Asenapine

Indications and Usage ( 1 ) 01/2017 Dosage and Administration ( 2.3 ) 01/2017 Contraindications ( 4 ) 01/2017 Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.4 , 5.5 , 5.7 , 5.9 , 5.10 , 5.11 , 5.12 , 5.13 , 5.14 , 5.15 ) 01/2017 Warnings and Precautions ( 5.8 ) 02/2017

1 INDICATIONS AND USAGE Asenapine sublingual tablets are indicated for: Schizophrenia in adults [see Clinical Studies (14.1) ] Bipolar I disorder [see Clinical Studies (14.2) ] Acute monotherapy of manic or mixed episodes, in adults and pediatric patients 10 to 17 years of age Adjunctive treatment to lithium or valproate in adults Maintenance monotherapy treatment in adults Asenapine sublingual tablets are an atypical antipsychotic indicated for ( 1 ): Schizophrenia in adults Bipolar I disorder Acute monotherapy treatment of manic or mixed episodes, in adults and pediatric patients 10 to 17 years of age Adjunctive treatment to lithium or valproate in adults Maintenance monotherapy treatment in adults

2 DOSAGE AND ADMINISTRATION Starting Dose Recommended Dose Maximum Dose Schizophrenia – acute treatment in adults ( 2.2 ) 5 mg sublingually twice daily 5 mg sublingually twice daily 10 mg sublingually twice daily Schizophrenia – maintenance treatment in adults ( 2.2 ) 5 mg sublingually twice daily 5-10 mg sublingually twice daily 10 mg sublingually twice daily Bipolar mania-adults: acute and maintenance monotherapy ( 2.3 ) 5-10 mg sublingually twice daily 5-10 mg sublingually twice daily 10 mg sublingually twice daily Bipolar mania – pediatric patients (10 to 17 years): monotherapy ( 2.3 ) 2.5 mg sublingually twice daily 2.5-10 mg sublingually twice daily 10 mg sublingually twice daily 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 tablets 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 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 tablets 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) ] . 2.2 Schizophrenia The recommended dose of asenapine sublingual tablets is 5 mg given twice daily. In short-term controlled trials, there was no suggestion of added benefit with a 10 mg twice daily dose, but there was a clear increase in certain adverse reactions. If tolerated, daily dosage can be increased to 10 mg twice daily after one week. The safety of doses above 10 mg twice daily has not been evaluated in clinical studies [see Clinical Studies (14.1) ]. 2.3 Bipolar I Disorder Acute Treatment of Manic or Mixed Episodes: Monotherapy in Adults : The recommended starting and treatment dose of asenapine sublingual tablets is 5 mg to 10 mg twice daily. The safety of doses above 10 mg twice daily has not been evaluated in clinical trials [see Clinical Studies (14.2) ]. Monotherapy in Pediatric Patients: The recommended dose of asenapine sublingual tablets are 2.5 mg to 10 mg twice daily in pediatric patients 10 to 17 years of age, and dose may be adjusted for individual response and tolerability. The starting dose of asenapine sublingual tablets is 2.5 mg twice daily. After 3 days, the dose can be increased to 5 mg twice daily, and from 5 mg to 10 mg twice daily after 3 additional days. Pediatric patients aged 10 to 17 years appear to be more sensitive to dystonia with initial dosing with asenapine sublingual tablets when the recommended escalation schedule is not followed [see Use in Specific Populations (8.4) ] . The safety of doses greater than 10 mg twice daily has not been evaluated in clinical trials [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3) ] . Adjunctive Therapy in Adults: The recommended starting dose of asenapine sublingual tablets 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 sublingual tablets, whether used as monotherapy or as adjunctive therapy with lithium or valproate, it is generally recommended that responding patients continue treatment beyond the acute episode. Maintenance Treatment of Bipolar I Disorder: Monotherapy in Adults: Continue on the asenapine sublingual tablet …

3 DOSAGE FORMS AND STRENGTHS Asenapine sublingual 5 mg tablets are round, white, uncoated tablets debossed “B” on one side and “1” on the other side. Asenapine sublingual 10 mg tablets are round, white, uncoated tablets debossed “B” on one side and “2” on the other side. Asenapine sublingual 2.5 mg tablets, black cherry flavor, are white colored, round shaped, uncoated tablets debossed with "B" on one side and "5" on the other side. Asenapine sublingual 5 mg tablets, black cherry flavor, are round, white, uncoated tablets debossed “B” on one side and “3” on the other side. Asenapine sublingual 10 mg tablets, black cherry flavor, are round, white, uncoated tablets debossed "B" on one side and "4" on the other side. Sublingual tablets: 5 mg and 10 mg ( 3 ) Sublingual tablets, black cherry flavor: 2.5 mg, 5 mg and 10 mg ( 3 )

