Fluoxetine Hydrochloride (Page 3 of 14)

2.8 Discontinuation of Treatment

Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [see WARNINGS AND PRECAUTIONS (5.13)].

3 DOSAGE FORMS AND STRENGTHS

  • 10 mg fluoxetine capsules USP is a white capsule, imprinted GG 575 with single green ink bands
  • 20 mg fluoxetine capsules USP is a white capsule, imprinted GG 550 with green and black ink bands
  • 40 mg fluoxetine capsules USP is a white capsule, imprinted GG 540 with single orange ink bands

4 CONTRAINDICATIONS

When using fluoxetine and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax.

The use of fluoxetine is contraindicated with the following:

  • Monoamine Oxidase Inhibitors [see DRUG INTERACTIONS (7.1)]
  • Pimozide [see DRUG INTERACTIONS (7.9)]
  • Thioridazine [see DRUG INTERACTIONS (7.9)]

5 WARNINGS AND PRECAUTIONS

When using fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax.

5.1 Clinical Worsening and Suicide Risk

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 differences (drug versus 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 2.

Table 2. Suicidality per 1000 Patients Treated
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 trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug 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 abrupt discontinuation can be associated with certain symptoms [see WARNINGS AND PRECAUTIONS (5.13)].

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 fluoxetine should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

It should be noted that fluoxetine is approved in the pediatric population only for Major Depressive Disorder and Obsessive Compulsive Disorder. Safety and effectiveness of fluoxetine and olanzapine in combination in patients less than 18 years of age have not been established.

5.2 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions

The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including fluoxetine treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.

The concomitant use of fluoxetine with MAOIs intended to treat depression is contraindicated [see CONTRAINDICATIONS (4) and DRUG INTERACTIONS (7.1)].

If concomitant treatment of fluoxetine with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see DRUG INTERACTIONS (7.4)].

The concomitant use of fluoxetine with serotonin precursors (such as tryptophan) is not recommended [see DRUG INTERACTIONS (7.3)].

Treatment with fluoxetine and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above reactions occur, and supportive symptomatic treatment should be initiated.

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