Asenapine Maleate Drug Information

Asenapine sublingual tablets are indicated for: Schizophrenia in adults Bipolar I disorder 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 : 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

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. Adult Patients with Schizophrenia: The following findings are based on the short-term placebo-controlled pre-marketing trials for schizophrenia (a pool of three 6-week fixed-dose trials and one 6-week flexible-dose trial) in which sublingual asenapine sublingual tablets was administered in doses ranging from 5 to 10 mg twice daily. Adverse Reactions Associated with Discontinuation of Treatment: A total of 9% of asenapine sublingual tablets-treated patients and 10% of placebo-treated patients discontinued due to adverse reactions.

There were no drug-related adverse reactions associated with discontinuation in patients treated with asenapine sublingual tablets at the rate of at least 1% and at least twice the placebo rate. Adverse Reactions Occurring at an Incidence of 2% or More in asenapine sublingual tablets -Treated Patients with Schizophrenia: Adverse reactions associated with the use of asenapine sublingual tablets (incidence of 2% or greater, rounded to the nearest percent, and asenapine sublingual tablets incidence greater than placebo) that occurred during acute therapy (up to 6-weeks in patients with schizophrenia) are shown in Table 8. Table 8: Adverse Reactions Reported in 2% or More of Adult Patients in Any Asenapine Sublingual Tablets Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in 6-Week Schizophrenia Trials System Organ Class/ Preferred Term Placebo N=378 % Asenapine Sublingual Tablets 5 mg twice daily N=274 % Asenapine Sublingual Tablets 10mg twice daily N=208 % All Asenapine Sublingual Tablets§ 5mg or 10 mg twice daily N=572 % Gastrointestinal disorders Constipation 6 7 4 5 Dry mouth 1 3 1 2 Oral hypoesthesia 1 6 7 5 Salivary hypersecretion 0 <1 4 2 Stomach discomfort 1 <1 3 2 Vomiting 5 4 7 5 General disorders Fatigue 3 4 3 3 Irritability <1 2 1 2 Investigations Increased weight <1 2 2 3 Metabolism disorders Increased appetite <1 3 0 2 Nervous system disorders Akathisia * 3 4 11 6 Dizziness 4 7 3 5 Extrapyramidal symptoms (excluding akathisia)† 7 9 12 10 Somnolence‡ 7 15 13 13 Psychiatric disorders Insomnia 13 16 15 15 Vascular disorders Hypertension 2 2 3 2 * Akathisia includes: akathisia and hyperkinesia. † Extrapyramidal symptoms included dystonia, oculogyration, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, tremor, and extrapyramidal disorder (excluding akathisia). ‡ Somnolence includes the following events: somnolence, sedation, and hypersomnia. § Also includes the Flexible-dose trial (N=90). Dose-Related Adverse Reactions : In the short term schizophrenia trials the incidence of akathisia appeared to be dose-related (see Table 8). Monotherapy in Adult Patients with Bipolar Mania: The following findings are based on the short-term placebo-controlled trials for bipolar mania (a pool of two 3-week flexible-dose trials and one 3-week fixed-dose trial) in which sublingual asenapine sublingual tablets was administered in doses of 5 mg or 10 mg twice daily. Adverse Reactions Associated with Discontinuation of Treatment: Approximately 10% (61/620) of asenapine sublingual tablets-treated patients in short-term, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with about 7% (22/329) on placebo.

