Author: druginteractionchecker_lgaiz4

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS CNS depressant effects: Impaired alertness and motor coordination, including risk of morning impairment.

Caution patients against driving and other activities requiring complete mental alertness the morning after use.

( 5.1 ) Need to evaluate for co-morbid diagnoses: Revaluate if insomnia persists after 7 to 10 days of use.

( 5.2 ) Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported.

Do not rechallenge if such reactions occur.

( 5.3 ) “Sleep-driving” and other complex behaviors while not fully awake.

Risk increases with dose and use with other CNS depressants and alcohol.

Immediately evaluate any new onset behavioral changes.

( 5.4 ) Depression: Worsening of depression or, suicidal thinking may occur.

Prescribe the least amount of tablets feasible to avoid intentional overdose.

( 5.5 ) Respiratory Depression: Consider this risk before prescribing in patients with compromised respiratory function.

( 5.6 ) Hepatic Impairment: Avoid AMBIEN CR use in patients with severe hepatic impairment.

( 5.7 ) Withdrawal effects: Symptoms may occur with rapid dose reduction or discontinuation.

( 5.8 , 9.3 ) Severe Injuries: Drowsiness may lead to fall including severe injuries.

( 5.9 ) 5.1 CNS Depressant Effects and Next-Day Impairment AMBIEN CR is a central nervous system (CNS) depressant and can impair daytime function in some patients even when used as prescribed.

Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of subjective symptoms, and may not be reliably detected by ordinary clinical exam (i.e.

less than formal psychomotor testing).

While pharmacodynamic tolerance or adaptation to some adverse depressant effects of AMBIEN CR may develop, patients using AMBIEN CR should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness the day after use.

Additive effects occur with concomitant use of other CNS depressants (e.g.

benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use.

Downward dose adjustment of AMBIEN CR and concomitant CNS depressants should be considered [see Dosage and Administration (2.3) ] .

The use of AMBIEN CR with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended.

The risk of next-day psychomotor impairment is increased if AMBIEN CR is taken with less than a full night of sleep remaining (7 to 8 hours); if higher than the recommended dose is taken; if co-administered with other CNS depressants or alcohol; or co-administered with other drugs that increase the blood levels of zolpidem.

Patients should be warned against driving and other activities requiring complete mental alertness if Ambien CR is taken in these circumstances [see Dosage and Administration (2) and Clinical Studies (14.2) ] .

Vehicle drivers and machine operators should be warned that, as with other hypnotics, there may be a possible risk of adverse reactions including drowsiness, prolonged reaction time, dizziness, sleepiness, blurred/double vision, reduced alertness and impaired driving the morning after therapy.

In order to minimize this risk a full night of sleep (7-8 hours) is recommended.

5.2 Need to Evaluate for Co-morbid Diagnoses Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient.

The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated.

Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder.

Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including zolpidem.

5.3 Severe Anaphylactic and Anaphylactoid Reactions Cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including zolpidem.

Some patients have had additional symptoms such as dyspnea, throat closing or nausea and vomiting that suggest anaphylaxis.

Some patients have required medical therapy in the emergency department.

If angioedema involves the throat, glottis or larynx, airway obstruction may occur and be fatal.

Patients who develop angioedema after treatment with zolpidem should not be rechallenged with the drug.

5.4 Abnormal Thinking and Behavioral Changes Abnormal thinking and behavior changes have been reported in patients treated with sedative/hypnotics, including AMBIEN CR.

Some of these changes included decreased inhibition (e.g.

aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation and depersonalization.

Visual and auditory hallucinations have been reported.

In controlled trials, <1% of adults with insomnia reported hallucinations.

In a clinical trial, 7% of pediatric patients treated with AMBIEN 0.25 mg/kg taken at bedtime reported hallucinations versus 0% treated with placebo [see Use in Specific Populations (8.4) ] .

Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons.

Although behaviors such as “sleep-driving” have occurred with AMBIEN CR alone at therapeutic doses, the co-administration of alcohol and other CNS depressants increases the risk of such behaviors, as does the use of AMBIEN CR at doses exceeding the maximum recommended dose.

Due to the risk to the patient and the community, discontinuation of AMBIEN CR should be strongly considered for patients who report a “sleep-driving” episode.

Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic.

As with “sleep-driving”, patients usually do not remember these events.

Amnesia, anxiety and other neuro-psychiatric symptoms may also occur.

It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder.

Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

5.5 Use in Patients with Depression In primarily depressed patients treated with sedative-hypnotics, worsening of depression, and suicidal thoughts and actions (including completed suicides), have been reported.

Suicidal tendencies may be present in such patients and protective measures may be required.

Intentional overdosage is more common in this group of patients; therefore, the lowest number of tablets that is feasible should be prescribed for the patient at any one time.

5.6 Respiratory Depression Although studies with 10 mg zolpidem tartrate did not reveal respiratory depressant effects at hypnotic doses in healthy subjects or in patients with mild-to-moderate chronic obstructive pulmonary disease (COPD), a reduction in the Total Arousal Index, together with a reduction in lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90%, was observed in patients with mild-to-moderate sleep apnea when treated with zolpidem compared to placebo.

Since sedative-hypnotics have the capacity to depress respiratory drive, precautions should be taken if AMBIEN CR is prescribed to patients with compromised respiratory function.

Post-marketing reports of respiratory insufficiency in patients receiving 10 mg of zolpidem tartrate, most of whom had pre-existing respiratory impairment, have been reported.

The risk of respiratory depression should be considered prior to prescribing AMBIEN CR in patients with respiratory impairment including sleep apnea and myasthenia gravis.

5.7 Precipitation of Hepatic Encephalopathy GABA agonists such as zolpidem tartrate have been associated with precipitation of hepatic encephalopathy in patients with hepatic insufficiency.

In addition, patients with hepatic insufficiency do not clear zolpidem tartrate as rapidly as patients with normal hepatic function.

Avoid AMBIEN CR use in patients with severe hepatic impairment as it may contribute to encephalopathy [see Dosage and Administration (2.2) , Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] .

5.8 Withdrawal Effects There have been reports of withdrawal signs and symptoms following the rapid dose decrease or abrupt discontinuation of zolpidem.

