Author: druginteractionchecker_lgaiz4

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: and 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 (5.12) Hyperprolactinemia: May elevate prolactin levels (5.15) 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.

(5.17) 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, Warnings and Precautions (5.14) , and Patient Counseling Information (17.2) ].

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 (17.2) ].

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 (17.3) ].

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 ( 17.4 )].

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 Physicians 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 ( 17.5 ) ].

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 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 HbA1c increase from baseline of 0.04% (median exposure 21 days), compared to a mean HbA1c decrease of 0.06% in placebo-treated subjects (median exposure 17 days).

In an analysis of 8 placebo-controlled studies (median treatment exposure 4 to 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 ( 17.6 ) ].

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 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 to 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 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 ( 17.7 ) ] 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 >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.

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cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

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

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

Given these considerations, 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 ( 17.8 ) ] 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 (17.9) ].

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 (17.10) ].

5.14 Use in Patients with Concomitant Illness Clinical experience with olanzapine in patients with certain concomitant systemic illnesses is limited [see Clinical Pharmacology (12.3) ].

Olanzapine exhibits in vitro muscarinic receptor affinity.

In premarketing clinical trials with olanzapine, 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 from olanzapine, but olanzapine should be used with caution in patients with clinically significant prostatic hypertrophy, narrow angle glaucoma, or a history of paralytic ileus or related conditions.

In 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following treatment-emergent adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations.

The rate of discontinuation due to adverse reactions was greater with olanzapine than placebo (13% vs 7%).

Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo.

Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1 )and Patient Counseling Information (17.2) ].

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

Patients with these diagnoses were excluded from premarketing clinical studies.

Because of the risk of orthostatic hypotension with olanzapine, caution should be observed in cardiac patients [see Warnings and Precautions ( 5.7 ) ] 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 olanzapinetreated 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 ( 5.4 ), and Patient Counseling Information ( 17.5 , 17.6 )].

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Patients should not use VIAGRA if sexual activity is inadvisable due to cardiovascular status ( 5.1 ) • Patients should seek emergency treatment if an erection lasts >4 hours.

Use VIAGRA with caution in patients predisposed to priapism ( 5.2 ) • Patients should stop VIAGRA and seek medical care if a sudden loss of vision occurs in one or both eyes, which could be a sign of non arteritic anterior ischemic optic neuropathy (NAION).

VIAGRA should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION.

Patients with a “crowded” optic disc may also be at an increased risk of NAION.

( 5.3 ) • Patients should stop VIAGRA and seek prompt medical attention in the event of sudden decrease or loss of hearing ( 5.4 ) • Caution is advised when VIAGRA is co-administered with alpha-blockers or anti-hypertensives.

Concomitant use may lead to hypotension ( 5.5 ) • Decreased blood pressure, syncope, and prolonged erection may occur at higher sildenafil exposures.

In patients taking strong CYP inhibitors, such as ritonavir, sildenafil exposure is increased.

Decrease in VIAGRA dosage is recommended ( 2.4 , 5.6 ) 5.1 Cardiovascular There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease.

Therefore, treatments for erectile dysfunction, including VIAGRA, should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.

The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment.

VIAGRA has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 8.4/5.5 mmHg), [ see Clinical Pharmacology (12.2) ].

While this normally would be expected to be of little consequence in most patients, prior to prescribing VIAGRA, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity.

Use with caution in patients with the following underlying conditions which can be particularly sensitive to the actions of vasodilators including VIAGRA – those with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure.

There are no controlled clinical data on the safety or efficacy of VIAGRA in the following groups; if prescribed, this should be done with caution.

• Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months; • Patients with resting hypotension (BP 170/110 mmHg); • Patients with cardiac failure or coronary artery disease causing unstable angina.

5.2 Prolonged Erection and Priapism Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of VIAGRA.

In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance.

If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.

VIAGRA should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

However, there are no controlled clinical data on the safety or efficacy of VIAGRA in patients with sickle cell or related anemias.

5.3 Effects on the Eye Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including VIAGRA, and seek medical attention in the event of a sudden loss of vision in one or both eyes.

Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision including permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors.

Based on published literature, the annual incidence of NAION is 2.5–11.8 cases per 100,000 in males aged ≥ 50.

An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period.

The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34).

A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20).

Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies.

Neither the rare post-marketing reports, nor the association of PDE5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE5 inhibitor use and NAION [ see Adverse Reactions (6.2) ].

Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors.

Individuals who have already experienced NAION are at increased risk of NAION recurrence.

Therefore, PDE5 inhibitors, including VIAGRA, should be used with caution in these patients and only when the anticipated benefits outweigh the risks.

Individuals with “crowded” optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including VIAGRA, for this uncommon condition.

There are no controlled clinical data on the safety or efficacy of VIAGRA in patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases); if prescribed, this should be done with caution.

5.4 Hearing Loss Physicians should advise patients to stop taking PDE5 inhibitors, including VIAGRA, and seek prompt medical attention in the event of sudden decrease or loss of hearing.

These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including VIAGRA.

It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [ see Adverse Reactions (6.1 , 6.2) ].

5.5 Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives Alpha-blockers Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers.

PDE5 inhibitors, including VIAGRA, and alpha-adrenergic blocking agents are both vasodilators with blood pressure lowering effects.

When vasodilators are used in combination, an additive effect on blood pressure may occur.

In some patients, concomitant use of these two drug classes can lower blood pressure significantly [ see Drug Interactions (7.2) and Clinical Pharmacology (12.2) ] leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting).

Consideration should be given to the following: • Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.

Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor.

• In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose [ see Dosage and Administration (2.3) ].

• In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose.

Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor.

• Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.

Anti-hypertensives VIAGRA has systemic vasodilatory properties and may further lower blood pressure in patients taking anti-hypertensive medications.

In a separate drug interaction study, when amlodipine, 5 mg or 10 mg, and VIAGRA, 100 mg were orally administered concomitantly to hypertensive patients mean additional blood pressure reduction of 8 mmHg systolic and 7 mmHg diastolic were noted [ see Drug Interactions (7.3) and Clinical Pharmacology (12.2) ].

5.6 Adverse Reactions with the Concomitant Use of Ritonavir The concomitant administration of the protease inhibitor ritonavir substantially increases serum concentrations of sildenafil (11-fold increase in AUC).

If VIAGRA is prescribed to patients taking ritonavir, caution should be used.

Data from subjects exposed to high systemic levels of sildenafil are limited.

Decreased blood pressure, syncope, and prolonged erection were reported in some healthy volunteers exposed to high doses of sildenafil (200–800 mg).

To decrease the chance of adverse reactions in patients taking ritonavir, a decrease in sildenafil dosage is recommended [ see Dosage and Administration (2.4) , Drug Interactions (7.4) , and Clinical Pharmacology (12.3) ].

5.7 Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies The safety and efficacy of combinations of VIAGRA with other PDE5 Inhibitors, including REVATIO or other pulmonary arterial hypertension (PAH) treatments containing sildenafil, or other treatments for erectile dysfunction have not been studied.

Such combinations may further lower blood pressure.

Therefore, the use of such combinations is not recommended.

5.8 Effects on Bleeding There have been postmarketing reports of bleeding events in patients who have taken VIAGRA.

A causal relationship between VIAGRA and these events has not been established.

In humans, VIAGRA has no effect on bleeding time when taken alone or with aspirin.

However, in vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor).

In addition, the combination of heparin and VIAGRA had an additive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studied in humans.

The safety of VIAGRA is unknown in patients with bleeding disorders and patients with active peptic ulceration.

5.9 Counseling Patients About Sexually Transmitted Diseases The use of VIAGRA offers no protection against sexually transmitted diseases.

Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone.

If it occurs, discontinue PRISTIQ and serotonergic agents and initiate supportive treatment ( 5.2 ).

• Elevated Blood Pressure: Control hypertension before initiating treatment.

Monitor blood pressure regularly during treatment ( 5.3 ).

• Increased Risk of Bleeding: Concomitant use of aspirin, NSAIDs, other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk ( 5.4 ).

