Author: druginteractionchecker_lgaiz4

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Clinical Worsening/Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior ( 5.1 ).

• Serotonin Syndrome or Neuroleptic Malignant Syndrome-Like Reactions: Have been reported with antidepressants.

Discontinue trazodone hydrochloride tablets and initiate supportive treatment ( 5.2 , 7 ).

• Activation of Mania/Hypomania: Screen for bipolar disorder and monitor for mania/hypomania ( 5.3 ).

• QT Prolongation: Increases the QT interval.

Avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval ( 5.4 ).

• Use in Patients With Heart Disease: Use with caution in patients with cardiac disease ( 5.5 ).

• Orthostatic Hypotension and Syncope: Have occurred.

Warn patients of risk and symptoms of hypotension ( 5.6 ).

• Abnormal Bleeding: May increase the risk of bleeding.

Use with NSAIDs, aspirin, or other drugs that affect coagulation may compound this risk ( 5.7 , 7 ).

• Interaction With MAOIs: Do not use concomitantly or within 14 days of monoamine oxidase inhibitors ( 5.8 , 7 ).

• Priapism: Has occurred.

Warn male patients of this risk and how/when to seek medical attention ( 5.9 ).

• Hyponatremia: Can occur in association with SIADH ( 5.10 ).

• Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills.

Advise patients to use caution when operating machinery ( 5.11 ).

• Angle-Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants.

( 5.12 ) • Discontinuation Symptoms: May occur with abrupt discontinuation and include anxiety and sleep disturbance.

Upon discontinuation, taper trazodone hydrochloride tablets and monitor for symptoms ( 5.13 ).

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 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 4,400 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 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 1,000 patients treated) are provided in Table 1 .

Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 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.

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 healthcare providers .

Such monitoring should include daily observation by families and caregivers .

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

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 antidepressants alone and may occur with trazodone treatment, but particularly with concomitant use of other serotoninergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs]), or with antipsychotics or other dopamine antagonists.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and 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.

Treatment with trazodone hydrochloride tablets 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.

Trazodone hydrochloride tablets should not be used within 14 days of an MAOI [see Warnings and Precautions ( 5.8 ) and Drug Interactions ( 7 )].

If concomitant treatment with trazodone hydrochloride tablets and an SSRI, SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

The concomitant use of trazodone hydrochloride tablets with serotonin precursors (such as tryptophan) is not recommended.

5.3 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania 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 for clinical worsening and suicide risk 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 trazodone hydrochloride tablets are not approved for use in treating bipolar depression.

5.4 QT Prolongation and Risk of Sudden Death Trazodone is known to prolong the QT/QT c interval.

Some drugs that prolong the QT/QT c interval can cause torsade de pointes with sudden, unexplained death.

The relationship of QT prolongation is clearest for larger increases (20 msec and greater), but it is possible that smaller QT/QT c prolongations may also increase risk, especially in susceptible individuals, such as those with hypokalemia, hypomagnesemia, or a genetic predisposition to prolonged QT/QT c .

Although torsade de pointes has not been observed with the use of trazodone hydrochloride tablets at recommended doses in premarketing trials, experience is too limited to rule out an increased risk.

However, there have been postmarketing reports of torsade de pointes with the immediate-release form of trazodone (in the presence of multiple confounding factors), even at doses of 100 mg per day or less.

5.5 Use in Patients With Heart Disease Trazodone hydrochloride is not recommended for use during the initial recovery phase of myocardial infarction.

Caution should be used when administering trazodone hydrochloride tablets to patients with cardiac disease and such patients should be closely monitored, since antidepressant drugs (including trazodone hydrochloride) may cause cardiac arrhythmias.

QT prolongation has been reported with trazodone therapy [see Warnings and Precautions (5.4)] .

Clinical studies in patients with preexisting cardiac disease indicate that trazodone hydrochloride may be arrhythmogenic in some patients in that population.

Arrhythmias identified include isolated PVCs, ventricular couplets, tachycardia with syncope, and torsade de pointes.

Postmarketing events have been reported at doses of 100 mg or less with the immediate-release form of trazodone.

Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia.

5.6 Orthostatic Hypotension and Syncope Hypotension, including orthostatic hypotension and syncope has been reported in patients receiving trazodone hydrochloride.

Concomitant use with an antihypertensive may require a reduction in the dose of the antihypertensive drug.

5.7 Abnormal Bleeding Postmarketing data have shown an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal (GI) bleeding.

While no association between trazodone and bleeding events, in particular GI bleeding, was shown, patients should be cautioned about potential risk of bleeding associated with the concomitant use of trazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.

Other bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

5.8 Interaction With MAOIs In patients receiving serotonergic drugs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal reactions including hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuation in vital signs, and mental status changes that include extreme agitation progressing to delirium and coma.

These reactions have also been reported in patients who have recently discontinued antidepressant treatment and have been started on an MAOI.

Some cases presented with features resembling neuroleptic malignant syndrome.

Furthermore, limited animal data on the effects of combined use of serotonergic antidepressants and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation.

Therefore, it is recommended that trazodone hydrochloride tablets should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI.

Similarly, at least 14 days should be allowed after stopping trazodone hydrochloride tablets before starting an MAOI.

5.9 Priapism Rare cases of priapism (painful erections greater than 6 hours in duration) were reported in men receiving trazodone.

Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue.

Men who have an erection lasting greater than 6 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention [see Adverse Reactions ( 6.2 ) and Overdosage ( 10 )].

Trazodone should be used with caution in men who have conditions that might predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia), or in men with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease).

5.10 Hyponatremia Hyponatremia may occur as a result of treatment with antidepressants.

In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Cases with serum sodium lower than 110 mmol/L have been reported.

Elderly patients may be at greater risk of developing hyponatremia with antidepressants.

Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk.

Discontinuation of trazodone hydrochloride tablets should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls.

Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.11 Potential for Cognitive and Motor Impairment Trazodone hydrochloride tablets may cause somnolence or sedation and may impair the mental and/or physical ability required for the performance of potentially hazardous tasks.

Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely 5.12 Angle-Closure Glaucoma Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including trazodone hydrochloride tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy 5.13 Discontinuation Symptoms Withdrawal symptoms including anxiety, agitation and sleep disturbances, have been reported with trazodone.

Clinical experience suggests that the dose should be gradually reduced before complete discontinuation of the treatment.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Agranulocytosis : If sore throat, fever, stomatitis or signs of infection occur, along with a low white blood cell count, treatment with REMERON/REMERONSolTab should be discontinued and the patient should be closely monitored.

( 5.2 ) Serotonin Syndrome : Increased risk when co-administered with other serotonergic drugs (e.g., SSRI, SNRI, triptans), but also when taken alone.

If it occurs, discontinue REMERON/REMERONSolTab and initiate supportive treatment.

( 2.4 , 4 , 5.3 , 7 ) Angle-Closure Glaucoma : Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants.

( 5.4 ) QT Prolongation : Use REMERON/REMERONSolTab with caution in patients with risk factors for QT prolongation.

( 5.5 , 7 ) Increased Appetite/Weight Gain : REMERON/REMERONSolTab has been associated with increased appetite and weight gain.

( 5.6 ) Somnolence : May impair judgment, thinking and/or motor skills.

Use with caution when engaging in activities requiring alertness, such as driving or operating machinery.

( 5.7 , 7 ) Activation of Mania/Hypomania : Screen patients for bipolar disorder prior to initiating treatment.

( 2.3 , 5.8 ) Seizures : Use with caution in patients with a seizure disorder.

( 5.9 ) Elevated Cholesterol/Triglycerides : Has been reported with REMERON use.

( 5.10 ) Hyponatremia : May occur as a result of treatment with serotonergic antidepressants, including REMERON/REMERONSolTab.

( 5.11 ) Transaminase Elevations : Clinically significant elevations have occurred.

Use with caution in patients with impaired hepatic function.

( 5.12 ) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients.

There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied.

There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD.

The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1.

Table 1: Risk Differences of the Number of Patients with Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18–24 years old 5 additional patients Decreases Compared to Placebo 25–64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months.

However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication of clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes.

Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider.

Consider changing the therapeutic regimen, including possibly discontinuing REMERON/REMERONSolTab, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Agranulocytosis In premarketing clinical trials, 2 (1 with Sjögren’s Syndrome) out of 2796 patients treated with REMERON developed agranulocytosis [absolute neutrophil count (ANC) <500/mm 3 with associated signs and symptoms, e.g., fever, infection, etc.] and a third patient developed severe neutropenia (ANC <500/mm 3 without any associated symptoms).

For these 3 patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively.