There were no adverse reactions associated with discontinuation in patients treated with asenapine sublingual tablets at the rate of at least 1% and at least twice the placebo rate Adverse Reactions Occurring at an Incidence of 2% or More Among asenapine sublingual tablets -Treated (Monotherapy) patients with Bipolar I Disorder: Adverse reactions associated with the use of asenapine sublingual tablets (incidence of 2% or greater, rounded to the nearest percent, and asenapine sublingual tablets incidence greater than placebo) that occurred during acute monotherapy (up to 3-weeks in patients with bipolar mania) are shown in Table 9. Table 9: Adverse Reactions Reported in 2% or More of Adult Patients in Any Asenapine Sublingual Tablets Dose Group and Which Occurred at Greater Incidence Than in the Respective Placebo Group in 3-Week Bipolar Mania Fixed and Flexible Dose Trials (Fixed Dose Study) All Placebo a All Asenapine Sublingual Tablets 5 mg or 10 mg twice daily b System Organ Class/Preferred Term Placebo Asenapine Sublingual Tablets 5 mg twice daily Asenapine Sublingual Tablets 10 mg twice daily N=126 % N=122 % N=119 % N=329 % N=620 % Gastrointestinal disorders Oral Hypoesthesia c 2 13 24 1 10 Nausea 3 4 5 5 5 Constipation 2 4 3 4 4 Dyspepsia b 6 4 5 4 4 Vomiting 2 1 3 3 3 Abdominal Pain d 0 2 3 3 3 Dry Mouth 5 3 1 2 3 Toothache 1 2 2 2 3 General disorders Fatigue e 2 2 5 2 4 Infections and Infestations Nasopharyngitis i 2 1 5 2 3 Investigations Weight Increase 1 0 1 1 3 Alanine Aminotransferase Increase 0 0 3 0 1 Metabolism disorders Increased appetite 2 1 6 2 4 Musculoskeletal and connective tissue disorders Arthralgia 1 1 2 1 2 Nervous system disorders Somnolence f 4 20 26 5 23 Dizziness 5 3 5 4 8 Extrapyramidal symptoms (excluding akathisia) g 7 7 11 4 8 Akathisia 1 4 15 2 6 Dysgeusia 0 3 9 <1 4 Psychiatric Disorders Bipolar Disorder/Mania j 3 8 3 5 6 Agitation 1 4 3 3 4 Anxiety 3 0 3 2 3 a Includes fixed and flexible dose trials b Asenapine sublingual tablets 5 mg to 10 mg twice daily with fixed and flexible dosing. c Oral Hypoesthesia includes the preferred terms: oral hypoesthesia, oral paresthesia, and oral dysaesthesia. d Abdominal pain includes the preferred terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. e Fatigue includes the preferred terms: fatigue and lethargy. f Somnolence includes the preferred terms: somnolence, sedation, and hypersomnia. g Extrapyramidal symptoms (excluding akathisia) includes the preferred terms: dyskinesia, dystonia, resting tremor, tremor, oromandibular dystonia, myoclonus, muscle spasms, muscle rigidity, musculoskeletal stiffness, muscle contractions involuntary, blepharospasm, tongue disorder, and Parkinsonism. h Dyspepsia includes the preferred terms: dyspepsia and gastrooesophageal reflux disease. i Nasopharyngitis includes the preferred terms: nasopharyngitis and upper respiratory tract infection. j Bipolar Disorder/Mania includes the preferred terms: bipolar disorder, bipolar I disorder and mania. Monotherapy in Pediatric Patients with Bipolar Mania: The following findings are based on a 3-week, placebo-controlled trial for bipolar mania in which asenapine sublingual tablets was administered at doses of 2.5 mg, 5 mg, or 10 mg twice daily. Adverse Reactions Leading to Discontinuation of Treatment: A total of 6.7% (7/104) of patients treated with asenapine sublingual tablets 2.5 mg twice daily, 5.1% (5/99) of patients treated with asenapine sublingual tablets 5 mg twice daily, and 5.1% (5/99) of patients treated with asenapine sublingual tablets 10 mg twice daily discontinued treatment due to adverse reactions compared to 4% (4/101) on placebo.