• Angle Closure Glaucoma: Avoid use of antidepressants, including PRISTIQ, in patients with untreated anatomically narrow angles treated ( 5.5 ).

• Activation of Mania/Hypomania: Use cautiously in patients with Bipolar Disorder.

Caution patients about risk of activation of mania/hypomania ( 5.6 ).

• Discontinuation Syndrome: Taper dose when possible and monitor for discontinuation symptoms ( 5.7 ).

• Seizure: Can occur.

Use cautiously in patients with seizure disorder ( 5.8 ).

• Hyponatremia: Can occur in association with SIADH ( 5.9 ).

• Interstitial Lung Disease and Eosinophilic Pneumonia: Can occur ( 5.10 ).

• Sexual Dysfunction: PRISTIQ may cause symptoms of sexual dysfunction ( 5.11 ).

5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients Patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.

Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4,400 patients.

The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.

There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.

There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.

The risk differences (drug vs.

placebo), however, were relatively stable within age strata and across indications.

These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.

Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric studies.

There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.

However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression.

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

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

Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

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

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Dosage and Administration (2.4) , Warnings and Precautions (5.7) ] .

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers.

Such monitoring should include daily observation by families and caregivers.

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

Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder.

It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.

Whether any of the symptoms described above represent such a conversion is unknown.

However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

It should be noted that PRISTIQ is not approved for use in treating bipolar depression.

5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective-serotonin reuptake inhibitors (SSRIs), including PRISTIQ, 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, meperidine, methadone, tryptophan, buspirone, amphetamines, and St.

John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4) , Drug Interactions (7.1) ] .

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 PRISTIQ with MAOIs is contraindicated.

In addition, do not initiate PRISTIQ 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 PRISTIQ, discontinue PRISTIQ before initiating treatment with the MAOI [see Contraindications (4) , Drug Interactions (7.1) ] .

Monitor all patients taking PRISTIQ for the emergence of serotonin syndrome.

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

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

5.3 Elevated Blood Pressure Patients receiving PRISTIQ should have regular monitoring of blood pressure since increases in blood pressure were observed in clinical studies [see Adverse Reactions (6.1) ] .

Pre-existing hypertension should be controlled before initiating treatment with PRISTIQ.

Caution should be exercised in treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure.

Cases of elevated blood pressure requiring immediate treatment have been reported with PRISTIQ.

Sustained blood pressure increases could have adverse consequences.

For patients who experience a sustained increase in blood pressure while receiving PRISTIQ, either dose reduction or discontinuation should be considered [see Adverse Reactions (6.1) ] .

5.4 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including PRISTIQ, may increase the risk of bleeding events.

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

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

Based on data from the published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1) ] .

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

Inform patients about the increased risk of bleeding associated with the concomitant use of PRISTIQ and antiplatelet agents or anticoagulants.

For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing PRISTIQ.

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

Avoid use of antidepressants, including PRISTIQ, in patients with untreated anatomically narrow angles.

5.6 Activation of Mania/Hypomania During all MDD phase 2 and phase 3 studies, mania was reported for approximately 0.02% of patients treated with PRISTIQ.

Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants.

As with all antidepressants, PRISTIQ should be used cautiously in patients with a history or family history of mania or hypomania.

5.7 Discontinuation Syndrome Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures [see Adverse Reactions (6.1) ].

There have been postmarketing reports of serious discontinuation symptoms with PRISTIQ, which can be protracted and severe.

Completed suicide, suicidal thoughts, and severe aggression (including hostility, rage, and homicidal ideation) have been observed in patients during reduction in PRISTIQ dosage, including during discontinuation.

Other postmarketing reports describe visual changes (such as blurred vision or trouble focusing) and increased blood pressure after stopping or reducing the dose of PRISTIQ .

Patients should be monitored when discontinuing treatment with PRISTIQ.

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

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

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

In some patients, discontinuation may need to occur over a period of several months [see Dosage and Administration (2.5) ] .

