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 Cerebrovascular Adverse Reactions: Increased incidence of cerebrovascular adverse events (e.g.

stroke, transient ischemic attack) has been seen in elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs ( 5.3 ) Neuroleptic Malignant Syndrome (NMS): Manage with immediate discontinuation and close monitoring ( 5.4 ) Metabolic Changes: Atypical antipsychotics have been associated with metabolic changes.

These metabolic changes include hyperglycemia, dyslipidemia, and weight gain ( 5.5 ) Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

Monitor glucose regularly in patients with diabetes or at risk for diabetes Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically, during treatment Weight Gain: Gain in body weight has been observed; clinical monitoring of weight is recommended Tardive Dyskinesia: Discontinue if clinically appropriate ( 5.6 ) Hypotension: Use with caution in patients with known cardiovascular or cerebrovascular disease ( 5.7 ) Increased Blood Pressure in Children and Adolescents: Monitor blood pressure at the beginning of, and periodically during treatment in children and adolescents ( 5.9 ) Leukopenia, Neutropenia and Agranulocytosis: Monitor complete blood count frequently during the first few months of treatment in patients with a pre-existing low white cell count or a history of leukopenia/neutropenia and discontinue quetiapine at the first sign of a decline in WBC in absence of other causative factors ( 5.10 ) Cataracts: Lens changes have been observed in patients during long-term quetiapine treatment.

Lens examination is recommended when starting treatment and at 6-month intervals during chronic treatment ( 5.11 ) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Analysis of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.

Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality.

The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

Quetiapine is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING ].

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

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

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

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

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

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.

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

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

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

The risk differences (drug vs.

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

These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.

Table 2: Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Age Range Drug – Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials.

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

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

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

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

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

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

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

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

Such monitoring should include daily observation by families and caregivers.

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

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

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

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

However, prior to initiating treatment with an antidepressant, including quetiapine, 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.

5.3 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects.

Quetiapine is not approved for the treatment of patients with dementia-related psychosis [see also BOXED WARNING and WARNINGS AND PRECAUTIONS ( 5.1 )].

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

Rare cases of NMS have been reported with quetiapine.

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 (CNS) pathology.

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

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

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

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

5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain.

While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

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

Changes in these metabolic profiles should be managed as clinically appropriate.

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

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

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

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

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

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

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

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

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

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

Adults: Table 3: Fasting Glucose-Proportion of Patients Shifting to ≥126 mg/dL in Short-Term (≤12 weeks) Placebo-Controlled Studies * * Includes quetiapine and quetiapine extended-release data Laboratory Analyte Category Change ( At Least Once ) from Baseline Treatment Arm N Patients n (%) Normal to High (<100 mg/dL to ≥126 mg/dL) Quetiapine 2907 71 (2.4%) Placebo 1346 19 (1.4%) Fasting Glucose Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) Quetiapine 572 67 (11.7%) Placebo 279 33 (11.8%) In a 24-week trial (active-controlled, 115 patients treated with quetiapine) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at week 24 the incidence of a treatment-emergent post-glucose challenge glucose level ≥200 mg/dL was 1.7% and the incidence of a fasting treatment-emergent blood glucose level ≥126 mg/dL was 2.6%.

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

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

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

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

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

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

In a placebo-controlled quetiapine extended-release monotherapy study (8 weeks duration) of children and adolescent patients (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the mean change in fasting glucose levels for quetiapine extended-release (n=60) compared to placebo (n=62) was 1.8 mg/dL versus 1.6 mg/dL.

In this study, there were no patients in the quetiapine extended-release or placebo-treated groups with a baseline normal fasting glucose level (126 mg/dL.

There was one patient in the quetiapine extended-release group with a baseline borderline fasting glucose level (>100 mg/dL and 126 mg/dL compared to zero patients in the placebo group.

Dyslipidemia Adults: Table 4 shows the percentage of adult patients with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline by indication in clinical trials with quetiapine.