The most common adverse reactions that led to discontinuation in pediatric patients treated with asenapine sublingual tablets (rates at least 2% in any asenapine sublingual tablets arm and at least twice the placebo rate) were somnolence (3% in the 2.5mg twice daily group, 1% in the 5mg twice daily group, and 2% in the 10mg twice daily group), abdominal pain (2% in the 10mg twice daily group), and nausea (2% in the 10 mg twice daily group). No placebo-treated patients dropped out for these events. Adverse Reactions Occurring with Asenapine Sublingual Tablets at an Incidence of 2% or More in Asenapine Sublingual Tablets-treated Bipolar I Patients: Adverse reactions associated with the use of asenapine sublingual tablets (incidence of ≥2% in any asenapine sublingual tablets dose group and greater than placebo) that occurred during acute therapy are shown in Table 10. Table 10: Adverse Reactions Reported in 2% or More of Pediatric Patients (Ages 10 to 17 Years) in Any Asenapine Sublingual Tablets Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in a 3-Week Bipolar Mania Trial System Organ Class/ AE Preferred Term Placebo Asenapine sublingual tablets 2.5 mg twice daily Asenapine sublingual tablets 5 mg twice daily Asenapine sublingual tablets 10 mg twice daily All Asenapine sublingual tablets 2.5, 5, and 10 mg N=101% N=104% N=99% N=99% N=302% Cardiac Disorders Tachycardia 1 0 3 0 1 1 Gastrointestinal Disorders Oral hypoesthesia 2 4 25 25 30 27 Nausea 3 6 6 6 6 Vomiting 3 4 4 4 4 Abdominal pain 3 7 9 3 5 6 Glossodynia 0 0 2 0 1 General Disorders and Administrative Site Disorders Fatigue 4 5 4 8 14 9 Irritability 1 1 1 2 1 Injury, Poisoning, and Procedural Complications Muscle strain 0 0 0 2 1 Investigations Increased weight 0 6 2 2 3 Hyperinsulinemia 5 0 1 3 1 2 ALT increased 0 0 0 2 1 AST increased 0 0 0 2 1 Metabolism and Nutrition Disorders Increased appetite 2 10 9 6 8 Dehydration 1 0 2 0 1 Musculoskeletal and Connective Tissue Disorders Myalgia 0 0 2 1 1 Nervous System Disorders Somnolence 6 12 46 53 49 49 Headache 6 8 11 9 9 Dizziness 3 6 10 5 7 Dysgeusia 2 4 5 9 6 Akathisia 0 2 2 1 2 Parkinsonism 0 1 0 2 1 Psychiatric Disorders Insomnia 3 3 4 3 3 Suicidal ideation 1 4 1 3 3 Anger 0 0 0 2 1 Reproductive System and Breast Disorders Dysmenorrhea 1 0 2 0 1 Respiratory, Thoracic, and Mediastinal Disorders Oropharyngeal pain 2 0 3 1 1 Nasal congestion 1 0 2 0 1 Dyspnea 0 0 2 0 1 Skin and Subcutaneous Tissue Disorders Rash 1 0 1 2 1 1 Includes the preferred terms tachycardia and heart rate increased. 2 Includes the preferred terms oral hypoesthesia, oral paresthesia, and oral dysesthesia. 3 Includes the preferred terms abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. 4 Includes the preferred terms fatigue and lethargy. 5 Includes the preferred terms hyperinsulinemia and blood insulin increased. 6 Includes the preferred terms somnolence, sedation, and hypersomnia. Dose-Related Adverse Reactions : In the short term pediatric bipolar I trial the incidence of fatigue appeared to be dose-related (see Table 10 ). 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 asenapine sublingual tablets 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 sublingual tablets-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 sublingual tablets (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 Sublingual Tablets -Treated (Adjunctive) Bipolar I Patients : Adverse reactions associated with the use of asenapine sublingual tablets (incidence of 2% or greater, rounded to the nearest percent, and asenapine sublingual tablets 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 Table 11. Table 11: Adverse Reactions Reported in 2% or More of Adult Patients In Any Asenapine Sublingual Tablets -Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group at 3 Weeks in Adjunctive Bipolar Mania Trials System Organ Class/Preferred Term Placebo N=166 % Asenapine Sublingual Tablets 5 mg or 10 mg twice daily* N=158 % Gastrointestinal disorders Dyspepsia 2 3 Oral hypoesthesia 0 5 General disorders Fatigue 2 4 Edema peripheral <1 3 Investigations Increased weight 0 3 Nervous system disorders Dizziness 2 4 Other extrapyramidal symptoms (excluding akathisia) † 5 6 Somnolence ‡ 10 22 Psychiatric disorders Insomnia 8 10 Vascular disorders Hypertension <1 3 *Asenapine sublingual tablets 5 mg to 10 mg twice daily with flexible dosing. † Extrapyramidal symptoms included: dystonia, parkinsonism, oculogyration, and tremor (excluding akathisia). ‡ Somnolence includes the following events: somnolence and sedation. Dystonia: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment.

Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups . Extrapyramidal Symptoms: In the short-term, placebo-controlled schizophrenia and bipolar mania adult trials, data was objectively collected on the Simpson Angus Rating Scale for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (for akathisia) and the Assessments of Involuntary Movement Scales (for dyskinesias). The mean change from baseline for the all-asenapine 5 mg or 10 mg twice daily treated group was comparable to placebo in each of the rating scale scores.