All 3 patients recovered after REMERON was stopped.

If a patient develops a sore throat, fever, stomatitis, or other signs of infection, along with a low white blood cell (WBC) count, treatment with REMERON/REMERONSolTab should be discontinued and the patient should be closely monitored.

5.3 Serotonin Syndrome Serotonergic antidepressants, including REMERON/REMERONSolTab, can precipitate serotonin syndrome, a potentially life-threatening condition.

The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St.

John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4) , Drug Interactions (7) ] .

Serotonin syndrome can also occur when these drugs are used alone.

Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of REMERON/REMERONSolTab with MAOIs is contraindicated.

In addition, do not initiate REMERON/REMERONSolTab in a patient being treated with MAOIs such as linezolid or intravenous methylene blue.

No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection).

If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking REMERON/REMERONSolTab, discontinue REMERON/REMERONSolTab before initiating treatment with the MAOI [see Contraindications (4) , Drug Interactions (7) ] .

Monitor all patients taking REMERON/REMERONSolTab for the emergence of serotonin syndrome.

Discontinue treatment with REMERON/REMERONSolTab and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment.

If concomitant use of REMERON/REMERONSolTab with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.4 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs, including REMERON/REMERONSolTab, may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.5 QT Prolongation and Torsades de Pointes The effect of REMERON (mirtazapine) on QTc interval was assessed in a clinical randomized trial with placebo and positive (moxifloxacin) controls involving 54 healthy volunteers using exposure response analysis.

This trial showed a positive relationship between mirtazapine concentrations and prolongation of the QTc interval.

However, the degree of QT prolongation observed with both 45 mg and 75 mg (1.67 times the maximum recommended daily dose) doses of mirtazapine was not at a level generally considered to be clinically meaningful.

During postmarketing use of mirtazapine, cases of QT prolongation, Torsades de Pointes, ventricular tachycardia, and sudden death, have been reported [see Adverse Reactions (6.1 , 6.2) ] .

The majority of reports occurred in association with overdose or in patients with other risk factors for QT prolongation, including concomitant use of QTc-prolonging medicines [see Drug Interactions (7) and Overdosage (10) ] .

Exercise caution when REMERON/REMERONSolTab is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other drugs thought to prolong the QTc interval.

5.6 Increased Appetite and Weight Gain In U.S.

controlled clinical studies, appetite increase was reported in 17% of patients treated with REMERON, compared to 2% for placebo.

In these same trials, weight gain of ≥7% of body weight was reported in 7.5% of patients treated with mirtazapine, compared to 0% for placebo.

In a pool of premarketing U.S.

clinical studies, including many patients for long-term, open-label treatment, 8% of patients receiving REMERON discontinued for weight gain.

In an 8-week-long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of REMERON-treated pediatric patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients.

The safety and effectiveness of REMERON/REMERONSolTab in pediatric patients with MDD have not been established [see Use in Specific Populations (8.4) ] .

5.7 Somnolence In U.S.

controlled studies, somnolence was reported in 54% of patients treated with REMERON, compared to 18% for placebo.

In these studies, somnolence resulted in discontinuation for 10.4% of REMERON-treated patients, compared to 2.2% for placebo.

It is unclear whether tolerance develops to the somnolent effects of REMERON/REMERONSolTab.

Because of the potentially significant effects of REMERON/REMERONSolTab on impairment of performance, caution patients about engaging in activities that require alertness, including operating hazardous machinery and motor vehicles, until they are reasonably certain that REMERON/REMERONSolTab does not affect them adversely.

The concomitant use of benzodiazepines and alcohol with REMERON/REMERONSolTab should be avoided [see Drug Interactions (7) ] .

5.8 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with REMERON/REMERONSolTab or another antidepressant may precipitate a mixed/manic episode.

In controlled clinical trials, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.2% of patients treated with REMERON.

Prior to initiating treatment with REMERON/REMERONSolTab, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

5.9 Seizures REMERON/REMERONSolTab has not been systematically evaluated in patients with seizure disorders.

In premarketing clinical trials, 1 seizure was reported among the 2796 U.S.

and non-U.S.

patients treated with REMERON.

REMERON/REMERONSolTab should be prescribed with caution in patients with a seizure disorder.

5.10 Elevated Cholesterol and Triglycerides In U.S.

controlled studies, nonfasting cholesterol increases to ≥20% above the upper limits of normal were observed in 15% of patients treated with REMERON, compared to 7% for placebo.

In these same studies, nonfasting triglyceride increases to ≥500 mg/dL were observed in 6% of patients treated with REMERON, compared to 3% for placebo.

5.11 Hyponatremia Hyponatremia may occur as a result of treatment with serotonergic antidepressants, including REMERON/REMERONSolTab.

Cases with serum sodium lower than 110 mmol/L have been reported.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.

Signs and symptoms associated with more severe or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

In patients with symptomatic hyponatremia, discontinue REMERON/REMERONSolTab and institute appropriate medical intervention.

Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia [see Use in Specific Populations (8.5) ] .

5.12 Transaminase Elevations Clinically significant ALT (SGPT) elevations (≥3 times the upper limit of the normal range) were observed in 2.0% (8/424) of patients treated with REMERON in a pool of short-term, U.S.

controlled trials, compared to 0.3% (1/328) of placebo patients.

While some patients were discontinued for the ALT increases, in other cases, the enzyme levels returned to normal despite continued REMERON treatment.

REMERON/REMERONSolTab should be used with caution in patients with impaired hepatic function [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] .

5.13 Discontinuation Syndrome There have been reports of adverse reactions upon the discontinuation of REMERON/REMERONSolTab (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paresthesia and electric shock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting, and sweating, or other symptoms which may be of clinical significance.

A gradual reduction in the dosage, rather than an abrupt cessation, is recommended [see Dosage and Administration (2.6) ].

5.14 Use in Patients with Concomitant Illness REMERON/REMERONSolTab has not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease.

REMERON was associated with significant orthostatic hypotension in early clinical pharmacology trials with normal volunteers.

Orthostatic hypotension was infrequently observed in clinical trials with depressed patients [see Adverse Reactions (6.1) ] .

REMERON/REMERONSolTab should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke) and conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication).

5.15 Risks in Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU).

REMERONSolTab contains phenylalanine, a component of aspartame.

REMERONSolTab contains the following amount of phenylalanine: 2.6 mg in 15 mg orally disintegrating tablet, 5.2 mg in 30 mg orally disintegrating tablet, and 7.8 mg in 45 mg orally disintegrating tablet.

Before prescribing REMERONSolTab to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including REMERONSolTab.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Clinical Worsening/Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior ( 5.1 ).

• Serotonin Syndrome or Neuroleptic Malignant Syndrome-Like Reactions: Have been reported with antidepressants.

Discontinue trazodone hydrochloride tablets and initiate supportive treatment ( 5.2 , 7 ).

• Activation of Mania/Hypomania: Screen for bipolar disorder and monitor for mania/hypomania ( 5.3 ).

• QT Prolongation: Increases the QT interval.

Avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval ( 5.4 ).

• Use in Patients With Heart Disease: Use with caution in patients with cardiac disease ( 5.5 ).

• Orthostatic Hypotension and Syncope: Have occurred.

Warn patients of risk and symptoms of hypotension ( 5.6 ).

• Abnormal Bleeding: May increase the risk of bleeding.

Use with NSAIDs, aspirin, or other drugs that affect coagulation may compound this risk ( 5.7 , 7 ).

• Interaction With MAOIs: Do not use concomitantly or within 14 days of monoamine oxidase inhibitors ( 5.8 , 7 ).

• Priapism: Has occurred.

Warn male patients of this risk and how/when to seek medical attention ( 5.9 ).

• Hyponatremia: Can occur in association with SIADH ( 5.10 ).

• Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills.

Advise patients to use caution when operating machinery ( 5.11 ).

• Angle-Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants.

( 5.12 ) • Discontinuation Symptoms: May occur with abrupt discontinuation and include anxiety and sleep disturbance.

Upon discontinuation, taper trazodone hydrochloride tablets and monitor for symptoms ( 5.13 ).

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 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 4,400 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 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 1,000 patients treated) are provided in Table 1 .

Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 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.

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 healthcare providers .

Such monitoring should include daily observation by families and caregivers .

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

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 antidepressants alone and may occur with trazodone treatment, but particularly with concomitant use of other serotoninergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs]), or with antipsychotics or other dopamine antagonists.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and 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.

Treatment with trazodone hydrochloride tablets 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.

Trazodone hydrochloride tablets should not be used within 14 days of an MAOI [see Warnings and Precautions ( 5.8 ) and Drug Interactions ( 7 )].