4 CONTRAINDICATIONS Asenapine sublingual tablets are 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 sublingual tablets, or to any components in the formulation. ( 4 , 5.6 , 17 )

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 with acute treatment in adults with schizophrenia were akathisia, oral hypoesthesia, and somnolence. The safety profile of asenapine sublingual tablets in the maintenance treatment of schizophrenia in adults was similar to that seen with acute treatment. The most common adverse reactions (≥5% and at least twice the rate of placebo) reported with acute monotherapy treatment of manic or mixed episodes associated with bipolar I disorder in adults were somnolence, oral hypoesthesia dizziness, extrapyramidal symptoms (excluding akathisia) and akathisia; and during the adjunctive therapy trial in bipolar I disorder in adults were somnolence and oral hypoesthesia. The rates were lower at the 5mg twice daily dose than the 10mg twice daily dose for all of these most common adverse reactions. The safety profile of asenapine sublingual tablets in the maintenance treatment of manic or mixed episodes associated with bipolar I disorder in adults was similar to that seen with acute treatment. The adult information below is derived from a clinical trial database for asenapine sublingual tablets consisting of over 5,355 patients and/or healthy subjects exposed to one or more sublingual doses of asenapine sublingual tablets. A total of 1,427 asenapine-treated patients were treated for at least 24 weeks and 785 asenapine sublingual tablets-treated patients had at least 52 weeks of exposure at therapeutic doses. In a 3-week monotherapy trial, the most common adverse reactions (≥5% and at least twice the rate of placebo) reported in pediatric patients with bipolar I disorder treated with asenapine sublingual tablets were somnolence, dizziness, dysgeusia, oral hypoesthesia, nausea, increased appetite, fatigue, and increased weight. No new major safety findings were reported from a 50-week, open-label, uncontrolled safety trial. A total of 651 pediatric patients were treated with asenapine sublingual tablets. Of these patients, 352 pediatric patients were treated with asenapine sublingual tablets for at least 180 days and 58 pediatric patients treated with asenapine sublingual tablets had at least 1 year of exposure. The safety of asenapine sublingual tablets was evaluated in 403 pediatric patients with bipolar I disorder who participated in a 3-week, placebo-controlled, double-blind trial, of whom 302 patients received asenapine sublingual tablets at fixed doses ranging from 2.5 mg to 10 mg twice daily. 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 …

7 DRUG INTERACTIONS Antihypertensive Drugs: Asenapine sublingual tablets may cause hypotension. ( 5.7 , 7.1 , 12.3 ) Paroxetine (CYP2D6 substrate and inhibitor): Reduce paroxetine by half when used in combination with asenapine sublingual tablets. ( 7.1 , 12.3 ) 7.1 Drugs Having Clinically Important Drug Interactions with Asenapine Sublingual Tablets Table 12: Clinically Important Drug Interactions with Asenapine Sublingual Tablets 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 sublingual tablets 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 sublingual tablets are metabolized by CYP1A2. Marginal increase of asenapine exposure was observed when asenapine sublingual tablets are 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 sublingual tablets based on clinical response may be necessary. CYP2D6 substrates and inhibitors (e.g., paroxetine) Asenapine sublingual tablets may enhance the inhibitory effects of paroxetine on its own metabolism. Concomitant use of paroxetine with asenapine sublingual tablets 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 sublingual tablets. 7.2 Drugs Having No Clinically Important Interactions with Asenapine Sublingual Tablets No dosage adjustment of asenapine sublingual tablets are 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.

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. (8.1) Pediatric Use: Safety and efficacy in the treatment of bipolar I disorder in patients less than 10 years of age have not been evaluated. (8.4) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asenapine during pregnancy. For more information contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. Studies have not been conducted with asenapine in pregnant women. There are no available human data informing the drug-associated risk. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. No teratogenicity was observed in animal reproduction studies with intravenous administration of asenapine to rats and rabbits during organogenesis at doses 0.7 and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 10 mg sublingually twice daily. In a pre-and post-natal study in rats, intravenous administration of asenapine at doses up to 0.7 times the MRHD produced increases in post-implantation loss and early pup deaths, and decreases in subsequent pup survival and weight gain [see Data]. Advise pregnant women of the potential risk to a fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Data Animal Data In animal studies, asenapine increased post-implantation loss and decreased pup weight and survival at doses similar to or less than recommended clinical doses. In these studies there was no increase in the incidence of structural abnormalities caused by asenapine. Asenapine was not teratogenic in reproduction studies in rats and rabbits at intravenous doses up to 1.5 mg/kg in rats and 0.44 mg/kg in rabbits administered during organogenesis. These doses are 0.7 and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 10 mg twice daily given sublingually on a mg/m 2 basis. Plasma levels of asenapine were measured in the rabbit study, and the area under the curve (AUC) at the highest dose tested was 2 times that in humans receiving the MRHD. In a study in which rats were treated from day 6 of gestation through day 21 postpartum with intravenous doses of asenapine of 0.3, 0.9, and 1.5 mg/kg/day (0.15, 0.4, and 0.7 times the MRHD of 10 mg twice daily given sublingually on a mg/m 2 basis), increases in post-implantation loss and early pup deaths were seen at all doses, and decreases in subsequent pup survival and weight gain were seen at the two higher doses. A cross-fostering study indicated that the decreases in pup survival were largely due to prenatal drug effects. Increases in post-implantation loss and decreases in pup weight and survival were also seen when pregnant rats were dosed orally with asenapine. 8.2 Lactation Risk Summary Lactation studies have not been conducted to assess the presence of asenapine in human milk, the effects of asenapine on the breastfed infant, or the effects of asenap …