Table 4: Percentage of Adult Patients with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication Laboratory Analyte Indication Treatment Arm N Patients n (%) Schizophrenia 6 weeks duration Quetiapine 137 24 (18%) Placebo 92 6 (7%) Total Cholesterol ≥240 mg/dL Bipolar Depression 8 weeks duration Quetiapine 463 41 (9%) Placebo 250 15 (6%) Schizophrenia Quetiapine 120 26 (22%) Placebo 70 11 (16%) Triglycerides ≥200 mg/dL Bipolar Depression Quetiapine 436 59 (14%) Placebo 232 20 (9%) Schizophrenia Quetiapine na Parameters not measured in the quetiapine registration studies for schizophrenia.

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

na Placebo na na LDL- Cholesterol ≥160 mg/dL Bipolar Depression Quetiapine 465 29 (6%) Placebo 256 12 (5%) Schizophrenia Quetiapine na na Placebo na na HDL-Cholesterol ≤40 mg/dL Bipolar Depression Quetiapine 393 56 (14%) Placebo 214 29 (14%) Children and Adolescents: Table 5 shows the percentage of children and adolescents with changes in total cholesterol, triglycerides LDL-cholesterol and HDL-cholesterol from baseline in clinical trials with quetiapine.

Table 5: Percentage of Children and Adolescents with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels Laboratory Analyte Indication Treatment Arm N Patients n (%) Schizophrenia 13 to 17 years, 6 weeks duration Quetiapine 107 13 (12%) Placebo 56 1 (2%) Total Cholesterol ≥200 mg/dL Bipolar Mania 10 to 17 years, 3 weeks duration Quetiapine 159 16 (10%) Placebo 66 2 (3%) Schizophrenia Quetiapine 103 17 (17%) Placebo 51 4 (8%) Triglycerides ≥150 mg/dL Bipolar Mania Quetiapine 149 32 (22%) Placebo 60 8 (13%) Schizophrenia Quetiapine 112 4 (4%) Placebo 60 1 (2%) LDL-Cholesterol ≥130 mg/dL Bipolar Mania Quetiapine 169 13 (8%) Placebo 74 4 (5%) Schizophrenia Quetiapine 104 16 (15%) Placebo 54 10 (19%) HDL-Cholesterol ≤40 mg/dL Bipolar Mania Quetiapine 154 16 (10%) Placebo 61 4 (7%) In a placebo-controlled quetiapine extended-release monotherapy study (8 weeks duration) of children and adolescent patients (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the percentage of children and adolescents with shifts in total cholesterol (≥200 mg/dL), triglycerides (≥150 mg/dL), LDL-cholesterol (≥130 mg/dL) and HDL-cholesterol (≤40 mg/dL) from baseline to clinically significant levels were: total cholesterol 8% (7/83) for quetiapine extended-release vs.

6% (5/84) for placebo; triglycerides 28% (22/80) for quetiapine extended-release vs.

9% (7/82) for placebo; LDL-cholesterol 2% (2/86) for quetiapine extended-release vs.

4% (3/85) for placebo and HDL-cholesterol 20% (13/65) for quetiapine extended-release vs.

15% (11/74) for placebo.

Weight Gain Increases in weight have been observed in clinical trials.

Patients receiving quetiapine should receive regular monitoring of weight.

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

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

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

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

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

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

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

In a clinical trial for quetiapine extended-release in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the percentage of patients with weight gain ≥7% of body weight at any time was 15% (14/92) for quetiapine extended-release vs.

10% (10/100) for placebo.

The mean change in body weight was 1.4 kg in the quetiapine extended-release group vs.

0.6 kg in the placebo group.

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

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

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

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

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

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

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

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

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

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

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

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

The need for continued treatment should be reassessed periodically.

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

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

5.7 Hypotension Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α 1 -adrenergic antagonist properties.

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

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

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

The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 25 mg twice daily [see DOSAGE AND ADMINISTRATION ( 2.2 )].