5.8 Seizure Cases of seizure have been reported in pre-marketing clinical studies with PRISTIQ.

PRISTIQ has not been systematically evaluated in patients with a seizure disorder.

Patients with a history of seizures were excluded from pre-marketing clinical studies.

PRISTIQ should be prescribed with caution in patients with a seizure disorder.

5.9 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including PRISTIQ.

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

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

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

Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ] .

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

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

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

5.10 Interstitial Lung Disease and Eosinophilic Pneumonia Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent drug of PRISTIQ) therapy have been rarely reported.

The possibility of these adverse events should be considered in patients treated with PRISTIQ who present with progressive dyspnea, cough, or chest discomfort.

Such patients should undergo a prompt medical evaluation, and discontinuation of PRISTIQ should be considered.

5.11 Sexual Dysfunction Use of SNRIs, including PRISTIQ, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1) ] .

In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction.

In female patients, SNRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of PRISTIQ and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported.

When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder.

Discuss potential management strategies to support patients in making informed decisions about treatment.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Prolongation of the QT interval and isolated cases of torsade de pointes has been reported.

Avoid use in patients with known prolongation, proarrhythmic conditions such as clinically significant bradycardia or acute myocardial ischemia, hypokalemia, hypomagnesemia, and with drugs that prolong the QT interval.

(5.6 , 7.5 , 8.5) Hypersensitivity and other serious reactions: Serious and sometimes fatal reactions, including anaphylactic reactions, may occur after first or subsequent doses of moxifloxacin hydrochloride.

Discontinue moxifloxacin hydrochloride at first sign of skin rash, jaundice or any other sign of hypersensitivity.

(5.7 , 5.8) Clostridioides difficile -Associated Diarrhea: Evaluate if diarrhea occurs.

(5.10) 5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects Fluoroquinolones, including moxifloxacin hydrochloride, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient.

Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion).

These reactions can occur within hours to weeks after starting moxifloxacin hydrochloride.

Patients of any age or without pre-existing risk factors have experienced these adverse reactions [see Warnings and Precautions (5.2 , 5.3 , 5.4) ].

Discontinue moxifloxacin hydrochloride immediately at the first signs or symptoms of any serious adverse reaction.

In addition, avoid the use of fluoroquinolones, including moxifloxacin hydrochloride, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

5.2 Tendinitis and Tendon Rupture Fluoroquinolones, including moxifloxacin hydrochloride, have been associated with an increased risk of tendinitis and tendon rupture in all ages [see Warnings and Precautions (5.1) and Adverse Reactions (6.2) ].

This adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons.

Tendinitis or tendon rupture can occur within hours or days of starting moxifloxacin or as long as several months after completion of therapy.

Tendinitis and tendon rupture can occur bilaterally.

The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.

Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis.

Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors.

Discontinue moxifloxacin hydrochloride immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon.

Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug.

Avoid fluoroquinolones, including moxifloxacin hydrochloride, in patients who have a history of tendon disorders or who have experienced tendinitis or tendon rupture [see Adverse Reactions (6.2) ].

5.3 Peripheral Neuropathy Fluoroquinolones, including moxifloxacin hydrochloride, have been associated with an increased risk of peripheral neuropathy.

Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones including moxifloxacin hydrochloride.

Symptoms may occur soon after initiation of moxifloxacin hydrochloride and may be irreversible in some patients [see Warnings and Precautions (5.1) and Adverse Reactions (6.1 , 6.2) ].

Discontinue moxifloxacin hydrochloride immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation.

Avoid fluoroquinolones, including moxifloxacin hydrochloride, in patients who have previously experienced peripheral neuropathy.

5.4 Central Nervous System Effects Psychiatric Adverse Reactions Fluoroquinolones, including moxifloxacin hydrochloride, have been associated with an increased risk of psychiatric adverse reactions, including: toxic psychosis, hallucinations, or paranoia; depression or suicidal thoughts or acts; anxiety, agitation, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; memory impairment.

These adverse reactions may occur following the first dose.

If these reactions occur in patients receiving moxifloxacin hydrochloride, discontinue moxifloxacin hydrochloride immediately and institute appropriate measures [see Adverse Reactions (6.1 , 6.2) ].

