ASENAPINE

1 INDICATIONS AND USAGE Asenapine sublingual tablet(s) is indicated for: Bipolar I disorder [see Clinical Studies ( 14.2 )] Adjunctive treatment to lithium or valproate in adults Asenapine is an atypical antipsychotic indicated for ( 1 ): Bipolar I disorder Adjunctive treatment to lithium or valproate in adults

2 DOSAGE AND ADMINISTRATION Starting Dose Recommended Dose Maximum Dose Bipolar mania – adults: as an adjunct to lithium or valproate ( 2.3 ) 5 mg sublingually twice daily 5-10 mg sublingually twice daily 10 mg sublingually twice daily Do not swallow tablet. Asenapine sublingual tablet(s) should be placed under the tongue and left to dissolve completely. The tablet will dissolve in saliva within seconds. Eating and drinking should be avoided for 10 minutes after administration. ( 2.1 , 17 ) 2.1 Administration Instructions Asenapine sublingual tablet(s) is a sublingual tablet. To ensure optimal absorption, patients should be instructed to place the tablet under the tongue and allow it to dissolve completely. The tablet will dissolve in saliva within seconds. Asenapine sublingual tablet(s) should not be split, crushed, chewed, or swallowed [see Clinical Pharmacology ( 12.3 )] . Patients should be instructed to not eat or drink for 10 minutes after administration [see Clinical Pharmacology ( 12.3 )] . 2.3 Bipolar I Disorder Acute Treatment of Manic or Mixed Episodes: Adjunctive Therapy in Adults: The recommended starting dose of Asenapine sublingual tablet(s) is 5 mg twice daily when administered as adjunctive therapy with either lithium or valproate. Depending on the clinical response and tolerability in the individual patient, the dose can be increased to 10 mg twice daily. The safety of doses above 10 mg twice daily as adjunctive therapy with lithium or valproate has not been evaluated in clinical trials. For patients on asenapine, used as adjunctive therapy with lithium or valproate, it is generally recommended that responding patients continue treatment beyond the acute episode.

5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack). ( 5.2 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. ( 5.3 ) Tardive Dyskinesia: Discontinue if clinically appropriate. ( 5.4 ) Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. ( 5.5 ) Orthostatic Hypotension: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope. ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with a pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing asenapine sublingual tablet(s) if a clinically significant decline in WBC occurs in absence of other causative factors. ( 5.9 ) QT Prolongation: Increases in QT interval; avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval. ( 5.10 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. ( 5.12 ) Potential for Cognitive and Motor Impairment: Use caution when operating machinery. ( 5.13 ) 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. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the 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. Asenapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions ( 5.2 )]. 5.2 Cerebrovascular Adverse Events, Including Stroke, In Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attacks, including fatal stroke. Asenapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions ( 5.1 )]. 5.3 Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue asenapine and provide intensive symptomatic treatment and monitoring. 5.4 Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs, including asenapine. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict 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 tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop aft…

4 CONTRAINDICATIONS Asenapine is contraindicated in patients with: Severe hepatic impairment (Child-Pugh C) [see Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. A history of hypersensitivity reactions to asenapine. Reactions have included anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash [see Warnings and Precautions ( 5.6 ), Adverse Reactions ( 6 )]. Severe hepatic impairment (Child-Pugh C). ( 8.7 , 12.3 ) Known hypersensitivity to asenapine, or to any components in the formulation. ( 4 , 5.6 , 17 )