In the short-term, placebo-controlled schizophrenia adult trials, the incidence of reported EPS-related events, excluding events related to akathisia, for asenapine sublingual tablets -treated patients was 10% versus 7% for placebo; and the incidence of akathisia-related events for asenapine sublingual tablets-treated patients was 6% versus 3% for placebo. In short-term placebo-controlled bipolar mania adult trials, the incidence of EPS-related events, excluding events related to akathisia, for asenapine sublingual tablets-treated patients was 8% versus 4% for placebo; and the incidence of akathisia-related events for asenapine sublingual tablets-treated patients was 7% versus 3% for placebo. The incidence rates of all EPS events (including akathisia) were lower at the 5mg twice daily dose (11% of N=122) than the 10mg twice daily dose (25% of N=119) in a fixed-dose study.

In a 3-week, placebo-controlled pediatric trial with bipolar I disorder, the incidences of EPS-related events, excluding events related to akathisia, were 4%, 3%, and 5% for patients treated with asenapine sublingual tablets 2.5 mg, 5 mg, and 10 mg twice daily, respectively, as compared to 3% for placebo-treated patients. EPS-related events include: bradykinesia, dyskinesia, dystonia, oromandibular dystonia, muscle contractions involuntary, muscle twitching, musculoskeletal stiffness, parkinsonism, protrusion tongue, resting tremor, and tremor. For events of akathisia, incidences were 2%, 2%, and 1% for pediatric patients treated with asenapine sublingual tablets 2.5 mg, 5 mg, and 10 mg twice daily, respectively, as compared to 0% for placebo-treated patients.

Other Findings: Oral hypoesthesia and/or oral paresthesia may occur directly after administration of asenapine sublingual tablets and usually resolves within 1 hour. Laboratory Test Abnormalities: Transaminases : Transient elevations in serum transaminases (primarily ALT) in the short-term schizophrenia and bipolar mania adult trials were more common in treated patients. In short-term, placebo-controlled schizophrenia adult trials, the mean increase in transaminase levels for asenapine sublingual tablets-treated patients was 1.6 units/L compared to a decrease of 0.4 units/L for placebo-treated patients.

The proportion of patients with transaminase elevations ≥3 times ULN (at Endpoint) was 0.9% for asenapine sublingual tablets-treated patients versus 1.3% for placebo-treated patients. In short-term, placebo-controlled bipolar mania adult trials, the mean increase in transaminase levels for asenapine sublingual tablets-treated patients was 6.1 units/L compared to a decrease of 3.9 units/L in placebo-treated patients. The proportion of patients with transaminase elevations ≥3 times upper limit of normal (ULN) (at Endpoint) was 2.1% for asenapine sublingual tablets-treated patients versus 0.7% for placebo-treated patients.

The incidence rate of transaminase elevations ≥3 times ULN is 3% of N=95 for 10mg twice daily dose, and 0% of N=108 for the 5mg twice daily dose and 0% of N=115 for placebo in a fixed-dose study. In a 52-week, double-blind, comparator-controlled trial that included primarily adult patients with schizophrenia, the mean increase from baseline of ALT was 1.7 units/L. In a 3-week, placebo-controlled pediatric trial with bipolar I disorder, transient elevations in serum transaminases (primarily ALT) were more common in treated patients. The proportion of pediatric patients with ALT elevations ≥3 times upper limit of normal (ULN) was 2.4% for patients treated with asenapine sublingual tablets 10 mg twice daily versus none for the other asenapine sublingual tablets dose groups and placebo-treated patients.

Prolactin : In short-term, placebo-controlled adult schizophrenia trials, the mean decreases in prolactin levels were 6.5 ng/mL for asenapine sublingual tablets-treated patients compared to 10.7 ng/mL for placebo-treated patients. The proportion of patients with prolactin elevations ≥4 times ULN (at Endpoint) were 2.6% for asenapine sublingual tablets -treated patients versus 0.6% for placebo-treated patients. In short-term, placebo-controlled bipolar mania adult trials, the mean increase in prolactin levels was 6.7ng/mL for asenapine sublingual tablets-treated patients compared to a decrease of 1.0 ng/mL for placebo-treated patients.