If concomitant treatment with trazodone hydrochloride tablets and an SSRI, SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

The concomitant use of trazodone hydrochloride tablets with serotonin precursors (such as tryptophan) is not recommended.

5.3 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania 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 for clinical worsening and suicide risk 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 trazodone hydrochloride tablets are not approved for use in treating bipolar depression.

5.4 QT Prolongation and Risk of Sudden Death Trazodone is known to prolong the QT/QT c interval.

Some drugs that prolong the QT/QT c interval can cause torsade de pointes with sudden, unexplained death.

The relationship of QT prolongation is clearest for larger increases (20 msec and greater), but it is possible that smaller QT/QT c prolongations may also increase risk, especially in susceptible individuals, such as those with hypokalemia, hypomagnesemia, or a genetic predisposition to prolonged QT/QT c .

Although torsade de pointes has not been observed with the use of trazodone hydrochloride tablets at recommended doses in premarketing trials, experience is too limited to rule out an increased risk.

However, there have been postmarketing reports of torsade de pointes with the immediate-release form of trazodone (in the presence of multiple confounding factors), even at doses of 100 mg per day or less.

5.5 Use in Patients With Heart Disease Trazodone hydrochloride is not recommended for use during the initial recovery phase of myocardial infarction.

Caution should be used when administering trazodone hydrochloride tablets to patients with cardiac disease and such patients should be closely monitored, since antidepressant drugs (including trazodone hydrochloride) may cause cardiac arrhythmias.

QT prolongation has been reported with trazodone therapy [see Warnings and Precautions (5.4)] .

Clinical studies in patients with preexisting cardiac disease indicate that trazodone hydrochloride may be arrhythmogenic in some patients in that population.

Arrhythmias identified include isolated PVCs, ventricular couplets, tachycardia with syncope, and torsade de pointes.

Postmarketing events have been reported at doses of 100 mg or less with the immediate-release form of trazodone.

Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia.

5.6 Orthostatic Hypotension and Syncope Hypotension, including orthostatic hypotension and syncope has been reported in patients receiving trazodone hydrochloride.

Concomitant use with an antihypertensive may require a reduction in the dose of the antihypertensive drug.

5.7 Abnormal Bleeding Postmarketing data have shown an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal (GI) bleeding.

While no association between trazodone and bleeding events, in particular GI bleeding, was shown, patients should be cautioned about potential risk of bleeding associated with the concomitant use of trazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.

Other bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

5.8 Interaction With MAOIs In patients receiving serotonergic drugs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal reactions including hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuation in vital signs, and mental status changes that include extreme agitation progressing to delirium and coma.

These reactions have also been reported in patients who have recently discontinued antidepressant treatment and have been started on an MAOI.

Some cases presented with features resembling neuroleptic malignant syndrome.

Furthermore, limited animal data on the effects of combined use of serotonergic antidepressants and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation.

Therefore, it is recommended that trazodone hydrochloride tablets should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI.

Similarly, at least 14 days should be allowed after stopping trazodone hydrochloride tablets before starting an MAOI.

5.9 Priapism Rare cases of priapism (painful erections greater than 6 hours in duration) were reported in men receiving trazodone.

Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue.

Men who have an erection lasting greater than 6 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention [see Adverse Reactions ( 6.2 ) and Overdosage ( 10 )].

Trazodone should be used with caution in men who have conditions that might predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia), or in men with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease).

5.10 Hyponatremia Hyponatremia may occur as a result of treatment with antidepressants.

In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Cases with serum sodium lower than 110 mmol/L have been reported.

Elderly patients may be at greater risk of developing hyponatremia with antidepressants.

Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk.

Discontinuation of trazodone hydrochloride tablets should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls.

Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.11 Potential for Cognitive and Motor Impairment Trazodone hydrochloride tablets may cause somnolence or sedation and may impair the mental and/or physical ability required for the performance of potentially hazardous tasks.

Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely 5.12 Angle-Closure Glaucoma Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including trazodone hydrochloride tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy 5.13 Discontinuation Symptoms Withdrawal symptoms including anxiety, agitation and sleep disturbances, have been reported with trazodone.

Clinical experience suggests that the dose should be gradually reduced before complete discontinuation of the treatment.

WARNING AND CAUTIONS

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.

Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults: Monitor for clinical worsening and suicidal thinking and behavior ( 5.1 ) Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including fluoxetine, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St.

John’s Wort).

If such symptoms occur, discontinue fluoxetine and initiate supportive treatment.

If concomitant use of fluoxetine with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases ( 5.2 ) Allergic Reactions and Rash: Discontinue upon appearance of rash or allergic phenomena ( 5.3 ) Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania ( 5.4 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold ( 5.5 ) Altered Appetite and Weight: Significant weight loss has occurred ( 5.6 ) Abnormal Bleeding: May increase the risk of bleeding.

Use with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding ( 5.7 ) Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.8 ) Hyponatremia: Has been reported with fluoxetine in association with syndrome of inappropriate antidiuretic hormone (SIADH).

Consider discontinuing if symptomatic hyponatremia occurs ( 5.9 ) Anxiety and Insomnia: May occur ( 5.10 ) QT Prolongation: QT prolongation and ventricular arrhythmia including Torsades de Pointes have been reported with fluoxetine use.

Use with caution in conditions that predispose to arrhythmias or increased fluoxetine exposure.

Use cautiously in patients with risk factors for QT prolongation ( 4.2 , 5.11 ) Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills.

Use caution when operating machinery ( 5.13 ) Long Half-Life: Changes in dose will not be fully reflected in plasma for several weeks ( 5.14 ) Fluoxetine and Olanzapine in Combination: When using fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax ( 5.16 ) 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 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 ( 5.15 ) ] .

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 healthcare providers.

Such monitoring should include daily observation by families and caregivers.

Prescriptions for fluoxetine capsules 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 for Major Depressive Disorder and Obsessive Compulsive Disorder; and fluoxetine in combination with olanzapine for the acute treatment of depressive episodes associated with Bipolar I Disorder.

5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including fluoxetine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St.

John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of fluoxetine with MAOIs intended to treat psychiatric disorders is contraindicated.

Fluoxetine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue.

All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg.

No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses.

There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking fluoxetine.

Fluoxetine should be discontinued before initiating treatment with the MAOI [see Contraindications ( 4.1 ) and Dosage and Administration (2.9 , 2.10)].

If concomitant use of fluoxetine with other serotonergic drugs, i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St.

John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with fluoxetine and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

5.3 Allergic Reactions and Rash In U.S.

fluoxetine clinical trials, 7% of 10,782 patients developed various types of rashes and/or urticaria.

Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash.

Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation.

Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these reactions were reported to recover completely.

In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness.

In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme.

Other patients have had systemic syndromes suggestive of serum sickness.

Since the introduction of fluoxetine, systemic reactions, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash.

Although these reactions are rare, they may be serious, involving the lung, kidney, or liver.

Death has been reported to occur in association with these systemic reactions.

Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported.

Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely.

These reactions have occurred with dyspnea as the only preceding symptom.

Whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known.

Furthermore, a specific underlying immunologic basis for these reactions has not been identified.

Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, fluoxetine should be discontinued.

5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania 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 for clinical worsening and suicide risk 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 fluoxetine and olanzapine in combination is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder [ see Warnings and Precautions section of the package insert for Symbyax ].

Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

In U.S.

placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patients treated with fluoxetine and 0.1% of patients treated with placebo.

Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of Major Depressive Disorder [ see Use in Specific Populations ( 8.4 ) ] .

In U.S.

placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with fluoxetine and no patients treated with placebo.

No patients reported mania/hypomania in U.S.

placebo-controlled clinical trials for bulimia.

In U.S.

fluoxetine clinical trials, 0.7% of 10,782 patients reported mania/hypomania [ see Use in Specific Populations ( 8.4 ) ] .

5.5 Seizures In U.S.

placebo-controlled clinical trials for Major Depressive Disorder, convulsions (or reactions described as possibly having been seizures) were reported in 0.1% of patients treated with fluoxetine and 0.2% of patients treated with placebo.

No patients reported convulsions in U.S.

placebo-controlled clinical trials for either OCD or bulimia.

In U.S.

fluoxetine clinical trials, 0.2% of 10,782 patients reported convulsions.

The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of Major Depressive Disorder.

Fluoxetine should be introduced with care in patients with a history of seizures.

5.6 Altered Appetite and Weight Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with fluoxetine.

In U.S.

placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with fluoxetine and 2% of patients treated with placebo reported anorexia (decreased appetite).