Monitor patients for tolerance, abuse, and dependence [see Drug Abuse and Dependence (9.2) and (9.3) ] .

5.9 Severe Injuries Zolpidem can cause drowsiness and a decreased level of consciousness, which may lead to falls and consequently to severe injuries.

Severe injuries such as hip fractures and intracranial hemorrhage have been reported.

WARNING AND CAUTIONS

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

Elderly Patients with Dementia-Related Psychosis: Increased risk of death and increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack).

( 5.1 ) Suicide: The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I disorder, and close supervision of high-risk patients should accompany drug therapy; when using in combination with fluoxetine, also refer to the Boxed Warning and Warnings and Precautions sections of the package insert for Symbyax.

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

( 5.3 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue if DRESS is suspected.

( 5.4) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain.

( 5.5 ) Hyperglycemia a nd Diabetes Mellitus : In some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking olanzapine.

Patients taking olanzapine should be monitored for symptoms of hyperglycemia and undergo fasting blood glucose testing at the beginning of, and periodically during, treatment.

( 5.

5) Dyslipidemia: Undesirable alterations in lipids have been observed.

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

( 5.5 ) Weight Gain: Potential consequences of weight gain should be considered.

Patients should receive regular monitoring of weight.

( 5.5 ) Tardive Dyskinesia: Discontinue if clinically appropriate.

( 5.6 ) Orthostatic Hypotension: Orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, may occur especially during initial dose titration.

Use caution in patients with cardiovascular disease, cerebrovascular disease, and those conditions that could affect hemodynamic responses.

( 5.

7) Leukopenia, Neutropenia, and Agranulocytosis: Has been reported with antipsychotics, including olanzapine.

Patients with a history of a clinically significant low white blood cell count (WBC) or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of olanzapine should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

( 5.9 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold.

( 5.

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

Use caution when operating machinery.

( 5.1 2) Anticholinergic (antimuscarinic) Effects: Use with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus or related conditions.

( 5.14 ) Hyperprolactinemia: May elevate prolactin levels.

( 5.1 5) Use in Combination with Fluoxetine, Lithium or Valproate: Also refer to the package inserts for Symbyax, lithium, or valproate.

( 5.16 ) Laboratory Tests: Monitor fasting blood glucose and lipid profiles at the beginning of, and periodically during, treatment.

( 5.1 7) 5.1 Elderly Patients with Dementia-Related Psychosis Increased Mortality — Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Use in Specific Populations (8.5) , and Patient Counseling Information (17)] .

In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).

Cerebrovascular Adverse Events (CVAE), Including Stroke — Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis.

In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with olanzapine compared to patients treated with placebo.

Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Patient Counseling Information (17 )] .

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

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

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 olanzapine.

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 creatinine 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 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 [see Patient Counseling Information (17) ] .

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure.

DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis.

DRESS is sometimes fatal.

Discontinue olanzapine if DRESS is suspected [ see Patient Counseling Information (17 )] .

5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain.

Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk.

Olanzapine’s specific metabolic profile is presented below.

Hyperglycemia and Diabetes Mellitus Healthcare providers should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100 to 126 mg/dL, nonfasting 140 to 200 mg/dL).

Patients taking olanzapine should be monitored regularly for worsening of glucose control.

Patients starting treatment with olanzapine 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 [see Patient Counseling Information (17) ] .

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

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.

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

While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.

Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).

The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15.0 mg/dL.

In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase compared to baseline in fasting blood glucose of 2.3 mg/dL.

Placebo-treated subjects (N=19) had a mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL.

Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled adult olanzapine monotherapy studies with a median treatment duration of approximately 3 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (2.76 mg/dL versus 0.17 mg/dL).

The difference in mean changes between olanzapine and placebo was greater in patients with evidence of glucose dysregulation at baseline (patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with anti-diabetic agents, patients with a baseline random glucose level ≥200 mg/dL, and/or a baseline fasting glucose level ≥126 mg/dL).

Olanzapine-treated patients had a greater mean HbA 1c increase from baseline of 0.04% (median exposure 21 days), compared to a mean HbA 1c decrease of 0.06% in placebo-treated subjects (median exposure 17 days).

In an analysis of 8 placebo-controlled studies (median treatment exposure 4-5 weeks), 6.1% of olanzapine-treated subjects (N=855) had treatment-emergent glycosuria compared to 2.8% of placebo-treated subjects (N=599).

Table 2 shows short-term and long-term changes in fasting glucose levels from adult olanzapine monotherapy studies.

Table 2: Changes in Fasting Glucose Levels from Adult Olanzapine Monotherapy Studies Up to 12 weeks exposure At least 48 weeks exposure Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients Fasting Glucose Normal to High (<100 mg/dL to ≥126 mg/dL) Olanzapine 543 2.2% 345 12.8% Placebo 293 3.4% NA a NA a Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) Olanzapine 178 17.4% 127 26% Placebo 96 11.5% NA a NA a a Not Applicable.

The mean change in fasting glucose for patients exposed at least 48 weeks was 4.2 mg/dL (N=487).

In analyses of patients who completed 9 to 12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over time.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 13 years.

In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fasting glucose levels compared to placebo (2.68 mg/dL versus -2.59 mg/dL).

The mean change in fasting glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (N=121).

Table 3 shows short-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies.

Table 3: Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies Up to 12 weeks exposure At least 24 weeks exposure Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients Fasting Glucose Normal to High (<100 mg/dL to ≥126 mg/dL) Olanzapine 124 0% 108 0.9% Placebo 53 1.9% NA a NA a Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) Olanzapine 14 14.3% 13 23.1% Placebo 13 0% NA a NA a a Not Applicable.

Dyslipidemia Undesirable alterations in lipids have been observed with olanzapine use.

Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using olanzapine, is recommended [see Patient Counseling Information (17)].

Clinically significant, and sometimes very high (>500 mg/dL), elevations in triglyceride levels have been observed with olanzapine use.

Modest mean increases in total cholesterol have also been seen with olanzapine use.

Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine-treated patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3.0 mg/dL, and 20.8 mg/dL respectively compared to decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL, 4.3 mg/dL, and 10.7 mg/dL for placebo-treated patients.

For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated patients and placebo-treated patients.

Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related adverse reactions, patients treated with lipid lowering agents, or patients with high baseline lipid levels.

In long-term studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 0.16 mg/dL.

In an analysis of patients who completed 12 months of therapy, the mean nonfasting total cholesterol did not increase further after approximately 4-6 months.

The proportion of patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides from normal or borderline to high, or changes in HDL cholesterol from normal or borderline to low, was greater in long-term studies (at least 48 weeks) as compared with short-term studies.

Table 4 shows categorical changes in fasting lipids values.

Table 4: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies Up to 12 weeks exposure At least 48 weeks exposure Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients Fasting Triglycerides Increase by ≥50 mg/dL Olanzapine 745 39.6% 487 61.4% Placebo 402 26.1% NA a NA a Normal to High (<150 mg/dL to ≥200 mg/dL) Olanzapine 457 9.2% 293 32.4% Placebo 251 4.4% NA a NA a Borderline to High (≥150 mg/dL and <200 mg/dL to ≥200 mg/dL) Olanzapine 135 39.3% 75 70.7% Placebo 65 20% NA a NA a Fasting Total Cholesterol Increase by ≥40 mg/dL Olanzapine 745 21.6% 489 32.9% Placebo 402 9.5% NA a NA a Normal to High (<200 mg/dL to ≥240 mg/dL) Olanzapine 392 2.8% 283 14.8% Placebo 207 2.4% NA a NA a Borderline to High (≥200 mg/dL and <240 mg/dL to ≥240 mg/dL) Olanzapine 222 23% 125 55.2% Placebo 112 12.5% NA a NA a Fasting LDL Cholesterol Increase by ≥30 mg/dL Olanzapine 536 23.7% 483 39.8% Placebo 304 14.1% NA a NA a Normal to High (<100 mg/dL to ≥160 mg/dL) Olanzapine 154 0% 123 7.3% Placebo 82 1.2% NA a NA a Borderline to High (≥100 mg/dL and <160 mg/dL to ≥160 mg/dL) Olanzapine 302 10.6% 284 31% Placebo 173 8.1% NA a NA a a Not Applicable.

In phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a median exposure of 9.2 months, the mean increase in triglycerides in patients taking olanzapine was 40.5 mg/dL.

In phase 1 of CATIE, the mean increase in total cholesterol was 9.4 mg/dL.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 13 years.

In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescents, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to increases from baseline in mean fasting total cholesterol and LDL cholesterol of 1.3 mg/dL and 1.0 mg/dL, and a decrease in triglycerides of 1.1 mg/dL for placebo-treated adolescents.

For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated adolescents and placebo-treated adolescents.

In long-term studies (at least 24 weeks), adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 4.5 mg/dL.

Table 5 shows categorical changes in fasting lipids values in adolescents.

Table 5: Changes in Fasting Lipids Values from Adolescent Olanzapine Monotherapy Studies Up to 6 weeks exposure At least 24 weeks exposure Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients Fasting Triglycerides Increase by ≥50 mg/dL Olanzapine 138 37% 122 45.9% Placebo 66 15.2% NA a NA a Normal to High (130 mg/dL) Olanzapine 67 26.9% 66 36.4% Placebo 28 10.7% NA a NA a Borderline to High (≥90 mg/dL and ≤130 mg/dL to >130 mg/dL) Olanzapine 37 59.5% 31 64.5% Placebo 17 35.3% NA a NA a Fasting Total Cholesterol Increase by ≥40 mg/dL Olanzapine 138 14.5% 122 14.8% Placebo 66 4.5% NA a NA a Normal to High (<170 mg/dL to ≥200 mg/dL) Olanzapine 87 6.9% 78 7.7% Placebo 43 2.3% NA a NA a Borderline to High (≥170 mg/dL and <200 mg/dL to ≥200 mg/dL) Olanzapine 36 38.9% 33 57.6% Placebo 13 7.7% NA a NA a Fasting LDL Cholesterol Increase by ≥30 mg/dL Olanzapine 137 17.5% 121 22.3% Placebo 63 11.1% NA a NA a Normal to High (<110 mg/dL to ≥130 mg/dL) Olanzapine 98 5.1% 92 10.9% Placebo 44 4.5% NA a NA a Borderline to High (≥110 mg/dL and <130 mg/dL to ≥130 mg/dL) Olanzapine 29 48.3% 21 47.6% Placebo 9 0% NA a NA a a Not Applicable.

Weight Gain Potential consequences of weight gain should be considered prior to starting olanzapine.

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

Olanzapine Monotherapy in Adults — In an analysis of 13 placebo-controlled olanzapine monotherapy studies, olanzapine-treated patients gained an average of 2.6 kg (5.7 lb) compared to an average 0.3 kg (0.6 lb) weight loss in placebo-treated patients with a median exposure of 6 weeks; 22.2% of olanzapine-treated patients gained at least 7% of their baseline weight, compared to 3% of placebo-treated patients, with a median exposure to event of 8 weeks; 4.2% of olanzapine-treated patients gained at least 15% of their baseline weight, compared to 0.3% of placebo-treated patients, with a median exposure to event of 12 weeks.

Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories.

Discontinuation due to weight gain occurred in 0.2% of olanzapine-treated patients and in 0% of placebo-treated patients.

In long-term studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, N=2021).

The percentages of patients who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively.

Discontinuation due to weight gain occurred in 0.4% of olanzapine-treated patients following at least 48 weeks of exposure.

Table 6 includes data on adult weight gain with olanzapine pooled from 86 clinical trials.

The data in each column represent data for those patients who completed treatment periods of the durations specified.

