Duloxetine (Page 2 of 14)


Duloxetine is available as delayed-release capsules:

20mg: Opaque green/opaque green size ‘4’ hard gelatin capsule filled with white to off-white-spherical enteric coated pellets and imprinted ‘RDY608′ on opaque green cap and ’20 mg’ on opaque green body with black ink.

30 mg: Opaque blue/opaque white size ‘3’ hard gelatin capsule filled with white to off-white-spherical enteric coated pellets and imprinted ‘RDY609′ on opaque blue cap and ’30 mg’ on opaque white body with golden yellow ink.

60 mg: Opaque blue/opaque green size ‘1’ hard gelatin capsule filled with white to off-white spherical enteric coated pellets and imprinted ‘RDY610′ on opaque blue cap and ’60 mg’ on opaque green body with white ink.


The use of MAOIs intended to treat psychiatric disorders with duloxetine delayed-release capsules or within 5 days of stopping treatment with duloxetine delayed-release capsules is contraindicated because of an increased risk of serotonin syndrome. The use of duloxetine delayed-release capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders is contraindicated [see Dosage and Administration (2.8)and Warnings and Precautions (5.4)].

Starting duloxetine delayed-release capsules in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.9) andWarnings and Precautions (5.4)].


5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, 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.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1

Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
Increases Compared to Placebo
<18 14 additional cases
18 to 24 5 additional cases
Decreases Compared to Placebo
25 to 64 1 fewer case
≥65 6 fewer cases

No suicides occurred in any of the pediatric duloxetine delayed-release capsules trials. There were suicides in the adult duloxetine delayed-release capsules trials, but the number was not sufficient to reach any conclusion about duloxetine delayed-release capsules effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms 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.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that discontinuation can be associated with certain symptoms [see Dosage and Administration (2.8) andWarnings and Precautions (5.7)] for descriptions of the risks of discontinuation of duloxetine delayed-release capsules.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for duloxetine delayed-release capsules should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that duloxetine delayed-release capsules are not approved for use in treating bipolar depression.

5.2 Hepatotoxicity

There have been reports of hepatic failure, sometimes fatal, in patients treated with duloxetine delayed-release capsules. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal (ULN) with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Duloxetine delayed-release capsules should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established.

Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis.

Duloxetine delayed-release capsules increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (92/34,756) of duloxetine delayed-release capsules-treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. In adult placebo-controlled trials, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the ULN occurred in 1.25% (144/11,496) of duloxetine delayed-release capsules-treated patients compared to 0.45% (39/8716) of placebo-treated patients. In adult placebo-controlled studies using a fixed dose design, there was evidence of a duloxetine delayed-release capsules dose response relationship for ALT and AST elevation of >3 times the ULN and >5 times the ULN, respectively.

Because it is possible that duloxetine delayed-release capsules and alcohol may interact to cause liver injury or that duloxetine delayed-release capsules may aggravate pre-existing liver disease, duloxetine delayed-release capsules should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

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