Weight loss was reported in 1.4% of patients treated with fluoxetine and in 0.5% of patients treated with placebo.

However, only rarely have patients discontinued treatment with fluoxetine because of anorexia or weight loss [ see Use in Specific Populations ( 8.4 ) ] .

In U.S.

placebo-controlled clinical trials for OCD, 17% of patients treated with fluoxetine and 10% of patients treated with placebo reported anorexia (decreased appetite).

One patient discontinued treatment with fluoxetine because of anorexia [ see Use in Specific Populations ( 8.4 ) ] .

In U.S.

placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with fluoxetine 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite).

Patients treated with fluoxetine 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial.

Weight change should be monitored during therapy.

5.7 Abnormal Bleeding SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions.

Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk.

Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding.

Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [ see Drug Interactions ( 7.4 ) ] .

5.8 Angle-Closure Glaucoma Angle-Closure Glaucoma — The pupillary dilation that occurs following use of many antidepressant drugs including fluoxetine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.9 Hyponatremia Hyponatremia has been reported during treatment with SNRIs and SSRIs, including fluoxetine.

In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when fluoxetine was discontinued.

Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs.

Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [ see Use in Specific Populations ( 8.5 ) ] .

Discontinuation of fluoxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.

More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.10 Anxiety and Insomnia In U.S.

placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with fluoxetine and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia.

In U.S.

placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with fluoxetine and in 22% of patients treated with placebo.

Anxiety was reported in 14% of patients treated with fluoxetine and in 7% of patients treated with placebo.

In U.S.

placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with fluoxetine 60 mg, and 13% of patients treated with placebo.

Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with fluoxetine 60 mg and in 9% and 5% of patients treated with placebo.

Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only a primary reaction associated with discontinuation) in U.S.

placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder) [see Table 5] .

5.11 QT Prolongation Post-marketing cases of QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with fluoxetine.

Fluoxetine should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia.

Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs).

Fluoxetine is primarily metabolized by CYP2D6 [see Contraindications ( 4.2 ), Adverse Reactions ( 6.2 ), Drug Interactions ( 7.7 , 7.8 ), Overdosage ( 10.1 ), and Clinical Pharmacology ( 12.3 )] .

Pimozide and thioridazine are contraindicated for use with fluoxetine.

Avoid the concomitant use of drugs known to prolong the QT interval.

These include specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol,); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Drug Interactions ( 7.7 , 7.8 ) and Clinical Pharmacology ( 12.3 )].

Consider ECG assessment and periodic ECG monitoring if initiating treatment with fluoxetine in patients with risk factors for QT prolongation and ventricular arrhythmia.

Consider discontinuing fluoxetine and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia.

5.12 Use in Patients with Concomitant Illness Clinical experience with fluoxetine in patients with concomitant systemic illness is limited.

Caution is advisable in using fluoxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Cardiovascular — Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease.

Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing.

However, the electrocardiograms of 312 patients who received fluoxetine in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed.

The mean heart rate was reduced by approximately 3 beats/min.

Glycemic Control — In patients with diabetes, fluoxetine may alter glycemic control.

Hypoglycemia has occurred during therapy with fluoxetine, and hyperglycemia has developed following discontinuation of the drug.

As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with fluoxetine is instituted or discontinued.

5.13 Potential for Cognitive and Motor Impairment As with any CNS-active drug, fluoxetine has the potential to impair judgment, thinking, or motor skills.

Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.

5.14 Long Elimination Half-Life Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment.

This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine [ see Clinical Pharmacology ( 12.3 ) ] .

5.15 Discontinuation Adverse Reactions During marketing of fluoxetine, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania.

While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine.

A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.

If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.

Subsequently, the healthcare provider may continue decreasing the dose but at a more gradual rate.

Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug.

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

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Agranulocytosis : If sore throat, fever, stomatitis or signs of infection occur, along with a low white blood cell count, treatment with REMERON/REMERONSolTab should be discontinued and the patient should be closely monitored.

( 5.2 ) Serotonin Syndrome : Increased risk when co-administered with other serotonergic drugs (e.g., SSRI, SNRI, triptans), but also when taken alone.

If it occurs, discontinue REMERON/REMERONSolTab and initiate supportive treatment.

( 2.4 , 4 , 5.3 , 7 ) Angle-Closure Glaucoma : Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants.

( 5.4 ) QT Prolongation : Use REMERON/REMERONSolTab with caution in patients with risk factors for QT prolongation.

( 5.5 , 7 ) Increased Appetite/Weight Gain : REMERON/REMERONSolTab has been associated with increased appetite and weight gain.

( 5.6 ) Somnolence : May impair judgment, thinking and/or motor skills.

Use with caution when engaging in activities requiring alertness, such as driving or operating machinery.

( 5.7 , 7 ) Activation of Mania/Hypomania : Screen patients for bipolar disorder prior to initiating treatment.

( 2.3 , 5.8 ) Seizures : Use with caution in patients with a seizure disorder.

( 5.9 ) Elevated Cholesterol/Triglycerides : Has been reported with REMERON use.

( 5.10 ) Hyponatremia : May occur as a result of treatment with serotonergic antidepressants, including REMERON/REMERONSolTab.

( 5.11 ) Transaminase Elevations : Clinically significant elevations have occurred.

Use with caution in patients with impaired hepatic function.

( 5.12 ) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients.

There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied.

There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD.

The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1.

Table 1: Risk Differences of the Number of Patients with Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18–24 years old 5 additional patients Decreases Compared to Placebo 25–64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months.

However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication of clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes.

Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider.

Consider changing the therapeutic regimen, including possibly discontinuing REMERON/REMERONSolTab, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Agranulocytosis In premarketing clinical trials, 2 (1 with Sjögren’s Syndrome) out of 2796 patients treated with REMERON developed agranulocytosis [absolute neutrophil count (ANC) <500/mm 3 with associated signs and symptoms, e.g., fever, infection, etc.] and a third patient developed severe neutropenia (ANC <500/mm 3 without any associated symptoms).

For these 3 patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively.

All 3 patients recovered after REMERON was stopped.

If a patient develops a sore throat, fever, stomatitis, or other signs of infection, along with a low white blood cell (WBC) count, treatment with REMERON/REMERONSolTab should be discontinued and the patient should be closely monitored.

5.3 Serotonin Syndrome Serotonergic antidepressants, including REMERON/REMERONSolTab, can precipitate serotonin syndrome, a potentially life-threatening condition.

The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St.

John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4) , Drug Interactions (7) ] .

Serotonin syndrome can also occur when these drugs are used alone.

Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of REMERON/REMERONSolTab with MAOIs is contraindicated.

In addition, do not initiate REMERON/REMERONSolTab in a patient being treated with MAOIs such as linezolid or intravenous methylene blue.

No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection).

If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking REMERON/REMERONSolTab, discontinue REMERON/REMERONSolTab before initiating treatment with the MAOI [see Contraindications (4) , Drug Interactions (7) ] .

Monitor all patients taking REMERON/REMERONSolTab for the emergence of serotonin syndrome.

Discontinue treatment with REMERON/REMERONSolTab and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment.

If concomitant use of REMERON/REMERONSolTab with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.4 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs, including REMERON/REMERONSolTab, may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.5 QT Prolongation and Torsades de Pointes The effect of REMERON (mirtazapine) on QTc interval was assessed in a clinical randomized trial with placebo and positive (moxifloxacin) controls involving 54 healthy volunteers using exposure response analysis.

This trial showed a positive relationship between mirtazapine concentrations and prolongation of the QTc interval.

However, the degree of QT prolongation observed with both 45 mg and 75 mg (1.67 times the maximum recommended daily dose) doses of mirtazapine was not at a level generally considered to be clinically meaningful.

During postmarketing use of mirtazapine, cases of QT prolongation, Torsades de Pointes, ventricular tachycardia, and sudden death, have been reported [see Adverse Reactions (6.1 , 6.2) ] .

The majority of reports occurred in association with overdose or in patients with other risk factors for QT prolongation, including concomitant use of QTc-prolonging medicines [see Drug Interactions (7) and Overdosage (10) ] .

Exercise caution when REMERON/REMERONSolTab is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other drugs thought to prolong the QTc interval.

5.6 Increased Appetite and Weight Gain In U.S.

controlled clinical studies, appetite increase was reported in 17% of patients treated with REMERON, compared to 2% for placebo.

In these same trials, weight gain of ≥7% of body weight was reported in 7.5% of patients treated with mirtazapine, compared to 0% for placebo.

In a pool of premarketing U.S.

clinical studies, including many patients for long-term, open-label treatment, 8% of patients receiving REMERON discontinued for weight gain.