Table 6: Weight Gain with Olanzapine Use in Adults Amount Gained kg (lb) 6 Weeks (N=7465) (%) 6 Months (N=4162) (%) 12 Months (N=1345) (%) 24 Months (N=474) (%) 36 Months (N=147) (%) ≤0 26.2 24.3 20.8 23.2 17 0 to ≤5 (0-11 lb) 57 36 26 23.4 25.2 >5 to ≤10 (11-22 lb) 14.9 24.6 24.2 24.1 18.4 >10 to ≤15 (22-33 lb) 1.8 10.9 14.9 11.4 17 >15 to ≤20 (33-44 lb) 0.1 3.1 8.6 9.3 11.6 >20 to ≤25 (44-55 lb) 0 0.9 3.3 5.1 4.1 >25 to ≤30 (55-66 lb) 0 0.2 1.4 2.3 4.8 >30 (>66 lb) 0 0.1 0.8 1.2 2 Dose group differences with respect to weight gain have been observed.

In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day.

Olanzapine Monotherapy in Adolescents – The safety and efficacy of olanzapine have not been established in patients under the age of 13 years.

Mean increase in weight in adolescents was greater than in adults.

In 4 placebo-controlled trials, discontinuation due to weight gain occurred in 1% of olanzapine-treated patients, compared to 0% of placebo-treated patients.

Table 7: Weight Gain with Olanzapine Use in Adolescents from 4 Placebo-Controlled Trials Olanzapine-treated patients Placebo-treated patients Mean change in body weight from baseline (median exposure = 3 weeks) 4.6 kg (10.1 lb) 0.3 kg (0.7 lb) Percentage of patients who gained at least 7% of baseline body weight 40.6% (median exposure to 7% = 4 weeks) 9.8% (median exposure to 7% = 8 weeks) Percentage of patients who gained at least 15% of baseline body weight 7.1% (median exposure to 15% = 19 weeks) 2.7% (median exposure to 15% = 8 weeks) In long-term studies (at least 24 weeks), the mean weight gain was 11.2 kg (24.6 lb); (median exposure of 201 days, N=179).

The percentages of adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 89%, 55%, and 29%, respectively.

Among adolescent patients, mean weight gain by baseline BMI category was 11.5 kg (25.3 lb), 12.1 kg (26.6 lb), and 12.7 kg (27.9 lb), respectively, for normal (N=106), overweight (N=26) and obese (N=17).

Discontinuation due to weight gain occurred in 2.2% of olanzapine-treated patients following at least 24 weeks of exposure.

Table 8 shows data on adolescent weight gain with olanzapine pooled from 6 clinical trials.

The data in each column represent data for those patients who completed treatment periods of the durations specified.

Little clinical trial data is available on weight gain in adolescents with olanzapine beyond 6 months of treatment.

Table 8: Weight Gain with Olanzapine Use in Adolescents Amount Gained kg (lb) 6 Weeks (N=243) (%) 6 Months (N=191) (%) ≤0 2.9 2.1 0 to ≤5 (0-11 lb) 47.3 24.6 >5 to ≤10 (11-22 lb) 42.4 26.7 >10 to ≤15 (22-33 lb) 5.8 22.0 >15 to ≤20 (33-44 lb) 0.8 12.6 >20 to ≤25 (44-55 lb) 0.8 9.4 >25 to ≤30 (55-66 lb) 0 2.1 >30 to ≤35 (66-77 lb) 0 0 >35 to ≤40 (77-88 lb) 0 0 >40 (>88 lb) 0 0.5 5.6 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs.

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.

Tardive dyskinesia 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, olanzapine 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 (1) who suffer from a chronic illness that 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 olanzapine, drug discontinuation should be considered.

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

For specific information about the warnings of lithium or valproate, refer to the Warnings section of the package inserts for these other products.

5.7 Orthostatic Hypotension Olanzapine may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α 1 -adrenergic antagonistic properties [see Patient Counseling Information (17) ] .

From an analysis of the vital sign data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, orthostatic hypotension was recorded in ≥20% (1277/6030) of patients.

For oral olanzapine therapy, the risk of orthostatic hypotension and syncope may be minimized by initiating therapy with 5 mg QD [see Dosage and Administration (2) ] .

A more gradual titration to the target dose should be considered if hypotension occurs.

Syncope was reported in 0.6% (15/2500) of olanzapine-treated patients in phase 2-3 oral olanzapine studies.

The risk for this sequence of hypotension, bradycardia, and sinus pause may be greater in nonpsychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs.

Olanzapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk.

Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression [see Drug Interactions (7) ] .

5.8 Falls Olanzapine may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.

For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.9 Leukopenia, Neutropenia, and Agranulocytosis Class Effect — In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including olanzapine.

Agranulocytosis has also been reported.

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

Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of olanzapine should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant 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 olanzapine and have their WBC followed until recovery.

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

Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s disease.

Olanzapine is not approved for the treatment of patients with Alzheimer’s disease.

5.11 Seizures During premarketing testing, seizures occurred in 0.9% (22/2500) of olanzapine-treated patients.

There were confounding factors that may have contributed to the occurrence of seizures in many of these cases.

Olanzapine 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.

Olanzapine is not approved for the treatment of patients with Alzheimer’s disease.

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

5.12 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse reaction associated with olanzapine treatment, occurring at an incidence of 26% in olanzapine patients compared to 15% in placebo patients.

This adverse reaction was also dose related.

Somnolence led to discontinuation in 0.4% (9/2500) of patients in the premarketing database.

Since olanzapine 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 olanzapine therapy does not affect them adversely [see Patient Counseling Information (17) ] .

5.13 Body Temperature Regulation Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents.

Appropriate care is advised when prescribing olanzapine 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 [see Patient Counseling Information (17) ].

5.14 Anticholinergic (antimuscarinic) Effects Olanzapine exhibits in vitro muscarinic receptor affinity [see Clinical Pharmacology 12.2 ] .

In premarketing clinical trials, olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism.

Such adverse reactions were not often the basis for discontinuations, but olanzapine should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions.

In post marketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications [see Drug Interactions (7.1 )].

5.15 Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, olanzapine elevates prolactin levels, and the elevation persists during chronic administration.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin 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 contemplated in a patient with previously detected breast cancer.

As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1) ] .

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; the available evidence is considered too limited to be conclusive at this time.

In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo.

In a pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual-related events 1 (2% [49/3240] of females), sexual function-related events 2 (2% [150/8136] of females and males), and breast-related events 3 (0.7% [23/3240] of females, 0.2% [9/4896] of males).