Central Nervous System Adverse Reactions Fluoroquinolones, including moxifloxacin hydrochloride, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (including pseudotumor cerebri), dizziness, and tremors.

As with all fluoroquinolones, use moxifloxacin hydrochloride with caution in patients with known or suspected CNS disorders (for example, severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold.

These adverse reactions may occur following the first dose.

If these reactions occur in patients receiving moxifloxacin hydrochloride, discontinue moxifloxacin hydrochloride immediately and institute appropriate measures [see Drug Interactions (7.4) , Adverse Reactions (6.1 , 6.2) , and Patient Counseling Information (17) ].

5.5 Exacerbation of Myasthenia Gravis Fluoroquinolones, including moxifloxacin hydrochloride, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis.

Postmarketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis.

Avoid moxifloxacin hydrochloride in patients with known history of myasthenia gravis.

5.6 QT Prolongation Moxifloxacin hydrochloride has been shown to prolong the QT interval of the electrocardiogram in some patients.

Following oral dosing with 400 mg of moxifloxacin hydrochloride the mean (± SD) change in QTc from the pre-dose value at the time of maximum drug concentration was 6 msec (± 26) (n = 787).

Following a course of daily intravenous dosing (400 mg; 1 hour infusion each day) the mean change in QTc from the Day 1 pre-dose value was 10 msec (±22) on Day 1 (n=667) and 7 msec (± 24) on Day 3 (n = 667).

Avoid moxifloxacin hydrochloride in patients with the following risk factors due to the lack of clinical experience with the drug in these patient populations: Known prolongation of the QT interval Ventricular arrhythmias including torsade de pointes because QT prolongation may lead to an increased risk for these conditions Ongoing proarrhythmic conditions, such as clinically significant bradycardia and acute myocardial ischemia, Uncorrected hypokalemia or hypomagnesemia Class IA (for example, quinidine, procainamide) or Class III (for example, amiodarone, sotalol) antiarrhythmic agents Other drugs that prolong the QT interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants Elderly patients using intravenous moxifloxacin hydrochloride may be more susceptible to drug-associated QT prolongation [see Use In Specific Populations (8.5) ].

In patients with mild, moderate, or severe liver cirrhosis, metabolic disturbances associated with hepatic insufficiency may lead to QT prolongation.

Monitor ECG in patients with liver cirrhosis treated with moxifloxacin hydrochloride [see Clinical Pharmacology (12.3) ].

The magnitude of QT prolongation may increase with increasing concentrations of the drug or increasing rates of infusion of the intravenous formulation.

Therefore the recommended dose or infusion rate should not be exceeded.

In premarketing clinical trials, the rate of cardiovascular adverse reactions was similar in 798 moxifloxacin hydrochloride and 702 comparator treated patients who received concomitant therapy with drugs known to prolong the QTc interval.

No excess in cardiovascular morbidity or mortality attributable to QTc prolongation occurred with moxifloxacin hydrochloride treatment in over 15,500 patients in controlled clinical studies, including 759 patients who were hypokalemic at the start of treatment, and there was no increase in mortality in over 18,000 moxifloxacin tablet treated patients in a postmarketing observational study in which ECGs were not performed.

5.7 Other Serious and Sometimes Fatal Adverse Reactions Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with fluoroquinolones, including moxifloxacin hydrochloride.

These reactions may be severe and generally occur following the administration of multiple doses.

Clinical manifestations may include one or more of the following: Fever, rash, or severe dermatologic reactions (for example, toxic epidermal necrolysis, Stevens-Johnson syndrome) Vasculitis; arthralgia; myalgia; serum sickness Allergic pneumonitis Interstitial nephritis; acute renal insufficiency or failure Hepatitis; jaundice; acute hepatic necrosis or failure Anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities Discontinue moxifloxacin hydrochloride immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and institute supportive measures.

5.8 Hypersensitivity Reactions Serious anaphylactic reactions, some following the first dose, have been reported in patients receiving fluoroquinolone therapy, including moxifloxacin hydrochloride.

Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching.

Discontinue moxifloxacin hydrochloride at the first appearance of a skin rash or any other sign of hypersensitivity [see Warnings and Precautions (5.7) ].

5.9 Risk of Aortic Aneurysm and Dissection Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients.

The cause for the increased risk has not been identified.

In patients with a known aortic aneurysm or patients who are at greater risk for aortic aneurysms, reserve moxifloxacin hydrochloride for use only when there are no alternative antibacterial treatments available.

5.10 Clostridioides difficile -Associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including moxifloxacin hydrochloride, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.

difficile .

C.

difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains of C.

difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibacterial use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.

difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.

difficile , and surgical evaluation should be instituted as clinically indicated.

5.11 Arthropathic Effects in Animals In immature dogs, oral administration of moxifloxacin hydrochloride caused lameness.

Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage.

Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species [see Nonclinical Toxicology (13.2) ].

5.12 Blood Glucose Disturbances As with all fluoroquinolones, disturbances in blood glucose, including both hypoglycemia and hyperglycemia have been reported with moxifloxacin hydrochloride.

In moxifloxacin hydrochloride-treated patients, dysglycemia occurred predominantly in elderly diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (for example, sulfonylurea) or with insulin.

Severe cases of hypoglycemia resulting in coma or death have been reported.

In diabetic patients, careful monitoring of blood glucose is recommended.

If a hypoglycemic reaction occurs, discontinue moxifloxacin hydrochloride and initiate appropriate therapy immediately [see Adverse Reactions (6.1) , Drug Interactions (7.3) , and Patient Counseling Information (17) ].

5.13 Photosensitivity/Phototoxicity Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (for example, burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of fluoroquinolones, including moxifloxacin hydrochloride, after sun or UV light exposure.

Therefore, excessive exposure to these sources of light should be avoided.

Moxifloxacin hydrochloride should be discontinued if phototoxicity occurs [see Clinical Pharmacology (12.2) ].

5.14 Development of Drug Resistant Bacteria Prescribing moxifloxacin hydrochloride in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS A mortality imbalance was seen in clinical trials in SIRTURO-treated patients with pulmonary TB due to Mycobacterium tuberculosis resistant to at least rifampin.

( 5.2 ) Hepatotoxicity may occur with use of SIRTURO.

Monitor liver-related laboratory tests.

Discontinue SIRTURO if evidence of liver injury occurs.

( 5.4 ) 5.1 QTc Prolongation SIRTURO prolongs the QTc interval [see Clinical Pharmacology (12.2) ] .

Use with drugs that prolong the QTc interval may cause additive QTc prolongation [see Adverse Reactions (6) ] .

In Study 4, where SIRTURO was administered with the QTc prolonging drugs clofazimine and levofloxacin, 5% of patients in the 40-week SIRTURO treatment group experienced a QTc ≥500 ms and 43% of patients experienced an increase in QTc ≥60 ms over baseline.

Of the clofazimine- and levofloxacin-treated patients in the 40-week control arm, 7% of patients experienced a QTc ≥500 ms and 39% experienced an increase in QTc ≥60 ms over baseline.

Obtain an ECG before initiation of treatment, 2 weeks after initiation, during treatment, as clinically indicated and at the expected time of maximum increase in the QTc interval of the concomitantly administered QTc prolonging drugs (as applicable).

Obtain electrolytes at baseline and during treatment and correct electrolytes as clinically indicated.

The following may increase the risk for QTc prolongation when patients are taking SIRTURO: use with other QTc prolonging drugs a history of Torsade de Pointes a history of congenital long QTc syndrome a history of or ongoing hypothyroidism a history of or ongoing bradyarrhythmias a history of uncompensated heart failure serum calcium, magnesium, or potassium levels below the lower limits of normal Discontinue SIRTURO if the patient develops: Clinically significant ventricular arrhythmia A QTc interval of greater than 500 ms (confirmed by repeat ECG) If syncope occurs, obtain an ECG to detect QTc prolongation.