In an 8-week-long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of REMERON-treated pediatric patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients.

The safety and effectiveness of REMERON/REMERONSolTab in pediatric patients with MDD have not been established [see Use in Specific Populations (8.4) ] .

5.7 Somnolence In U.S.

controlled studies, somnolence was reported in 54% of patients treated with REMERON, compared to 18% for placebo.

In these studies, somnolence resulted in discontinuation for 10.4% of REMERON-treated patients, compared to 2.2% for placebo.

It is unclear whether tolerance develops to the somnolent effects of REMERON/REMERONSolTab.

Because of the potentially significant effects of REMERON/REMERONSolTab on impairment of performance, caution patients about engaging in activities that require alertness, including operating hazardous machinery and motor vehicles, until they are reasonably certain that REMERON/REMERONSolTab does not affect them adversely.

The concomitant use of benzodiazepines and alcohol with REMERON/REMERONSolTab should be avoided [see Drug Interactions (7) ] .

5.8 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with REMERON/REMERONSolTab or another antidepressant may precipitate a mixed/manic episode.

In controlled clinical trials, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.2% of patients treated with REMERON.

Prior to initiating treatment with REMERON/REMERONSolTab, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

5.9 Seizures REMERON/REMERONSolTab has not been systematically evaluated in patients with seizure disorders.

In premarketing clinical trials, 1 seizure was reported among the 2796 U.S.

and non-U.S.

patients treated with REMERON.

REMERON/REMERONSolTab should be prescribed with caution in patients with a seizure disorder.

5.10 Elevated Cholesterol and Triglycerides In U.S.

controlled studies, nonfasting cholesterol increases to ≥20% above the upper limits of normal were observed in 15% of patients treated with REMERON, compared to 7% for placebo.

In these same studies, nonfasting triglyceride increases to ≥500 mg/dL were observed in 6% of patients treated with REMERON, compared to 3% for placebo.

5.11 Hyponatremia Hyponatremia may occur as a result of treatment with serotonergic antidepressants, including REMERON/REMERONSolTab.

Cases with serum sodium lower than 110 mmol/L have been reported.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.

Signs and symptoms associated with more severe or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

In patients with symptomatic hyponatremia, discontinue REMERON/REMERONSolTab and institute appropriate medical intervention.

Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia [see Use in Specific Populations (8.5) ] .

5.12 Transaminase Elevations Clinically significant ALT (SGPT) elevations (≥3 times the upper limit of the normal range) were observed in 2.0% (8/424) of patients treated with REMERON in a pool of short-term, U.S.

controlled trials, compared to 0.3% (1/328) of placebo patients.

While some patients were discontinued for the ALT increases, in other cases, the enzyme levels returned to normal despite continued REMERON treatment.

REMERON/REMERONSolTab should be used with caution in patients with impaired hepatic function [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] .

5.13 Discontinuation Syndrome There have been reports of adverse reactions upon the discontinuation of REMERON/REMERONSolTab (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paresthesia and electric shock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting, and sweating, or other symptoms which may be of clinical significance.

A gradual reduction in the dosage, rather than an abrupt cessation, is recommended [see Dosage and Administration (2.6) ].

5.14 Use in Patients with Concomitant Illness REMERON/REMERONSolTab has not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease.

REMERON was associated with significant orthostatic hypotension in early clinical pharmacology trials with normal volunteers.

Orthostatic hypotension was infrequently observed in clinical trials with depressed patients [see Adverse Reactions (6.1) ] .

REMERON/REMERONSolTab should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke) and conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication).

5.15 Risks in Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU).

REMERONSolTab contains phenylalanine, a component of aspartame.

REMERONSolTab contains the following amount of phenylalanine: 2.6 mg in 15 mg orally disintegrating tablet, 5.2 mg in 30 mg orally disintegrating tablet, and 7.8 mg in 45 mg orally disintegrating tablet.

Before prescribing REMERONSolTab to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including REMERONSolTab.

WARNING AND CAUTIONS

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.

Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults: Monitor for clinical worsening and suicidal thinking and behavior ( 5.1 ) Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including fluoxetine, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St.

John’s Wort).

If such symptoms occur, discontinue fluoxetine and initiate supportive treatment.

If concomitant use of fluoxetine with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases ( 5.2 ) Allergic Reactions and Rash: Discontinue upon appearance of rash or allergic phenomena ( 5.3 ) Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania ( 5.4 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold ( 5.5 ) Altered Appetite and Weight: Significant weight loss has occurred ( 5.6 ) Abnormal Bleeding: May increase the risk of bleeding.

Use with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding ( 5.7 ) Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.8 ) Hyponatremia: Has been reported with fluoxetine in association with syndrome of inappropriate antidiuretic hormone (SIADH).

Consider discontinuing if symptomatic hyponatremia occurs ( 5.9 ) Anxiety and Insomnia: May occur ( 5.10 ) QT Prolongation: QT prolongation and ventricular arrhythmia including Torsades de Pointes have been reported with fluoxetine use.

Use with caution in conditions that predispose to arrhythmias or increased fluoxetine exposure.

Use cautiously in patients with risk factors for QT prolongation ( 4.2 , 5.11 ) Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills.

Use caution when operating machinery ( 5.13 ) Long Half-Life: Changes in dose will not be fully reflected in plasma for several weeks ( 5.14 ) Fluoxetine and Olanzapine in Combination: When using fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax ( 5.16 ) 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 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 ( 5.15 ) ] .

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 healthcare providers.

Such monitoring should include daily observation by families and caregivers.

Prescriptions for fluoxetine capsules 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 for Major Depressive Disorder and Obsessive Compulsive Disorder; and fluoxetine in combination with olanzapine for the acute treatment of depressive episodes associated with Bipolar I Disorder.

5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including fluoxetine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St.

John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of fluoxetine with MAOIs intended to treat psychiatric disorders is contraindicated.

Fluoxetine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue.

All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg.

No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses.

There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking fluoxetine.

Fluoxetine should be discontinued before initiating treatment with the MAOI [see Contraindications ( 4.1 ) and Dosage and Administration (2.9 , 2.10)].

If concomitant use of fluoxetine with other serotonergic drugs, i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St.

John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with fluoxetine and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

5.3 Allergic Reactions and Rash In U.S.

fluoxetine clinical trials, 7% of 10,782 patients developed various types of rashes and/or urticaria.

Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash.

Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation.

Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these reactions were reported to recover completely.

In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness.

In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme.

Other patients have had systemic syndromes suggestive of serum sickness.

Since the introduction of fluoxetine, systemic reactions, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash.

Although these reactions are rare, they may be serious, involving the lung, kidney, or liver.

Death has been reported to occur in association with these systemic reactions.

Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported.

Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely.

These reactions have occurred with dyspnea as the only preceding symptom.

Whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known.

Furthermore, a specific underlying immunologic basis for these reactions has not been identified.

Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, fluoxetine should be discontinued.

5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania 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 for clinical worsening and suicide risk 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 fluoxetine and olanzapine in combination is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder [ see Warnings and Precautions section of the package insert for Symbyax ].

Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

In U.S.

placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patients treated with fluoxetine and 0.1% of patients treated with placebo.

Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of Major Depressive Disorder [ see Use in Specific Populations ( 8.4 ) ] .

In U.S.

placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with fluoxetine and no patients treated with placebo.

No patients reported mania/hypomania in U.S.

placebo-controlled clinical trials for bulimia.

In U.S.

fluoxetine clinical trials, 0.7% of 10,782 patients reported mania/hypomania [ see Use in Specific Populations ( 8.4 ) ] .

5.5 Seizures In U.S.

placebo-controlled clinical trials for Major Depressive Disorder, convulsions (or reactions described as possibly having been seizures) were reported in 0.1% of patients treated with fluoxetine and 0.2% of patients treated with placebo.

No patients reported convulsions in U.S.

placebo-controlled clinical trials for either OCD or bulimia.

In U.S.

fluoxetine clinical trials, 0.2% of 10,782 patients reported convulsions.

The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of Major Depressive Disorder.

Fluoxetine should be introduced with care in patients with a history of seizures.

5.6 Altered Appetite and Weight Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with fluoxetine.

In U.S.

placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with fluoxetine and 2% of patients treated with placebo reported anorexia (decreased appetite).

Weight loss was reported in 1.4% of patients treated with fluoxetine and in 0.5% of patients treated with placebo.

However, only rarely have patients discontinued treatment with fluoxetine because of anorexia or weight loss [ see Use in Specific Populations ( 8.4 ) ] .