In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine­-treated patients compared to 7% of placebo-treated patients.

In a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events 1 (1% [2/168] of females), sexual function-related events 2 (0.7% [3/454] of females and males), and breast-related events 3 (2% [3/168] of females, 2% [7/286] of males) [see Use in Specific Populations (8.4) ] .

1 Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea.

2 Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction.

3 Based on a search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder.

Dose group differences with respect to prolactin elevation have been observed.

In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) indicated significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day.

5.16 Use in Combination with Fluoxetine, Lithium, or Valproate When using olanzapine and fluoxetine in combination, the prescriber should also refer to the Warnings and Precautions section of the package insert for Symbyax.

When using olanzapine in combination with lithium or valproate, the prescriber should refer to the Warnings and Precautions sections of the package inserts for lithium or valproate [see Drug Interactions (7) ].

5.17 Laboratory Tests Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended [see Warnings and Precautions (5.5) and Patient Counseling Information (17 )].

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

Elderly Patients with Dementia-Related Psychosis: Increased risk of death and increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack).

( 5.1 ) Suicide: The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I disorder, and close supervision of high-risk patients should accompany drug therapy; when using in combination with fluoxetine, also refer to the Boxed Warning and Warnings and Precautions sections of the package insert for Symbyax.

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

( 5.3 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue if DRESS is suspected.

( 5.4) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain.

( 5.5 ) Hyperglycemia a nd Diabetes Mellitus : In some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking olanzapine.

Patients taking olanzapine should be monitored for symptoms of hyperglycemia and undergo fasting blood glucose testing at the beginning of, and periodically during, treatment.

( 5.

5) Dyslipidemia: Undesirable alterations in lipids have been observed.

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

( 5.5 ) Weight Gain: Potential consequences of weight gain should be considered.

Patients should receive regular monitoring of weight.

( 5.5 ) Tardive Dyskinesia: Discontinue if clinically appropriate.

( 5.6 ) Orthostatic Hypotension: Orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, may occur especially during initial dose titration.

Use caution in patients with cardiovascular disease, cerebrovascular disease, and those conditions that could affect hemodynamic responses.

( 5.

7) Leukopenia, Neutropenia, and Agranulocytosis: Has been reported with antipsychotics, including olanzapine.

Patients with a history of a clinically significant low white blood cell count (WBC) or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of olanzapine should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

( 5.9 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold.

( 5.

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

Use caution when operating machinery.

( 5.1 2) Anticholinergic (antimuscarinic) Effects: Use with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus or related conditions.

( 5.14 ) Hyperprolactinemia: May elevate prolactin levels.

( 5.1 5) Use in Combination with Fluoxetine, Lithium or Valproate: Also refer to the package inserts for Symbyax, lithium, or valproate.

( 5.16 ) Laboratory Tests: Monitor fasting blood glucose and lipid profiles at the beginning of, and periodically during, treatment.

( 5.1 7) 5.1 Elderly Patients with Dementia-Related Psychosis Increased Mortality — Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Use in Specific Populations (8.5) , and Patient Counseling Information (17)] .

In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).

Cerebrovascular Adverse Events (CVAE), Including Stroke — Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis.

In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with olanzapine compared to patients treated with placebo.

Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Patient Counseling Information (17 )] .

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

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

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 olanzapine.

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 creatinine 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 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 [see Patient Counseling Information (17) ] .

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure.

DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis.

DRESS is sometimes fatal.

Discontinue olanzapine if DRESS is suspected [ see Patient Counseling Information (17 )] .

5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain.

Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk.

Olanzapine’s specific metabolic profile is presented below.

Hyperglycemia and Diabetes Mellitus Healthcare providers should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100 to 126 mg/dL, nonfasting 140 to 200 mg/dL).

Patients taking olanzapine should be monitored regularly for worsening of glucose control.

Patients starting treatment with olanzapine 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 [see Patient Counseling Information (17) ] .

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

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.

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

While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.

Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).

The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15.0 mg/dL.

In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase compared to baseline in fasting blood glucose of 2.3 mg/dL.

Placebo-treated subjects (N=19) had a mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL.

Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled adult olanzapine monotherapy studies with a median treatment duration of approximately 3 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (2.76 mg/dL versus 0.17 mg/dL).

The difference in mean changes between olanzapine and placebo was greater in patients with evidence of glucose dysregulation at baseline (patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with anti-diabetic agents, patients with a baseline random glucose level ≥200 mg/dL, and/or a baseline fasting glucose level ≥126 mg/dL).

Olanzapine-treated patients had a greater mean HbA 1c increase from baseline of 0.04% (median exposure 21 days), compared to a mean HbA 1c decrease of 0.06% in placebo-treated subjects (median exposure 17 days).

In an analysis of 8 placebo-controlled studies (median treatment exposure 4-5 weeks), 6.1% of olanzapine-treated subjects (N=855) had treatment-emergent glycosuria compared to 2.8% of placebo-treated subjects (N=599).

Table 2 shows short-term and long-term changes in fasting glucose levels from adult olanzapine monotherapy studies.

Table 2: Changes in Fasting Glucose Levels from Adult Olanzapine Monotherapy Studies Up to 12 weeks exposure At least 48 weeks exposure Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients Fasting Glucose Normal to High (<100 mg/dL to ≥126 mg/dL) Olanzapine 543 2.2% 345 12.8% Placebo 293 3.4% NA a NA a Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) Olanzapine 178 17.4% 127 26% Placebo 96 11.5% NA a NA a a Not Applicable.

The mean change in fasting glucose for patients exposed at least 48 weeks was 4.2 mg/dL (N=487).

In analyses of patients who completed 9 to 12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over time.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 13 years.

In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fasting glucose levels compared to placebo (2.68 mg/dL versus -2.59 mg/dL).

The mean change in fasting glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (N=121).

Table 3 shows short-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies.

Table 3: Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies Up to 12 weeks exposure At least 24 weeks exposure Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients Fasting Glucose Normal to High (<100 mg/dL to ≥126 mg/dL) Olanzapine 124 0% 108 0.9% Placebo 53 1.9% NA a NA a Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) Olanzapine 14 14.3% 13 23.1% Placebo 13 0% NA a NA a a Not Applicable.