The proportion of patients with prolactin elevations ≥4 times ULN (at Endpoint) were 2.0% for asenapine sublingual tablets-treated patients versus 0.8% for placebo-treated patients. In a long-term (52-week), double-blind, comparator-controlled adult trial that included primarily patients with schizophrenia, the mean decrease in prolactin from baseline for asenapine-treated patients was 26.9 ng/mL. In a 3-week, placebo-controlled pediatric trial with bipolar I disorder, the mean increases (at Endpoint) in prolactin levels were 3.2 ng/mL for patients treated with asenapine sublingual tablets 2.5 mg twice daily, 2.1 ng/mL for patients treated with asenapine sublingual tablets 5 mg twice daily, and 6.4 ng/mL for patients treated with asenapine sublingual tablets 10 mg twice daily compared to an increase of 2.5 ng/mL for placebo-treated patients. There were no reports of prolactin elevations ≥4 times ULN (at Endpoint) for patients treated with asenapine sublingual tablets or placebo.

Galactorrhea or dysmenorrhea were reported in 0% of patients treated with asenapine sublingual tablets 2.5 mg twice daily, 2% of patients treated with asenapine sublingual tablets 5 mg twice daily, and 1% of patients treated with asenapine sublingual tablets 10 mg twice daily compared to 1% of placebo-treated patients. There were no reports of gynecomastia in this trial. Creatine Kinase (CK) : The proportion of adult patients with CK elevations >3 times ULN at any time were 6.4% and 11.1% for patients treated with asenapine sublingual tablets 5 mg twice daily and 10 mg twice daily, respectively, as compared to 6.7% for placebo-treated patients in pre-marketing short-term, fixed-dose trials in schizophrenia and bipolar mania.

The clinical relevance of this finding is unknown. The proportion of patients with CK elevations ≥3 times ULN during a 3-week trial in pediatric bipolar I disorder at any time were 1%, 0%, and 1% for patients treated with asenapine sublingual tablets 2.5 mg, 5 mg, and 10 mg twice daily, respectively, versus 3% for placebo-treated patients. Other Adverse Reactions Observed During the Premarketing Evaluation of Asenapine Sublingual Tablets: Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with sublingual asenapine sublingual tablets at multiple doses of ≥5 mg twice daily during any phase of a trial within the database of adult patients.

The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions already listed for either adults or pediatric patients in other parts of Adverse Reactions , or those considered in Contraindications , Warnings and Precautions or Overdosage are not included. Reactions are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent) (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); those occurring in 1/100 to 1/1,000 patients (infrequent); and those occurring in fewer than 1/1,000 patients (rare). Blood and lymphatic disorders: infrequent: anemia; rare: thrombocytopenia Cardiac disorders: infrequent: temporary bundle branch block Eye disorders: infrequent: accommodation disorder Gastrointestinal disorders: infrequent: swollen tongue General disorders: rare : idiosyncratic drug reaction Investigations: infrequent: hyponatremia Nervous system disorders: infrequent: dysarthria Following is a list of MedDRA terms not already listed either for adults or pediatric patients in other parts of Adverse Reactions , or those considered in Contraindications , Warnings and Precautions or Overdosage that reflect adverse reactions reported by pediatric patients (Ages 10 to 17 years) treated with sublingual asenapine sublingual tablets at doses of 2.5 mg, 5 mg, or 10 mg twice daily during any phase of a trial within the database of pediatric patients.

Eye disorders: infrequent: diplopia, vision blurred Gastrointestinal disorders: infrequent: gastroesophageal reflux disease Injury, Poisoning, and Procedural Complications: infrequent : fall Skin and subcutaneous tissue disorders: infrequent: photosensitivity reaction Renal and urinary disorders : infrequent: enuresis

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of asenapine sublingual tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure. In many cases, the occurrence of these adverse reactions led to discontinuation of therapy.

Application site reactions, primarily in the sublingual area, have been reported. These application site reactions included oral ulcers, blisters, peeling/sloughing, and inflammation. Choking has been reported by patients, some of whom may have also experienced oropharyngeal muscular dysfunction or hypoesthesia.

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. 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 . 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. Reduce paroxetine dose by half when paroxetine is used in combination with asenapine sublingual tablets.

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 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.

Asenapine sublingual tablets are contraindicated in patients with: Severe hepatic impairment (Child-Pugh C). A history of hypersensitivity reactions to asenapine. Reactions have included anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash. Severe hepatic impairment (Child-Pugh C). Known hypersensitivity to asenapine sublingual tablets, or to any components in the formulation.

• 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.