In U.S.

placebo-controlled clinical trials for OCD, 17% of patients treated with fluoxetine and 10% of patients treated with placebo reported anorexia (decreased appetite).

One patient discontinued treatment with fluoxetine because of anorexia [ see Use in Specific Populations ( 8.4 ) ] .

In U.S.

placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with fluoxetine 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite).

Patients treated with fluoxetine 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial.

Weight change should be monitored during therapy.

5.7 Abnormal Bleeding SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions.

Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk.

Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding.

Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [ see Drug Interactions ( 7.4 ) ] .

5.8 Angle-Closure Glaucoma Angle-Closure Glaucoma — The pupillary dilation that occurs following use of many antidepressant drugs including fluoxetine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.9 Hyponatremia Hyponatremia has been reported during treatment with SNRIs and SSRIs, including fluoxetine.

In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when fluoxetine was discontinued.

Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs.

Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [ see Use in Specific Populations ( 8.5 ) ] .

Discontinuation of fluoxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.

More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.10 Anxiety and Insomnia In U.S.

placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with fluoxetine and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia.

In U.S.

placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with fluoxetine and in 22% of patients treated with placebo.

Anxiety was reported in 14% of patients treated with fluoxetine and in 7% of patients treated with placebo.

In U.S.

placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with fluoxetine 60 mg, and 13% of patients treated with placebo.

Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with fluoxetine 60 mg and in 9% and 5% of patients treated with placebo.

Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only a primary reaction associated with discontinuation) in U.S.

placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder) [see Table 5] .

5.11 QT Prolongation Post-marketing cases of QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with fluoxetine.

Fluoxetine should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia.

Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs).

Fluoxetine is primarily metabolized by CYP2D6 [see Contraindications ( 4.2 ), Adverse Reactions ( 6.2 ), Drug Interactions ( 7.7 , 7.8 ), Overdosage ( 10.1 ), and Clinical Pharmacology ( 12.3 )] .

Pimozide and thioridazine are contraindicated for use with fluoxetine.

Avoid the concomitant use of drugs known to prolong the QT interval.

These include specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol,); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Drug Interactions ( 7.7 , 7.8 ) and Clinical Pharmacology ( 12.3 )].

Consider ECG assessment and periodic ECG monitoring if initiating treatment with fluoxetine in patients with risk factors for QT prolongation and ventricular arrhythmia.

Consider discontinuing fluoxetine and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia.

5.12 Use in Patients with Concomitant Illness Clinical experience with fluoxetine in patients with concomitant systemic illness is limited.

Caution is advisable in using fluoxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Cardiovascular — Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease.

Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing.

However, the electrocardiograms of 312 patients who received fluoxetine in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed.

The mean heart rate was reduced by approximately 3 beats/min.

Glycemic Control — In patients with diabetes, fluoxetine may alter glycemic control.

Hypoglycemia has occurred during therapy with fluoxetine, and hyperglycemia has developed following discontinuation of the drug.

As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with fluoxetine is instituted or discontinued.

5.13 Potential for Cognitive and Motor Impairment As with any CNS-active drug, fluoxetine has the potential to impair judgment, thinking, or motor skills.

Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.

5.14 Long Elimination Half-Life Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment.

This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine [ see Clinical Pharmacology ( 12.3 ) ] .

5.15 Discontinuation Adverse Reactions During marketing of fluoxetine, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania.

While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine.

A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.

If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.

Subsequently, the healthcare provider may continue decreasing the dose but at a more gradual rate.

Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug.

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

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Atypical antipsychotic drugs, including quetiapine, are associated with an increased risk of death; causes of death are variable.

( 5.1 ) Suicidality and Antidepressant Drugs: Increased the risk of suicidal thinking and behavior in children, adolescents and young adults taking antidepressants for major depressive disorder and other psychiatric disorders.

( 5.2 ) Neuroleptic Malignant Syndrome (NMS): Manage with immediate discontinuation and close monitoring.

( 5.3 ) Hyperglycemia and Diabetes Mellitus (DM): Ketoacidosis, hyperosmolar coma and death have been reported in patients treated with atypical antipsychotics, including quetiapine.

Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

When starting treatment, patients with diabetes or risk factors for diabetes should undergo blood glucose testing before and during treatment.

( 5.4 ) Hyperlipidemia: Undesirable alterations in lipids have been observed.

Increases in total cholesterol, LDL-cholesterol and triglycerides and decreases in HDL-cholesterol have been reported in clinical trials.

Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically during treatment.

( 5.5 ) Weight Gain: Patients should receive regular monitoring of weight.

( 5.6 ) Tardive Dyskinesia: Discontinue if clinically appropriate.

( 5.7 ) Orthostatic Hypotension: Associated dizziness, tachycardia and syncope may occur especially during the initial dose titration period.

( 5.8 ) Increased Blood Pressure in Children and Adolescents: Blood pressure should be measured at the beginning of, and periodically during treatment in children and adolescents.

( 5.9 ) Leukopenia, Neutropenia and Agranulocytosis have been reported with atypical antipsychotics including quetiapine fumarate tablets.

Patients with a pre-existing low white cell count (WBC) or a history of leukopenia/neutropenia should have complete blood count (CBC) monitored frequently during the first few months of treatment and should discontinue quetiapine fumarate at the first sign of a decline in WBC in absence of other causative factors.

( 5.10 ) Cataracts: Lens changes have been observed in patients during long-term quetiapine treatment.

Lens examination is recommended when starting treatment and at 6 month intervals during chronic treatment.

( 5.11 ) • QT Prolongation: Post-marketing case show increases in QT interval in patients who overdosed on quetiapine, in patients with concomitant illness, and in patients taking medicines know to cause electrolyte imbalance or increase QT interval.

Avoid use with drugs that increase the QT interval and in patients with risk factors for prolonged QT interval.

( 5.12 ) Suicide: The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder, and close supervision of high risk patients should accompany drug therapy.

( 5.21 ) See Full Prescribing Information for additional WARNINGS and PRECAUTIONS .

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Quetiapine fumarate tablets are not approved for the treatment of patients with dementia-related psychosis ( see Boxed Warning ).

5.2 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 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 18–24 5 additional cases Decreases Compared to Placebo 25–64 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.

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 healthcare providers.

Such monitoring should include daily observation by families and caregivers.

Prescriptions for quetiapine fumarate tablets should be written for the smallest quantity of tablets 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 quetiapine fumarate tablets are approved for use in treating adult bipolar depression.

5.3 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including quetiapine fumarate.

Rare cases of NMS have been reported with quetiapine fumarate.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).

Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated.

In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).

Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available.

There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.

The patient should be carefully monitored since recurrences of NMS have been reported.

5.4 Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including quetiapine.

Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population.

Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood.

However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.

Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment.

Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing.

In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose and lipids was observed in clinical studies.

Changes in these parameters should be managed as clinically appropriate.

Adults: Table 2: Fasting Glucose — Proportion of Patients Shifting to ≥ 126 mg/dL in Short-Term (≤ 12 weeks) Placebo-Controlled Studies Laboratory Analyte Category Change (At Least Once) from Baseline Treatment Arm N Patients n (%) Fasting Glucose Normal to High (<100 mg/dL to ≥ 126 mg/dL) Quetiapine 2907 71 (2.4%) Placebo 1346 19 (1.4%) Borderline to High (≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL) Quetiapine 572 67 (11.7%) Placebo 279 33 (11.8%) In a 24 week trial (active-controlled, 115 patients treated with quetiapine fumarate) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at week 24 the incidence of a treatment-emergent post-glucose challenge glucose level ≥ 200 mg/dL was 1.7% and the incidence of a fasting treatment-emergent blood glucose level ≥ 126 mg/dL was 2.6%.

The mean change in fasting glucose from baseline was 3.2 mg/dL and mean change in 2 hour glucose from baseline was -1.8 mg/dL for quetiapine.

In 2 long-term placebo-controlled randomized withdrawal clinical trials for bipolar maintenance, mean exposure of 213 days for quetiapine (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 mg/dL for quetiapine and –0.05 mg/dL for placebo.

The exposure-adjusted rate of any increased blood glucose level (≥ 126 mg/dL) for patients more than 8 hours since a meal (however, some patients may not have been precluded from calorie intake from fluids during fasting period) was 18.0 per 100 patient years for quetiapine (10.7% of patients; n=556) and 9.5 for placebo per 100 patient years (4.6% of patients; n=581).

Children and Adolescents: In a placebo-controlled quetiapine monotherapy study of adolescent patients (13 to 17 years of age) with schizophrenia (6 weeks duration), the mean change in fasting glucose levels for quetiapine (n=138) compared to placebo (n=67) was -0.75 mg/dL versus -1.70 mg/dL.