Dyslipidemia Undesirable alterations in lipids have been observed with olanzapine use.

Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using olanzapine, is recommended [see Patient Counseling Information (17)].

Clinically significant, and sometimes very high (>500 mg/dL), elevations in triglyceride levels have been observed with olanzapine use.

Modest mean increases in total cholesterol have also been seen with olanzapine use.

Olanzapine Monotherapy in Adults — In an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine-treated patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3.0 mg/dL, and 20.8 mg/dL respectively compared to decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL, 4.3 mg/dL, and 10.7 mg/dL for placebo-treated patients.

For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated patients and placebo-treated patients.

Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related adverse reactions, patients treated with lipid lowering agents, or patients with high baseline lipid levels.

In long-term studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 0.16 mg/dL.

In an analysis of patients who completed 12 months of therapy, the mean nonfasting total cholesterol did not increase further after approximately 4-6 months.

The proportion of patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides from normal or borderline to high, or changes in HDL cholesterol from normal or borderline to low, was greater in long-term studies (at least 48 weeks) as compared with short-term studies.

Table 4 shows categorical changes in fasting lipids values.

Table 4: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies Up to 12 weeks exposure At least 48 weeks exposure Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients Fasting Triglycerides Increase by ≥50 mg/dL Olanzapine 745 39.6% 487 61.4% Placebo 402 26.1% NA a NA a Normal to High (<150 mg/dL to ≥200 mg/dL) Olanzapine 457 9.2% 293 32.4% Placebo 251 4.4% NA a NA a Borderline to High (≥150 mg/dL and <200 mg/dL to ≥200 mg/dL) Olanzapine 135 39.3% 75 70.7% Placebo 65 20% NA a NA a Fasting Total Cholesterol Increase by ≥40 mg/dL Olanzapine 745 21.6% 489 32.9% Placebo 402 9.5% NA a NA a Normal to High (<200 mg/dL to ≥240 mg/dL) Olanzapine 392 2.8% 283 14.8% Placebo 207 2.4% NA a NA a Borderline to High (≥200 mg/dL and <240 mg/dL to ≥240 mg/dL) Olanzapine 222 23% 125 55.2% Placebo 112 12.5% NA a NA a Fasting LDL Cholesterol Increase by ≥30 mg/dL Olanzapine 536 23.7% 483 39.8% Placebo 304 14.1% NA a NA a Normal to High (<100 mg/dL to ≥160 mg/dL) Olanzapine 154 0% 123 7.3% Placebo 82 1.2% NA a NA a Borderline to High (≥100 mg/dL and <160 mg/dL to ≥160 mg/dL) Olanzapine 302 10.6% 284 31% Placebo 173 8.1% NA a NA a a Not Applicable.

In phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a median exposure of 9.2 months, the mean increase in triglycerides in patients taking olanzapine was 40.5 mg/dL.

In phase 1 of CATIE, the mean increase in total cholesterol was 9.4 mg/dL.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine have not been established in patients under the age of 13 years.

In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescents, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to increases from baseline in mean fasting total cholesterol and LDL cholesterol of 1.3 mg/dL and 1.0 mg/dL, and a decrease in triglycerides of 1.1 mg/dL for placebo-treated adolescents.

For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated adolescents and placebo-treated adolescents.

In long-term studies (at least 24 weeks), adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 4.5 mg/dL.

Table 5 shows categorical changes in fasting lipids values in adolescents.

Table 5: Changes in Fasting Lipids Values from Adolescent Olanzapine Monotherapy Studies Up to 6 weeks exposure At least 24 weeks exposure Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients N Patients Fasting Triglycerides Increase by ≥50 mg/dL Olanzapine 138 37% 122 45.9% Placebo 66 15.2% NA a NA a Normal to High (130 mg/dL) Olanzapine 67 26.9% 66 36.4% Placebo 28 10.7% NA a NA a Borderline to High (≥90 mg/dL and ≤130 mg/dL to >130 mg/dL) Olanzapine 37 59.5% 31 64.5% Placebo 17 35.3% NA a NA a Fasting Total Cholesterol Increase by ≥40 mg/dL Olanzapine 138 14.5% 122 14.8% Placebo 66 4.5% NA a NA a Normal to High (<170 mg/dL to ≥200 mg/dL) Olanzapine 87 6.9% 78 7.7% Placebo 43 2.3% NA a NA a Borderline to High (≥170 mg/dL and <200 mg/dL to ≥200 mg/dL) Olanzapine 36 38.9% 33 57.6% Placebo 13 7.7% NA a NA a Fasting LDL Cholesterol Increase by ≥30 mg/dL Olanzapine 137 17.5% 121 22.3% Placebo 63 11.1% NA a NA a Normal to High (<110 mg/dL to ≥130 mg/dL) Olanzapine 98 5.1% 92 10.9% Placebo 44 4.5% NA a NA a Borderline to High (≥110 mg/dL and <130 mg/dL to ≥130 mg/dL) Olanzapine 29 48.3% 21 47.6% Placebo 9 0% NA a NA a a Not Applicable.

Weight Gain Potential consequences of weight gain should be considered prior to starting olanzapine.

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

Olanzapine Monotherapy in Adults — In an analysis of 13 placebo-controlled olanzapine monotherapy studies, olanzapine-treated patients gained an average of 2.6 kg (5.7 lb) compared to an average 0.3 kg (0.6 lb) weight loss in placebo-treated patients with a median exposure of 6 weeks; 22.2% of olanzapine-treated patients gained at least 7% of their baseline weight, compared to 3% of placebo-treated patients, with a median exposure to event of 8 weeks; 4.2% of olanzapine-treated patients gained at least 15% of their baseline weight, compared to 0.3% of placebo-treated patients, with a median exposure to event of 12 weeks.

Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories.

Discontinuation due to weight gain occurred in 0.2% of olanzapine-treated patients and in 0% of placebo-treated patients.

In long-term studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, N=2021).

The percentages of patients who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively.