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

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

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

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

In a placebo-controlled quetiapine extended-release clinical trial (8 weeks duration) in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 6.5% (6/92) for quetiapine extended-release and 6.0% (6/100) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 46.7% (43/92) for quetiapine extended-release and 36.0% (36/100) for placebo.

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

Agranulocytosis (including fatal cases) has also been reported.

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

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

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

Patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) should discontinue quetiapine and have their WBC followed until recovery.

5.11 Cataracts The development of cataracts was observed in association with quetiapine treatment in chronic dog studies [see NONCLINICAL TOXICOLOGY ( 13.2 )].

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

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

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

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

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

In post marketing experience, there were cases reported of QT prolongation in patients who overdosed on quetiapine [see OVERDOSAGE ( 10.1 )], in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval [see DRUG INTERACTIONS ( 7.1 )].

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

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

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

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

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

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

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

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

The reduction in total and free thyroxine (T 4 ) of approximately 20% at the higher end of the therapeutic dose range was maximal in the first six weeks of treatment and maintained without adaptation or progression during more chronic therapy.

In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T 4 , irrespective of the duration of treatment.

The mechanism by which quetiapine effects the thyroid axis is unclear.

If there is an effect on the hypothalamic-pituitary axis, measurement of TSH alone may not accurately reflect a patient’s thyroid status.

Therefore, both TSH and free T 4 , in addition to clinical assessment, should be measured at baseline and at follow-up.

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

Of the quetiapine treated patients with elevated TSH levels, 3 had simultaneous low free T 4 levels (free T 4 <0.8 LLN).

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

Some patients with TSH increases needed replacement thyroid treatment.

In all quetiapine trials, the incidence of significant shifts in thyroid hormones and TSH were 1 : decrease in free T 4 (free T 4 <0.8 LLN), 2.0% (357/17513); decrease in total T 4 , 4.0% (75/1861); decrease in free T 3 , 0.4% (53/13766); decrease in total T 3 , 2.0% (26/1312), and increase in TSH, 4.9% (956/19412).

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

1 Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline.

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

Table 8 shows the incidence of these shifts in short-term placebo-controlled clinical trials.

Table 8: Incidence of Shifts in Thyroid Hormone Levels and TSH in Short-Term Placebo-Controlled Clinical Trials 1 , 2 1 Based on shifts from normal baseline to potentially clinically important value at any time post-baseline.

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

2 Includes quetiapine and quetiapine extended-release data.

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

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

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

0% (0/145, respectively).

Of the quetiapine treated patients with elevated TSH levels, 1 had simultaneous low free T 4 level at end of treatment.

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

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

Like other drugs that antagonize dopamine D 2 receptors, quetiapine elevates prolactin levels in some patients and the elevation may persist during chronic administration.

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

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

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

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

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

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

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

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

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

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

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

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

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

Somnolence may lead to falls.

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

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

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

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

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

5.19 Discontinuation Syndrome Acute withdrawal symptoms, such as insomnia, nausea, and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including quetiapine.

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

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

Gradual withdrawal is advised.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Hospitalization and, rarely, death have been reported due to application of multiple patches at same time.

Ensure patients or caregivers receive instruction on proper dosing and administration.

( 5.1 ) • Gastrointestinal Adverse Reactions: May include significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss, and may necessitate treatment interruption.

Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes.

( 5.2 ) • Application-site reactions may occur with the patch form of rivastigmine.

Discontinue treatment if application-site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g., increasing erythema, edema, papules, vesicles), and if symptoms do not significantly improve within 48 hours after patch removal.

( 5.3 ) 5.1 Medication Errors Resulting in Overdose Medication errors with EXELON PATCH have resulted in serious adverse reactions; some cases have required hospitalization, and rarely, led to death.

The majority of medication errors have involved not removing the old patch when putting on a new one and the use of multiple patches at one time.