In a placebo controlled quetiapine monotherapy study of children and adolescent patients (10 to 17 years of age) with bipolar mania (3 weeks duration), the mean change in fasting glucose level for quetiapine (n=170) compared to placebo (n=81) was 3.62 mg/dL versus -1.17 mg/dL.

No patient in either study with a baseline normal fasting glucose level (<100 mg/dL) or a baseline borderline fasting glucose level (≥100 mg/dL and <126 mg/dL) had a treatment-emergent blood glucose level of ≥126 mg/dL.

5.5 Hyperlipidemia Undesirable alterations in lipids have been observed with quetiapine use.

Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using quetiapine is recommended.

In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose and lipids was observed in clinical studies.

Changes in these parameters should be managed as clinically appropriate.

Adults: Table 3 shows the percentage of adult patients with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline by indication in clinical trials with quetiapine fumarate.

Table 3: Percentage of Adult Patients with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication Laboratory Analyte Indication Treatment Arm N Patients n (%) Total Cholesterol ≥ 240 mg/dL Schizophrenia 6 weeks duration Quetiapine Fumarate 137 24 (18%) Placebo 92 6 (7%) Bipolar Depression 8 weeks duration Quetiapine Fumarate 463 41 (9%) Placebo 250 15 (6%) Triglycerides ≥200 mg/dL Schizophrenia Quetiapine Fumarate 120 26 (22%) Placebo 70 11 (16%) Bipolar Depression Quetiapine Fumarate 436 59 (14%) Placebo 232 20 (9%) LDL-Cholesterol ≥ 160 mg/dL Schizophrenia Quetiapine Fumarate na Parameters not measured in the quetiapine fumarate registration studies for schizophrenia.

Lipid parameters also were not measured in the bipolar mania registration studies.

na Placebo na na Bipolar Depression Quetiapine Fumarate 465 29 (6%) Placebo 256 12 (5%) HDL-Cholesterol ≤ 40 mg/dL Schizophrenia Quetiapine Fumarate na na Placebo na na Bipolar Depression Quetiapine Fumarate 393 56 (14%) Placebo 214 29 (14%) Children and Adolescents: Table 4 shows the percentage of children and adolescents with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline in clinical trials with quetiapine fumarate.

Table 4: Percentage of Children and Adolescents with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels Laboratory Analyte Indication Treatment Arm N Patients n (%) Total Cholesterol ≥ 200 mg/dL Schizophrenia 13-17 years, 6 weeks duration Quetiapine Fumarate 107 13 (12%) Placebo 56 1 (2%) Bipolar Mania 10-17 years, 3 weeks duration Quetiapine Fumarate 159 16 (10%) Placebo 66 2 (3%) Triglycerides ≥150 mg/dL Schizophrenia Quetiapine Fumarate 103 17 (17%) Placebo 51 4 (8%) Bipolar Mania Quetiapine Fumarate 149 32 (22%) Placebo 60 8 (13%) LDL-Cholesterol ≥ 130 mg/dL Schizophrenia Quetiapine Fumarate 112 4 (4%) Placebo 60 1 (2%) Bipolar Mania Quetiapine Fumarate 169 13 (8%) Placebo 74 4 (5%) HDL-Cholesterol ≤ 40 mg/dL Schizophrenia Quetiapine Fumarate 104 16 (15%) Placebo 54 10 (19%) Bipolar Mania Quetiapine Fumarate 154 16 (10%) Placebo 61 4 (7%) 5.6 Weight Gain Increases in weight have been observed in clinical trials.

Patients receiving quetiapine should receive regular monitoring of weight [ see Patient Counseling Information (17)].

In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose and lipids was observed in clinical studies.

Changes in these parameters should be managed as clinically appropriate.

Adults: In clinical trials with quetiapine fumarate the following increases in weight have been reported.

Table 5: Proportion of Patients with Weight Gain ≥7% of Body Weight (Adults) Vital Sign Indication Treatment Arm N Patients n (%) Weight Gain ≥7% of Body Weight Schizophrenia up to 6 weeks duration Quetiapine Fumarate 391 89 (23%) Placebo 206 11 (6%) Bipolar Mania (monotherapy) up to 12 weeks duration Quetiapine Fumarate 209 44 (21%) Placebo 198 13 (7%) Bipolar Mania (adjunct therapy) up to 3 weeks duration Quetiapine Fumarate 196 25 (13%) Placebo 203 8 (4%) Bipolar Depression up to 8 weeks duration Quetiapine Fumarate 554 47 (8%) Placebo 295 7 (2%) Children and Adolescents: In two clinical trials with quetiapine fumarate, one in bipolar mania and one in schizophrenia, reported increases in weight are included in the table below.

Table 6: Proportion of Patients with Weight Gain ≥7% of Body Weight (Children and Adolescents) Vital Sign Indication Treatment Arm N Patients n (%) Weight Gain ≥7% of Body Weight Schizophrenia : 6 weeks duration Quetiapine Fumarate 111 23 (21%) Placebo 44 3 (7%) Bipolar Mania : 3 weeks duration Quetiapine Fumarate 157 18 (12%) Placebo 68 0 (0%) The mean change in body weight in the schizophrenia trial was 2.0 kg in the quetiapine fumarate group and -0.4 kg in the placebo group and in the bipolar mania trial it was 1.7 kg in the quetiapine fumarate group and 0.4 kg in the placebo group.

In an open-label study that enrolled patients from the above two pediatric trials, 63% of patients (241/380) completed 26 weeks of therapy with quetiapine fumarate.

After 26 weeks of treatment, the mean increase in body weight was 4.4 kg.

Forty-five percent of the patients gained ≥ 7% of their body weight, not adjusted for normal growth.

In order to adjust for normal growth over 26 weeks an increase of at least 0.5 standard deviation from baseline in BMI was used as a measure of a clinically significant change; 18.3% of patients on Quetiapine fumarate met this criterion after 26 weeks of treatment.

When treating pediatric patients with quetiapine fumarate for any indication, weight gain should be assessed against that expected for normal growth.

5.7 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including quetiapine.

Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.

Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase.

However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process.

The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, quetiapine fumarate should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.

Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.

In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.

The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on quetiapine fumarate, drug discontinuation should be considered.

However, some patients may require treatment with quetiapine fumarate despite the presence of the syndrome.

5.8 Orthostatic Hypotension Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α1-adrenergic antagonist properties.

Syncope was reported in 1% (28/3265) of the patients treated with quetiapine fumarate, compared with 0.2% (2/954) on placebo and about 0.4% (2/527) on active control drugs.

Orthostatic hypotension, dizziness, and syncope may lead to falls.

Quetiapine fumarate should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications) [ see Adverse Reactions (6.2)].

The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 25 mg twice daily [ see Dosage and Administration (2)].

If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.

5.9 Increases in Blood Pressure in Children and Adolescents In placebo-controlled trials in children and adolescents with schizophrenia (6 week duration) or bipolar mania (3 week duration), the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 15.2% (51/335) for quetiapine fumarate and 5.5% (9/163) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 40.6% (136/335) for quetiapine fumarate and 24.5% (40/163) for placebo.

In the 26 week open-label clinical trial, one child with a reported history of hypertension experienced a hypertensive crisis.

Blood pressure in children and adolescents should be measured at the beginning of, and periodically during treatment.

5.10 Leukopenia, Neutropenia and Agranulocytosis In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including quetiapine fumarate.

Agranulocytosis (including fatal cases) has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white cell count (WBC) and history of drug induced leukopenia/neutropenia.

Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue quetiapine fumarate at the first sign of a decline in WBC in absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur.

Patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) should discontinue quetiapine fumarate and have their WBC followed until recovery [ see Adverse Reactions (6.2)].

5.11 Cataracts The development of cataracts was observed in association with quetiapine treatment in chronic dog studies [ see Nonclinical Toxicology, Animal Toxicology (13.2)].

Lens changes have also been observed in adults, children and adolescents during long-term quetiapine treatment, but a causal relationship to quetiapine use has not been established.

Nevertheless, the possibility of lenticular changes cannot be excluded at this time.

Therefore, examination of the lens by methods adequate to detect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6-month intervals during chronic treatment.

5.12 QT Prolongation In clinical trials quetiapine was not associated with a persistent increase in QT intervals.

However, the QT effect was not systematically evaluated in a thorough QT study.

In post marketing experience, there were cases reported of QT prolongation in patients who overdosed on quetiapine [see Overdosage (10.1)], in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval [see Drug Interactions (7)].

The use of quetiapine should be avoided in combination with other drugs that are known to prolong QTc including Class 1A antiarrythmics (e.g., quinidine, procainamide) or Class III antiarrythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone).