5.2 Mortality Imbalance in Clinical Trials An increased risk of death was seen in the SIRTURO treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial in adults (Study 1; based on the 120 week visit window).

One death occurred during the 24 weeks of administration of SIRTURO.

The imbalance in deaths is unexplained.

No discernible pattern between death and sputum culture conversion, relapse, sensitivity to other drugs used to treat tuberculosis, HIV status, or severity of disease could be observed.

In a subsequent active-controlled trial in adults (Study 4), deaths by Week 132 occurred in 11/211 (5.2%) patients in the 40-week SIRTURO treatment group, 8/202 (4%) patients in the active-control treatment group including four of 29 patients who received SIRTURO as part of a salvage treatment, and 2/143 (1.4%) patients in the 28-week SIRTURO treatment group [see Adverse Reactions (6.1) ] .

5.3 Risk of Development of Resistance to Bedaquiline A potential for development of resistance to bedaquiline in M.

tuberculosis exists [see Microbiology (12.4) ].

Bedaquiline must only be used in an appropriate combination regimen for the treatment of pulmonary TB due to M.

tuberculosis resistant to at least rifampin and isoniazid, to reduce the risk of development of resistance to bedaquiline [see Indications and Usage (1) ] .

5.4 Hepatotoxicity In clinical trials, more hepatic-related adverse reactions were reported in adults with the use of SIRTURO plus other drugs used to treat TB compared to other drugs used to treat TB without the addition of SIRTURO.

Alcohol and other hepatotoxic drugs should be avoided while on SIRTURO, especially in patients with impaired hepatic function.

Hepatic-related adverse reactions have also been reported in pediatric patients 5 years of age and older [see Adverse Reactions (6.1) ] .

Monitor symptoms (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness and hepatomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at baseline, monthly while on treatment, and as needed.

Test for viral hepatitis and discontinue other hepatotoxic medications if evidence of new or worsening liver dysfunction occurs.

Discontinue SIRTURO if: transaminase elevations are accompanied by total bilirubin elevation greater than two times the upper limit of normal transaminase elevations are greater than eight times the upper limit of normal transaminase elevations are greater than five times the upper limit of normal and persist beyond two weeks 5.5 Drug Interactions CYP3A4 Inducers Coadministration of SIRTURO with a moderate or strong CYP3A4 inducer decreases the systemic exposure of bedaquiline and may reduce the therapeutic effect of SIRTURO.

Avoid coadministration of SIRTURO with moderate or strong CYP3A4 inducers, such as efavirenz and rifamycins (i.e., rifampin, rifapentine and rifabutin) [see Drug Interactions (7.1) ] .

CYP3A4 Inhibitors Coadministration of SIRTURO with CYP3A4 inhibitors increases the systemic exposure of bedaquiline, which may increase the risk of adverse reactions.

Closely monitor patient safety (e.g., liver function) when SIRTURO is coadministered with CYP3A4 inhibitors [see Drug Interactions (7.1) ] .

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Observe for signs and symptoms of hypotension ( 5.2 ) • Monitor renal function and potassium in susceptible patients ( 5.3 , 5.4 ) 5.1 Fetal Toxicity Valsartan can cause fetal harm when administered to a pregnant woman.

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue valsartan tablets as soon as possible [see Use in Specific Populations ( 8.1 )].

5.2 Hypotension Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with valsartan alone.

In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur.

This condition should be corrected prior to administration of valsartan, or the treatment should start under close medical supervision.

Patients with heart failure or post-myocardial infarction patients given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed.

In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients.

In the VALsartan In Acute myocardial infarcTion trial (VALIANT), hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients.

If excessive hypotension occurs, place the patient in the supine position and, if necessary, give intravenous normal saline.

A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

5.3 Impaired Renal Function Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics.

Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g.

patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on valsartan.

Monitor renal function periodically in these patients.

Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan tablets [see Drug Interactions ( 7 )].

5.4 Hyperkalemia Some patients with heart failure have developed increases in potassium.

These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment.

Dosage reduction and/or discontinuation of valsartan tablets may be required.

[see Adverse Reactions ( 6.1 )].