7 DRUG INTERACTIONS Antihypertensive Drugs: Asenapine may cause hypotension. ( 5.7 , 7.1 , 12.3 ) Paroxetine (CYP2D6 substrate and inhibitor): Reduce paroxetine by half when used in combination with asenapine. ( 7.1 , 12.3 ) 7.1 Drugs Having Clinically Important Drug Interactions with Asenapine Table 12: Clinically Important Drug Interactions with Asenapine Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Antihypertensive Drugs Because of its α 1 -adrenergic antagonism with potential for inducing hypotension, asenapine may enhance the effects of certain antihypertensive agents [see Warnings and Precautions ( 5.7 )] . Monitor blood pressure and adjust dosage of antihypertensive drug accordingly. Strong CYP1A2 Inhibitors (e.g., Fluvoxamine) Asenapine is metabolized by CYP1A2. Marginal increase of asenapine exposure was observed when asenapine is used with fluvoxamine at 25 mg administered twice daily [see Clinical Pharmacology ( 12.3 )]. However, the tested fluvoxamine dose was suboptimal. Full therapeutic dose of fluvoxamine is expected to cause a greater increase in asenapine exposure. Dosage reduction for asenapine based on clinical response may be necessary. CYP2D6 substrates and inhibitors (e.g., paroxetine) Asenapine may enhance the inhibitory effects of paroxetine on its own metabolism. Concomitant use of paroxetine with asenapine increased the paroxetine exposure by 2-fold as compared to use paroxetine alone [see Clinical Pharmacology ( 12.3 )]. Reduce paroxetine dose by half when paroxetine is used in combination with asenapine. 7.2 Drugs Having No Clinically Important Interactions with Asenapine No dosage adjustment of asenapine is necessary when administered concomitantly with paroxetine (see Table 12 in Drug Interactions ( 7.1 ) for paroxetine dosage adjustment), imipramine, cimetidine, valproate, lithium, or a CYP3A4 inducer (e.g., carbamazepine, phenytoin, rifampin). In addition, valproic acid and lithium pre-dose serum concentrations collected from an adjunctive therapy study were comparable between asenapine-treated patients and placebo-treated patients indicating a lack of effect of asenapine on valproic and lithium plasma levels.

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Use in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions ( 5.1 and 5.2 )] Neuroleptic Malignant Syndrome [see Warnings and Precautions ( 5.3 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.4 )] Metabolic Changes [see Warnings and Precautions ( 5.5 )] Hypersensitivity Reactions [see Contraindications, Warnings and Precautions ( 5.6 )] Orthostatic Hypotension, Syncope, and other Hemodynamic Effects [see Warnings and Precautions ( 5.7 )] Falls [see Warnings and Precautions ( 5.8 )] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions ( 5.9 )] QT Interval Prolongation [see Warnings and Precautions ( 5.10 )] Hyperprolactinemia [see Warnings and Precautions ( 5.11 )] Seizures [see Warnings and Precautions ( 5.12 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.13 )] Body Temperature Regulation [see Warnings and Precautions ( 5.14 )] Dysphagia [see Warnings and Precautions ( 5.15 )] The most common adverse reactions (≥5% and at least twice the rate of placebo) reported during the adjunctive therapy trial in bipolar I disorder in adults were somnolence and oral hypoesthesia. The rates were lower at the 5 mg twice daily dose than the 10 mg twice daily dose for all of these most common adverse reactions. The adult information below is derived from a clinical trial database for asenapine consisting of over 5355 patients and/or healthy subjects exposed to one or more sublingual doses of asenapine. A total of 1427 asenapine-treated patients were treated for at least 24 weeks and 785 asenapine-treated patients had at least 52 weeks of exposure at therapeutic doses. The stated frequencies of adverse reactions represent the proportion of individuals who experienced a treatment-emergent adverse event of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. The most commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) were ( 6.1 ): Bipolar I Disorder Adults (Adjunctive): somnolence, oral hypoesthesia. To report SUSPECTED ADVERSE REACTIONS, contact Sigmapharm Laboratories, LLC, Pharmacovigilance at 1-855-332-0731 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adjunctive Therapy in Adult Patients with Bipolar Mania: The following findings are based on a 12 week placebo-controlled trial (with a 3 week efficacy endpoint) in adult patients with bipolar mania in which sublingual asenapine was administered in doses of 5 mg or 10 mg twice daily as adjunctive therapy with lithium or valproate. Adverse Reactions Associated with Discontinuation of Treatment: Approximately 16% (25/158) of asenapine-treated patients discontinued treatment due to an adverse reaction, compared with about 11% (18/166) on placebo. The most common adverse reactions associated with discontinuation in subjects treated with asenapine (rates at least 1% and at least twice the placebo rate) were depression (2.5%), suicidal ideation (2.5%), bipolar I disorder (1.9%), insomnia (1.9%) and depressive symptoms (1.3%). Adverse Reactions Occurring at an Incidence of 2% or More Among Asenapine-Treated (Adjunctive) Bipolar I Patients: Adverse reactions associated with the use of asenapine (incidence of 2% or greater, rounded to the nearest percent, and asenapine incidence greater than placebo) that occurred during acute adjunctive therapy at 3 weeks, a time when most of the patients were still participating in the trial, are shown in Tab…