Instruct patients and their caregivers on important administration instructions for EXELON PATCH [see Dosage and Administration (2.4)] .

5.2 Gastrointestinal Adverse Reactions EXELON PATCH can cause gastrointestinal adverse reactions, including significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss.

Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes.

The incidence and severity of these reactions are dose-related [see Adverse Reactions (6.1)] .

For this reason, initiate treatment with EXELON PATCH at a dose of 4.6 mg/24 hours, and titrate to a dose of 9.5 mg/24 hours and then to a dose of 13.3 mg/24 hours, if appropriate [see Dosage and Administration (2.1)] .

If treatment is interrupted for more than 3 days because of intolerance, reinitiate EXELON PATCH with the 4.6 mg/24 hours dose to reduce the possibility of severe vomiting and its potentially serious sequelae.

A postmarketing report described a case of severe vomiting with esophageal rupture following inappropriate reinitiation of treatment of an oral formulation of rivastigmine without retitration after 8 weeks of treatment interruption.

Inform caregivers to monitor for gastrointestinal adverse reactions and to inform the physician if they occur.

It is critical to inform caregivers that if therapy has been interrupted for more than 3 days because of intolerance, the next dose should not be administered without contacting the physician regarding proper retitration.

5.3 Skin Reactions Skin application-site reactions may occur with EXELON PATCH.

These reactions are not in themselves an indication of sensitization.

However, use of rivastigmine patch may lead to allergic contact dermatitis.

Allergic contact dermatitis should be suspected if application-site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g., increasing erythema, edema, papules, vesicles), and if symptoms do not significantly improve within 48 hours after patch removal.

In these cases, treatment should be discontinued [see Contraindications (4)] .

In patients who develop application-site reactions to EXELON PATCH, suggestive of allergic contact dermatitis and who still require rivastigmine, treatment should be switched to oral rivastigmine only after negative allergy testing and under close medical supervision.

It is possible that some patients sensitized to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine in any form.

There have been isolated postmarketing reports of patients experiencing disseminated allergic dermatitis when administered rivastigmine irrespective of the route of administration (oral or transdermal).

In these cases, treatment should be discontinued [see Contraindications (4)] .

Patients and caregivers should be instructed accordingly.

5.4 Other Adverse Reactions From Increased Cholinergic Activity Neurologic Effects Extrapyramidal Symptoms : Cholinomimetics, including rivastigmine, may exacerbate or induce extrapyramidal symptoms.

Worsening of parkinsonian symptoms, particularly tremor, has been observed in patients with dementia associated with Parkinson’s disease who were treated with EXELON Capsules.

Seizures : Drugs that increase cholinergic activity are believed to have some potential for causing seizures.

However, seizure activity also may be a manifestation of Alzheimer’s disease.

Peptic Ulcers/Gastrointestinal Bleeding Cholinesterase inhibitors, including rivastigmine, may increase gastric acid secretion due to increased cholinergic activity.

Monitor patients using EXELON PATCH for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs).

Clinical studies of rivastigmine have shown no significant increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

Use with Anesthesia Rivastigmine, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.

Cardiac Conduction Effects Because rivastigmine increases cholinergic activity, use of the EXELON PATCH may have vagotonic effects on heart rate (e.g., bradycardia).

The potential for this action may be particularly important in patients with sick sinus syndrome or other supraventricular cardiac conduction conditions.

Genitourinary Effects Although not observed in clinical trials of rivastigmine, drugs that increase cholinergic activity may cause urinary obstruction.

Pulmonary Effects Drugs that increase cholinergic activity, including EXELON PATCH, should be used with care in patients with a history of asthma or obstructive pulmonary disease.

5.5 Impairment in Driving or Use of Machinery Dementia may cause gradual impairment of driving performance or compromise the ability to use machinery.

The administration of rivastigmine may also result in adverse reactions that are detrimental to these functions.

During treatment with EXELON PATCH, routinely evaluate the patient’s ability to continue driving or operating machinery.