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Drug Safety and Availability

New Molecular Entity (NME) - 3 Years Later - Volume 1, Number 2, Winter 2008

Duloxetine (marketed as Cymbalta)

Duloxetine hydrochloride (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.

Duloxetine was the first product reviewed as part of FDA's ongoing pilot evaluation of a new systematic method of reviewing the safety of New Molecular Entities (NMEs).  The purpose of the pilot is to determine the value of this systematic method of review, and to determine how, when, and for which products the reviews would be most useful.

The NME evaluation consists of a comprehensive review of safety data, including a review of adverse event reports in FDA's Adverse Event Reporting System (AERS) database, a data mining analysis of AERS data, a review of sponsor-submitted periodic safety reports, a literature review, a medication error analysis, an analysis of product use, and a review of postmarketing clinical trial and epidemiologic study findings. The results for duloxetine are summarized below.

Between August 2004 and December 2006, more than 3 million patients received a prescription for duloxetine.1 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%).2 Diagnoses related to bladder incontinence and female stress incontinence represented less than 1% of diagnoses2 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.1,3

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. Analysis of additional reports of liver injury is ongoing and labeling will be modified as needed.

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 AERS cases describing bleeding associated with duloxetine therapy. While most bleeding was in the gastrointestinal (GI) 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 GI 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, aspirin, or other NSAIDs (such as ibuprofen). 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. All of the selective serotonin reuptake inhibitors (SSRIs) and the other SNRI (venlafaxine) have labeling describing the potential for abnormal bleeding; this information has been added to the labeling for duloxetine as a result of the NME evaluation.

Hyponatremia and Falls: 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. Although hyponatremia is already described in the duloxetine labeling, FDA concluded that labeling would be more informative if it better described symptoms that suggest low serum sodium levels. Labeling therefore was supplemented to describe clinical manifestations of hyponatremia, including 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. The existing product labeling had previously described the possibility of urinary hesitation with duloxetine. It has been supplemented to inform healthcare providers of the potential for the serious outcomes (catheterization and/or hospitalization).

Medication Errors: 177 cases of medication errors were reviewed and classified by the following error types: wrong strength, administration errors associated with opening the capsules, and wrong drug. For each of these error types, reviewers identified contributing factors associated with the container label, carton, and insert labeling.

FDA Recommendations

As a result of this NME review, the following changes have been made to duloxetine labeling or to the product container label.

  • Information on the risk of hyponatremia, already described in the duloxetine labeling prior to this review, has been updated to provide more information about the clinical manifestations of hyponatremia. Changes have been made to the hyponatremia section of labeling, as well as to the overdosage section of labeling.

  • Information on the risk of bleeding has been added to the Warnings/Precautions and Patient Information sections and language has been added on concomitant use of duloxetine with warfarin and other drugs that affect hemostasis. The revised labeling states that concurrent use of an NSAID, aspirin, warfarin, or any other drug that affects hemostasis may potentiate the risk of bleeding. In addition, it states that patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued.

  • The information in labeling regarding urinary hesitancy/retention has been updated (cautionary information in the Warnings/Precautions Section).

  • Changes have been made to the product container labels and labeling to prevent future medication errors, including warning against opening the capsules, which can affect the enteric coating.


FDA will continue to monitor the potential for liver toxicity with duloxetine, but has concluded that this risk is appropriately reflected in the current labeling.

FDA is currently reviewing cases of drug interactions associated with duloxetine use.

Healthcare professionals are requested to report any suspected serious adverse reactions in association with duloxetine therapy.

Relevant Web Sites

Duloxetine (Cymbalta) product labeling (PDF - 321KB)

Public Health Advisory (7/19/2006)

Information for Healthcare Professionals: Duloxetine (marketed as Cymbalta)


  1. Verispan, LLC: Total Patient Tracker, Aug04-Dec06, Extracted Feb07.
  2. Verispan, LLC: Physician Drug and Diagnosis Audit, Aug04-Dec06, Extracted Feb07.
  3. Verispan, LLC: Vector One®: National, Aug04-Dec06, Extracted Feb07, Mar07.