Duloxetine - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS • Hepatotoxicity : Hepatic failure, sometimes fatal, has been reported.

Discontinue duloxetine delayed-release capsules in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established.

Avoid use in patients with substantial alcohol use or evidence of chronic liver disease • Orthostatic Hypotension, Falls and Syncope : Consider dosage reduction or discontinuation if these events occur • Serotonin Syndrome : Increased risk when co-administered with other serotonergic agents, but also when taken alone.

If it occurs, discontinue duloxetine delayed-release capsules and serotonergic agents • Increased Risk of Bleeding : May increase the risk of bleeding events.

Concomitant use of antiplatelet drugs and anticoagulants may increase this risk ( 5.5 , 7.4 , 8.1 ) • Severe Skin Reactions : Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur; Discontinue at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified • Activation of Mania or Hypomania : Prior to initiating, screen patients for personal or family history of bipolar disorder, mania, or hypomania • Angle-Closure Glaucoma : Has occurred in patients with untreated anatomically narrow angles treated with antidepressants • Seizures : Prescribe with care in patients with a history of seizure disorder • Blood Pressure Increases : Monitor blood pressure prior to initiating treatment and periodically throughout treatment • Inhibitors of CYP1A2 or Thioridazine : Avoid co-administration with duloxetine delayed-release capsules • Hyponatremia : Can occur in association with SIADH; consider discontinuation • Glucose Control in Diabetes : In DPNP patients, increases in fasting blood glucose, and HbA 1c have been observed • Conditions that Slow Gastric Emptying : Use cautiously in these patients • Sexual Dysfunction : Duloxetine delayed-release capsules may cause symptoms of sexual dysfunction 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 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 capsule trials.

There were suicides in the adult duloxetine delayed-release capsule 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 and Warnings and Precautions ] 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.