Discontinuation due to weight gain occurred in 0.4% of olanzapine-treated patients following at least 48 weeks of exposure.

Table 6 includes data on adult weight gain with olanzapine pooled from 86 clinical trials.

The data in each column represent data for those patients who completed treatment periods of the durations specified.

Table 6: Weight Gain with Olanzapine Use in Adults Amount Gained kg (lb) 6 Weeks (N=7465) (%) 6 Months (N=4162) (%) 12 Months (N=1345) (%) 24 Months (N=474) (%) 36 Months (N=147) (%) ≤0 26.2 24.3 20.8 23.2 17 0 to ≤5 (0-11 lb) 57 36 26 23.4 25.2 >5 to ≤10 (11-22 lb) 14.9 24.6 24.2 24.1 18.4 >10 to ≤15 (22-33 lb) 1.8 10.9 14.9 11.4 17 >15 to ≤20 (33-44 lb) 0.1 3.1 8.6 9.3 11.6 >20 to ≤25 (44-55 lb) 0 0.9 3.3 5.1 4.1 >25 to ≤30 (55-66 lb) 0 0.2 1.4 2.3 4.8 >30 (>66 lb) 0 0.1 0.8 1.2 2 Dose group differences with respect to weight gain have been observed.

In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day.

Olanzapine Monotherapy in Adolescents – The safety and efficacy of olanzapine have not been established in patients under the age of 13 years.

Mean increase in weight in adolescents was greater than in adults.

In 4 placebo-controlled trials, discontinuation due to weight gain occurred in 1% of olanzapine-treated patients, compared to 0% of placebo-treated patients.

Table 7: Weight Gain with Olanzapine Use in Adolescents from 4 Placebo-Controlled Trials Olanzapine-treated patients Placebo-treated patients Mean change in body weight from baseline (median exposure = 3 weeks) 4.6 kg (10.1 lb) 0.3 kg (0.7 lb) Percentage of patients who gained at least 7% of baseline body weight 40.6% (median exposure to 7% = 4 weeks) 9.8% (median exposure to 7% = 8 weeks) Percentage of patients who gained at least 15% of baseline body weight 7.1% (median exposure to 15% = 19 weeks) 2.7% (median exposure to 15% = 8 weeks) In long-term studies (at least 24 weeks), the mean weight gain was 11.2 kg (24.6 lb); (median exposure of 201 days, N=179).

The percentages of adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 89%, 55%, and 29%, respectively.

Among adolescent patients, mean weight gain by baseline BMI category was 11.5 kg (25.3 lb), 12.1 kg (26.6 lb), and 12.7 kg (27.9 lb), respectively, for normal (N=106), overweight (N=26) and obese (N=17).

Discontinuation due to weight gain occurred in 2.2% of olanzapine-treated patients following at least 24 weeks of exposure.

Table 8 shows data on adolescent weight gain with olanzapine pooled from 6 clinical trials.

The data in each column represent data for those patients who completed treatment periods of the durations specified.

Little clinical trial data is available on weight gain in adolescents with olanzapine beyond 6 months of treatment.

Table 8: Weight Gain with Olanzapine Use in Adolescents Amount Gained kg (lb) 6 Weeks (N=243) (%) 6 Months (N=191) (%) ≤0 2.9 2.1 0 to ≤5 (0-11 lb) 47.3 24.6 >5 to ≤10 (11-22 lb) 42.4 26.7 >10 to ≤15 (22-33 lb) 5.8 22.0 >15 to ≤20 (33-44 lb) 0.8 12.6 >20 to ≤25 (44-55 lb) 0.8 9.4 >25 to ≤30 (55-66 lb) 0 2.1 >30 to ≤35 (66-77 lb) 0 0 >35 to ≤40 (77-88 lb) 0 0 >40 (>88 lb) 0 0.5 5.6 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs.

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.

Tardive dyskinesia 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, olanzapine 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 (1) who suffer from a chronic illness that 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 olanzapine, drug discontinuation should be considered.

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

For specific information about the warnings of lithium or valproate, refer to the Warnings section of the package inserts for these other products.

5.7 Orthostatic Hypotension Olanzapine may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α 1 -adrenergic antagonistic properties [see Patient Counseling Information (17) ] .

From an analysis of the vital sign data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, orthostatic hypotension was recorded in ≥20% (1277/6030) of patients.

For oral olanzapine therapy, the risk of orthostatic hypotension and syncope may be minimized by initiating therapy with 5 mg QD [see Dosage and Administration (2) ] .

A more gradual titration to the target dose should be considered if hypotension occurs.

Syncope was reported in 0.6% (15/2500) of olanzapine-treated patients in phase 2-3 oral olanzapine studies.

The risk for this sequence of hypotension, bradycardia, and sinus pause may be greater in nonpsychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs.

Olanzapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk.

Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression [see Drug Interactions (7) ] .

5.8 Falls Olanzapine may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.

For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.9 Leukopenia, Neutropenia, and Agranulocytosis Class Effect — In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including olanzapine.

Agranulocytosis has also been reported.

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

Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of olanzapine should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant 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 olanzapine and have their WBC followed until recovery.

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

Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s disease.

Olanzapine is not approved for the treatment of patients with Alzheimer’s disease.

5.11 Seizures During premarketing testing, seizures occurred in 0.9% (22/2500) of olanzapine-treated patients.

There were confounding factors that may have contributed to the occurrence of seizures in many of these cases.

Olanzapine 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.

Olanzapine is not approved for the treatment of patients with Alzheimer’s disease.

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

5.12 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse reaction associated with olanzapine treatment, occurring at an incidence of 26% in olanzapine patients compared to 15% in placebo patients.

This adverse reaction was also dose related.

Somnolence led to discontinuation in 0.4% (9/2500) of patients in the premarketing database.

Since olanzapine 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 olanzapine therapy does not affect them adversely [see Patient Counseling Information (17) ] .

5.13 Body Temperature Regulation Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents.

Appropriate care is advised when prescribing olanzapine 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 [see Patient Counseling Information (17) ].

5.14 Anticholinergic (antimuscarinic) Effects Olanzapine exhibits in vitro muscarinic receptor affinity [see Clinical Pharmacology 12.2 ] .