Quetiapine should also be avoided in circumstances that may increase the risk of occurrence of torsade de pointes and/or sudden death including (1) a history of cardiac arrhythmias such as bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

Caution should also be exercised when quetiapine is prescribed in patients with increased risk of QT prolongation (e.g.

cardiovascular disease, family history of QT prolongation, the elderly, congestive heart failure and heart hypertrophy).

5.13 Seizures During clinical trials, seizures occurred in 0.5% (20/3490) of patients treated with quetiapine fumarate compared to 0.2% (2/954) on placebo and 0.7% (4/527) on active control drugs.

As with other antipsychotics, quetiapine fumarate should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia.

Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

5.14 Hypothyroidism Adults: Clinical trials with quetiapine demonstrated a dose-related decreases in thyroid hormone levels.

The reduction in total and free thyroxine (T4) of approximately 20% at the higher end of the therapeutic dose range was maximal in the first six weeks of treatment and maintained without adaptation or progression during more chronic therapy.

In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment.

About 0.7% (26/3489) of quetiapine patients did experience TSH increases in monotherapy studies.

Some patients with TSH increases needed replacement thyroid treatment.

In the mania adjunct studies, where quetiapine was added to lithium or divalproex, 12% (24/196) of quetiapine-treated patients compared to 7% (15/203) of placebo-treated patients had elevated TSH levels.

Of the quetiatpine-treated patients with elevated TSH levels, 3 had simultaneous low free T4 levels.

In all quetiapine trials, the incidence of potentially clinically significant shifts in thyroid hormones and TSH were*: decrease in free T4, 2.0% (357/17513); decrease in total T4, 4.0% (75/1861); decrease in free T3, 0.4% (53/13766); decrease in total T3, 2.0% (26/1312), and increase in TSH, 4.9% (956/19412).

In eight patients, where TBG was measured, levels of TBG were unchanged.

Table 7 shows the incidence of these shifts in short-term placebo-controlled clinical trials.

Table 7: Incidence of potentially clinically significant shifts in thyroid hormone levels and TSH in short term placebo-controlled clinical trials Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline.

Shifts in total T 4 , free T 4 , total T 3 and free T 3 are defined as 5 mIU/L at any time.

Total T 4 Free T 4 Total T 3 Free T 3 TSH Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo 3.4 % (37/1097) 0.6% (4/651) 0.7% (52/7218) 0.1% (4/3668) 0.5% (2/369) 0.0% (0/113) 0.2% (11/5673) 0.0% (1/2679) 3.2% (240/7587) 2.7% (105/3912) In short-term placebo-controlled monotherapy trials, the incidence of reciprocal, potentially clinically significant shifts in T 3 and TSH was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for T 4 and TSH the shifts were 0.1% (7/6154) for quetiapine versus 0.0% (1/3007) for placebo.

Generally, these changes in thyroid hormone levels were of no clinical significance.

Children and Adolescents: In acute placebo-controlled trials in children and adolescent patients with schizophrenia (6 week duration) or bipolar mania (3 week duration), the incidence of shifts to potentially clinically important thyroid function values at any time for quetiapine treated patients and placebo-treated patients for elevated TSH was 2.9% (8/280) vs.

0.7% (1/138), respectively and for decreased total thyroxine was 2.8% (8/289) vs.

0% (0/145, respectively).

Of the quetiapine treated patients with elevated TSH levels, 1 had simultaneous low free T4 level at end of treatment.

5.15 Hyperprolactinemia Adults: During clinical trials with quetiapine, the incidence of shifts in prolactin levels to a clinically significant value occurred in 3.6% (158/4416) of patients treated with quetiapine compared to 2.6% (51/1968) on placebo.

Children and Adolescents: In acute placebo-controlled trials in children and adolescent patients with bipolar mania (3 week duration) or schizophrenia (6 week duration), the incidence of shifts in prolactin levels to a clinically significant value (>20 µg/L males; > 26 µg/L females at any time) was 13.4% (18/134) for quetiapine compared to 4% (3/75) for placebo in males and 8.7% (9/104) for quetiapine compared to 0% (0/39) for placebo in females.

Like other drugs that antagonize dopamine D2 receptors, quetiapine elevates prolactin levels in some patients and the elevation may persist during chronic administration.

Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion.

This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients.

Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer.

As is common with compounds which increase prolactin release, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in carcinogenicity studies conducted in mice and rats.

Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive [ see Carcinogenesis, Mutagenesis, Impairment of Fertility (13.1)].

5.16 Transaminase Elevations Asymptomatic, transient and reversible elevations in serum transaminases (primarily ALT) have been reported.

In schizophrenia trials in adults, the proportions of patients with transaminase elevations of > 3 times the upper limits of the normal reference range in a pool of 3 to 6 week placebo-controlled trials were approximately 6% (29/483) for quetiapine fumarate compared to 1% (3/194) for placebo.

In acute bipolar mania trials in adults, the proportions of patients with transaminase elevations of > 3 times the upper limits of the normal reference range in a pool of 3 to 12 week placebo-controlled trials were approximately 1% for both quetiapine fumarate (3/560) and placebo (3/294).

These hepatic enzyme elevations usually occurred within the first 3 weeks of drug treatment and promptly returned to pre-study levels with ongoing treatment with quetiapine fumarate.

In bipolar depression trials, the proportions of patients with transaminase elevations of > 3 times the upper limits of the normal reference range in two 8 week placebo-controlled trials was 1% (5/698) for quetiapine fumarate and 2% (6/347) for placebo.

5.17 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse event reported in patients treated with quetiapine fumarate especially during the 3-5 day period of initial dose-titration.

In schizophrenia trials, somnolence was reported in 18% (89/510) of patients on quetiapine fumarate compared to 11% (22/206) of placebo patients.

In acute bipolar mania trials using quetiapine fumarate as monotherapy, somnolence was reported in 16% (34/209) of patients on quetiapine fumarate compared to 4% of placebo patients.

In acute bipolar mania trials using quetiapine fumarate as adjunct therapy, somnolence was reported in 34% (66/196) of patients on quetiapine fumarate compared to 9% (19/203) of placebo patients.

In bipolar depression trials, somnolence was reported in 57% (398/698) of patients on quetiapine fumarate compared to 15% (51/347) of placebo patients.

Since quetiapine fumarate has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that quetiapine fumarate therapy does not affect them adversely.

Somnolence may lead to falls.

5.18 Priapism One case of priapism in a patient receiving quetiapine fumarate has been reported prior to market introduction.

While a causal relationship to use of quetiapine fumarate has not been established, other drugs with alpha-adrenergic blocking effects have been reported to induce priapism, and it is possible that quetiapine fumarate may share this capacity.

Severe priapism may require surgical intervention.

5.19 Body Temperature Regulation Although not reported with quetiapine fumarate, disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents.

Appropriate care is advised when prescribing quetiapine fumarate tablets for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

5.20 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.

Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia.

Quetiapine fumarate and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

5.21 Suicide The possibility of a suicide attempt is inherent in bipolar disorder and schizophrenia; close supervision of high risk patients should accompany drug therapy.

Prescriptions for quetiapine fumarate should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.

In two 8 week clinical studies in patients with bipolar depression (N=1048), the incidence of treatment emergent suicidal ideation or suicide attempt was low and similar to placebo (quetiapine fumarate 300 mg, 6/350, 1.7%; quetiapine fumarate 600 mg, 9/348, 2.6%; Placebo, 7/347, 2.0%).

5.22 Use in Patients with Concomitant Illness Clinical experience with quetiapine fumarate in patients with certain concomitant systemic illnesses is limited [ see Pharmacokinetics (12.3)].

Quetiapine fumarate has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease.

Patients with these diagnoses were excluded from premarketing clinical studies.

Because of the risk of orthostatic hypotension with quetiapine fumarate, caution should be observed in cardiac patients [ see Warnings and Precautions (5.8)].

5.23 Withdrawal Acute withdrawal symptoms, such as insomnia, nausea, and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including quetiapine fumarate.

In short-term placebo-controlled, monotherapy clinical trials with quetiapine fumarate extended-release tablets that included a discontinuation phase which evaluated discontinuation symptoms, the aggregated incidence of patients experiencing one or more discontinuation symptoms after abrupt cessation was 12.1% (241/1993) for quetiapine fumarate extended-release tablets and 6.7% (71/1065) for placebo.

The incidence of the individual adverse events (i.e., insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability) did not exceed 5.3% in any treatment group and usually resolved after 1 week post-discontinuation.

Gradual withdrawal is advised.