaired attention, movement disorders, muscle twitching, musculoskeletal pain, thirst, stomatitis, hypothyroidism, urinary disorders, and photosensitivity;rarely mania and angle-closure glaucoma;also reported supraventricular arrhythmia, chest pain, hallucinations, suicidal behaviour (see Suicidal Behaviour and Antidepressant Therapy), seizures, hypersensitivity reactions including urticaria, angioedema, rash (including Stevens-Johnson syndrome) and anaphylaxis, hyponatraemia (see Hyponatraemia and Antidepressant Therapy)

 

Interactions

  • 5HT1 Agonists possible increased serotonergic effects when duloxetine given with 5HT1 agonists
  • Amitriptyline possible increased serotonergic effects when duloxetine given with amitriptyline
  • Antidepressants, SSRI possible increased serotonergic effects when duloxetine given with SSRIs
  • Ciprofloxacinmetabolism of duloxetine inhibited by ciprofloxacin ?avoid concomitant use
  • Clomipramine possible increased serotonergic effects when duloxetine given with clomipramine
  • Fluvoxamine metabolism of duloxetine inhibited by fluvoxamine ?avoid concomitant use
  • MAOIs duloxetine should not be started until 2 weeks after stopping MAOIs , also MAOIs should not be started until at least 5 days after stopping duloxetine
  • Moclobemidepossible increased serotonergic effects when duloxetine given with moclobemide
  • Pethidine possible increased serotonergic effects when duloxetine given with pethidine
  • St John's Wort possible increased serotonergic effects when duloxetine given with St John's wort
  • Venlafaxine possible increased serotonergic effects when duloxetine given with venlafaxine

Literature

Trials in North America and Europe have provided evidence for the safety and efficacy of duloxetine as a pharmacological treatment for stress incontinence of urine in women.

  • A study from Australia included 458 women aged 27-79 years with stress incontinence of urine enrolled in a double-blind, placebo-controlled trial. 0801

    • They were randomly assigned to receive placebo (231) or duloxetine 40 mg twice daily (227) for 12 weeks.

    • The primary outcome variables included the incontinence episode Frequency and Quality of Life questionnaire.

    • Results:

      The mean baseline incontinence episode Frequency was 18.4/week; 55% of patients had a baseline incontinence episode Frequency of > or = 14.

    • There was a significantly greater median decrease in incontinence episode Frequency with duloxetine with placebo (54% vs 40%, P = 0.05), with comparable significant improvements in quality of life (Quality of Life  score increases of 10.3 vs 6.4, P = 0.007).

    • The improvements with duloxetine were associated with significantly greater increases in voiding intervals than with placebo (20.4 vs 8.5 min, P < 0.001).

    • The placebo response was 10.7%.

    • Discontinuation rates for adverse events were 1.7% for placebo and 17.2% for duloxetine (P < 0.001), with nausea being the most common reason for discontinuation (3.1%); it was the most common adverse event with duloxetine, but was mild or moderate in most (81%), did not worsen in any patient and resolved within 7 days in 60% and within 1 month in 86% of continuing patients; 88% of women who experienced nausea while taking duloxetine completed the trial.

    • Conclusions:

      These results show improvements in incontinence and quality of life with duloxetine 40 mg twice daily for 12 weeks.

--------------------

A new form of drug treatment with a serotonin-noradrenaline reuptake inhibitor (SNRI), duloxetine, may now have a place in treatment of this condition.0501

  • All randomised or quasi-randomised controlled trials of treatment for SUI or MUI, in which at least one management arm involved a SNRI.
  • Nine randomised trials were included, involving 3327 adults with predominantly SUI, randomised to receive duloxetine or placebo.
  • Treatment duration was between three weeks and 12 weeks.
  • Duloxetine was significantly better than placebo in terms of improving patients' quality of life (and perception of improvement.
  • Individual studies demonstrated a significant reduction in the Incontinence Episode Frequency (IEF) by approximately 50% during treatment with duloxetine.
  • With regard to objective cure, however, meta-analysis of stress pad test and 24 hour pad weight change failed to demonstrate a benefit for duloxetine over placebo though data were relatively few.
  • Subjective cure favoured duloxetine, albeit with a small effect size (3%).
  • Although significant side effects were commonly associated with duloxetine, they were reported as acceptable.
  • Adverse effects are common but not serious. About one in three participants allocated duloxetine reported adverse effects (most commonly nausea) related to treatment, and about one in eight allocated duloxetine stopped treatment as a consequence.


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