12.1 Mechanism of Action The mechanism of action of asenapine in schizophrenia and bipolar I disorder, is unknown. It has been suggested that the efficacy of asenapine in schizophrenia could be mediated through a combination of antagonist activity at D 2 and 5-HT 2A receptors.

11 DESCRIPTION Asenapine sublingual tablets contain asenapine maleate which is an atypical antipsychotic that is available for sublingual administration. Asenapine belongs to the class dibenzo-oxepino pyrroles. The chemical designation is (3a RS ,12b RS )-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1 H dibenzo[2,3:6,7]oxepino[4,5- c ]pyrrole (2 Z )-2-butenedioate (1:1). Its molecular formula is C 17 H 16 ClNO∙C 4 H 4 O 4 and its molecular weight is 401.84 (free base: 285.8). The chemical structure is: Asenapine maleate is a white to off-white powder. Asenapine sublingual tablets (Unflavored) are supplied for sublingual administration in tablets containing 5 mg or 10 mg asenapine; inactive ingredients include aspartame, colloidal silicon dioxide, crospovidone, low substituted hydroxypropyl cellulose, microcrystalline cellulose, magnesium stearate and povidone. Asenapine sublingual tablets, black cherry flavor, are supplied for sublingual administration in tablets containing 2.5 mg, 5 mg or 10 mg asenapine; inactive ingredients include aspartame, colloidal silicon dioxide, crospovidone, low substituted hydroxypropyl cellulose, microcrystalline cellulose, magnesium stearate and povidone and black cherry flavor (components are nature identical flavorings, natural flavoring substances, natural flavoring complexes, maize maltodextrin and moisture). Chemical Structure

10 OVERDOSAGE Human Experience: In adult pre-marketing clinical studies involving more than 3,350 patients and/or healthy subjects, accidental or intentional acute overdosage of asenapine sublingual tablets was identified in 3 patients. Among these few reported cases of overdose, the highest estimated ingestion of asenapine sublingual tablets was 400 mg. Reported adverse reactions at the highest dosage included agitation and confusion. Management of Overdosage: There is no specific antidote to asenapine sublingual tablets. The possibility of multiple drug involvement should be considered. An electrocardiogram should be obtained and management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Consult with a Certified Poison Control Center for up-to-date guidance and advice on the management of overdosage (1-800-222-1222.) Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of asenapine sublingual tablets-induced alpha blockade). In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

16 HOW SUPPLIED/STORAGE AND HANDLING Asenapine sublingual tablets are supplied as: 5 mg Tablets Round, white, uncoated tablets debossed "B" on one side and "1" on the other side. Child-resistant packaging Box of 60 - 6 blisters with 10 tablets NDC 51991-359-60 Hospital Unit Dose Box of 100 - 10 blisters with 10 tablets NDC 51991-359-11 10 mg Tablets Round, white, uncoated tablets debossed "B" on one side and "2" on the other side. Child-resistant packaging Box of 60 - 6 blisters with 10 tablets NDC 51991-361-60 Hospital Unit Dose Box of 100 - 10 blisters with 10 tablets NDC 51991-361-11 2.5 mg Tablets, black cherry flavor White colored, round shaped, uncoated tablets debossed with "B" on one side and "5" on the other side. Child-resistant packaging Box of 60 - 6 blisters with 10 tablets NDC 51991-928-60 Hospital Unit Dose Box of 100 - 10 blisters with 10 tablets NDC 51991-928-11 5 mg Tablets, black cherry flavor Round, white, uncoated tablets debossed "B" on one side and "3" on the other side. Child-resistant packaging Box of 60 - 6 blisters with 10 tablets NDC 51991-358-60 Hospital Unit Dose Box of 100 - 10 blisters with 10 tablets NDC 51991-358-11 10 mg Tablets, black cherry flavor Round, white, uncoated tablets debossed "B" on one side and "4" on the other side. Child-resistant packaging Box of 60 - 6 blisters with 10 tablets NDC 51991-360-60 Hospital Unit Dose Box of 100 - 10 blisters with 10 tablets NDC 51991-360-11 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].