Duloxetine ( Cymbalta ) is a serotonin and norepinephrine reuptake inhibitor ( SNRI ) for oral administration initially approved in August 2004 to treat major depressive disorder. Subsequently, FDA approved Duloxetine for the treatment of diabetic peripheral neuropathic pain ( September 2004 ) and generalized anxiety disorder ( February 2007 ) in adult patients.
Between August 2004 and December 2006, more than 3 million patients received a prescription for Duloxetine.The most common diagnoses in office-based practice settings for which Duloxetine was prescribed during this period were psychiatric disorders ( 72% ) and pain/neuropathy ( 17% ).
Diagnoses related to bladder incontinence and female stress incontinence represented less than 1% of diagnoses for which Duloxetine was prescribed and are unapproved indications.
Approximately 50% of use was among patients aged 41-60 years. Pediatric patients ( ages 0-16 years ) accounted for less than 1% of total dispensed prescriptions.
Initial review of the safety data identified a number of adverse events requiring further evaluation and more detailed review. These events included reports of bleeding, blindness, drug interactions, falls, loss of consciousness, hyponatremia, urinary hesitancy/retention, medication errors, and liver toxicity.
The cases of blindness were subsequently determined to be related to underlying disease or other causes, rather than to drug use.
The underlying cause of loss of consciousness already appeared to be appropriately reflected in current labeling.
The potential risk of liver toxicity had been previously identified in clinical trials and prior analyses of postmarketing information, and is reflected in current labeling.
The remaining adverse events identified in this review - bleeding, hyponatremia, falls, urinary retention/hesitancy, as well as medication errors - are discussed below.
Bleeding disorders: There were 170 unique postmarketing cases describing bleeding associated with Duloxetine therapy. While most bleeding was in the gastrointestinal tract, bleeding also was reported in the vascular system ( such as cerebral hemorrhage ), renal/urinary system, reproductive system ( such as vaginal bleeding ), respiratory system, ears, and eyes.
Bleeding ranged in severity from bruising to fatal gastrointestinal hemorrhage.
There were 6 cases of bleeding with death as an outcome; 4 of the deaths were considered unlikely to be related to Duloxetine, but in the remaining 2 cases a role of Duloxetine could not be excluded.
There were an additional 33 hospitalizations attributed to a bleeding event. In 12 of these cases, the patients were taking concomitant medications that may have increased the risk of bleeding, including Warfarin, Acid Acetylsalicylic, or other NSAIDs.
The 170 cases also included 1 case of platelet dysfunction, 9 cases of thrombocytopenia, and 5 cases of increased prothrombin time/international normalized ratio ( PT/INR ).
Serotonin plays an important role in the coagulation process and abnormal bleeding is an expected effect of drugs that interfere with serotonin reuptake.
Hyponatremia: Eleven unique postmarketing cases of hyponatremia were identified during evaluation of reports related to fall and loss of consciousness. The patients had serum sodium levels in the range of 100-120 mmol/L.
Clinical manifestations of hyponatremia include: headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls, as well as hallucination, syncope, seizure, coma, respiratory arrest, and death in more severe and/or acute cases.
Urinary retention / hesitancy: There were 78 unique postmarketing cases of urinary retention / hesitancy associated with Duloxetine use.
Twenty-six of the 78 cases reported serious outcomes in 16 females and 10 males, with 8 of the females and 4 of the males described as having had a positive dechallenge.
These 26 cases included 9 hospitalizations with catheterization, 8 hospitalizations without catheterization, and 9 catheterizations without hospitalization.
Seven of the hospitalized patients had a primary or secondary diagnosis of urinary retention/hesitation.
Source: FDA, 2008