In premarketing clinical trials, olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism.

Such adverse reactions were not often the basis for discontinuations, but olanzapine should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions.

In post marketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications [see Drug Interactions (7.1 )].

5.15 Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, olanzapine elevates prolactin levels, and the elevation persists during chronic administration.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin 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 contemplated in a patient with previously detected breast cancer.

As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1) ] .

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; the available evidence is considered too limited to be conclusive at this time.

In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo.

In a pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual-related events 1 (2% [49/3240] of females), sexual function-related events 2 (2% [150/8136] of females and males), and breast-related events 3 (0.7% [23/3240] of females, 0.2% [9/4896] of males).

In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine­-treated patients compared to 7% of placebo-treated patients.

In a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events 1 (1% [2/168] of females), sexual function-related events 2 (0.7% [3/454] of females and males), and breast-related events 3 (2% [3/168] of females, 2% [7/286] of males) [see Use in Specific Populations (8.4) ] .

1 Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea.

2 Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction.

3 Based on a search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder.

Dose group differences with respect to prolactin elevation have been observed.

In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) indicated significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day.

5.16 Use in Combination with Fluoxetine, Lithium, or Valproate When using olanzapine and fluoxetine in combination, the prescriber should also refer to the Warnings and Precautions section of the package insert for Symbyax.

When using olanzapine in combination with lithium or valproate, the prescriber should refer to the Warnings and Precautions sections of the package inserts for lithium or valproate [see Drug Interactions (7) ].

5.17 Laboratory Tests Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended [see Warnings and Precautions (5.5) and Patient Counseling Information (17 )].

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 • Vascular risks : Stop Natazia if a thrombotic event occurs.

Stop Natazia at least 4 weeks before and through 2 weeks after major surgery.

Start Natazia no earlier than 4 weeks after delivery, in women who are not breastfeeding.

( 5.1 ) • Liver disease : Discontinue Natazia if jaundice occurs.

( 5.3 ) • High blood pressure : Do not prescribe Natazia for women with uncontrolled hypertension or hypertension with vascular disease.

( 5.4 ) • Carbohydrate and lipid metabolic effects : Monitor prediabetic and diabetic women taking Natazia.

Consider an alternate contraceptive method for women with uncontrolled dyslipidemia.

( 5.6 ) • Headache : Evaluate significant change in headaches and discontinue Natazia if indicated.

( 5.7 ) • Uterine bleeding : Evaluate irregular bleeding or amenorrhea.

( 5.8 ) • CYP3A4 induction : Women taking strong CYP3A4 inducers (for example, carbamazepine, phenytoin, rifampicin, and St.

John’s wort) should not choose Natazia as their oral contraceptive due to the possibility of decreased contraceptive efficacy.

( 5.13 , 7.1 ) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop Natazia if an arterial or venous thrombotic event (VTE) occurs.

The use of COCs increases the risk of venous thromboembolism.

However, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs.

The risk of VTE in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years.

The risk of VTE is highest during the first year of use.

Data from a large, prospective cohort safety study of various COCs suggest that this increased risk, as compared to that in non-COC users, is greatest during the first 6 months of COC use.

Data from this safety study indicate that the greatest risk of VTE is present after initially starting a COC or restarting (following a 4 week or greater pill-free interval) the same or a different COC.

Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events.

The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued.

If feasible, stop Natazia at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

Start Natazia no earlier than 4 weeks after delivery, in women who are not breastfeeding.

The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.

COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), hypertensive women who also smoke.

COCs also increase the risk for stroke in women with other underlying risk factors.

Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

Stop Natazia if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.

Evaluate for retinal vein thrombosis immediately.

[See Adverse Reactions ( 6 ).] 5.2 Malignant Neoplasms Breast Cancer Natazia is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications ( 4 )].

Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk.

Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer.

However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [see Adverse Reactions ( 6.2 )] .

Cervical Cancer Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia.

However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors.

5.3 Liver Disease Discontinue Natazia if jaundice develops.

Steroid hormones may be poorly metabolized in patients with impaired liver function.

Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded.

Hepatic adenomas are associated with COC use.

An estimate of the attributable risk is 3.3 cases/100,000 COC users.

Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users.

However, the attributable risk of liver cancers in COC users is less than one case per million users.

Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis.

Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use.

5.4 High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop Natazia if blood pressure rises significantly.

Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs.

An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use.

The incidence of hypertension increases with increasing concentration of progestin.

5.5 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users.

5.6 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking Natazia.

COCs may decrease glucose tolerance in a dose-related fashion.

Consider alternative contraception for women with uncontrolled dyslipidemia.

A small proportion of women will have adverse lipid changes while on COCs.

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

5.7 Headache If a woman taking Natazia develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Natazia if indicated.

An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.

5.8 Bleeding Irregularities Breakthrough bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use.

If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy.

If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC.

Women who are not pregnant and use Natazia, may experience amenorrhea.

Based on patient diaries, amenorrhea occurs in approximately 16% of cycles in women using Natazia.

Pregnancy should be ruled out in the event of amenorrhea occurring in two or more consecutive cycles.

Some women may encounter amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent.

Based on patient diaries from three clinical trials evaluating the safety and efficacy of Natazia for contraception, 10-23% of women experienced intracyclic bleeding per cycle.

5.9 COC Use Before or During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.

Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy.

Oral contraceptive use should be discontinued if pregnancy is confirmed.

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations ( 8.1 )] .

5.10 Depression Women with a history of depression should be carefully observed and Natazia discontinued if depression recurs to a serious degree .

5.11 Interference with Laboratory Tests The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs [see Clinical Pharmacology ( 12.3 )] .

5.12 Monitoring A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.

5.13 Drug Interactions Women who take medications that are strong cytochrome P450 3A4 (CYP3A4) inducers (for example, carbamazepine, phenytoin, rifampicin, and St.

John’s wort) should not choose Natazia as their oral contraceptive while using these inducers and for at least 28 days after discontinuation of these inducers due to the possibility of decreased contraceptive efficacy [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )].

5.14 Other Conditions In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum.

Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs.