SAPHRIS® (asenapine) sublingual tablets

Asenapine is a white to off-white powder.

SAPHRIS is supplied for sublingual administration in tablets containing 5-mg or 10-mg asenapine; inactive ingredients include gelatin and mannitol.

SAPHRIS, black cherry flavor, is supplied for sublingual administration in tablets containing 5-mg or 10-mg asenapine; inactive ingredients include gelatin, mannitol, sucralose, and black cherry flavor.

Mechanism of Action
The mechanism of action of asenapine, as with other drugs having efficacy in schizophrenia and bipolar disorder, is unknown. It has been suggested that the efficacy of asenapine in schizophrenia is mediated through a combination of antagonist activity at D2 and 5-HT2A receptors.

Bipolar Disorder
Monotherapy: SAPHRIS is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder. Efficacy was established in two 3-week monotherapy trials in adults.

Adjunctive Therapy: SAPHRIS is indicated as adjunctive therapy with either lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder. Efficacy was established in one 3-week adjunctive trial in adults

• Cerebrovascular Adverse Events: An 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.
• Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring.
• Tardive Dyskinesia: Discontinue if clinically appropriate.
• Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with, and at risk for, diabetes.
• Weight Gain: Patients should receive regular monitoring of weight.
• Hypersensitivity Reactions: Hypersensitivity reactions, including anaphylaxis and angioedema, have been observed.
• Orthostatic Hypotension and Syncope: Dizziness, tachycardia or bradycardia, and syncope may occur, especially early in treatment. Use with caution in patients with known cardiovascular or cerebrovascular disease, and in antipsychotic-naïve patients.
• Leukopenia, Neutropenia, and Agranulocytosis have been reported with antipsychotics. Patients with a pre-existing low white blood cell count (WBC) or a history of leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and SAPHRIS should be discontinued at the first sign of a decline in WBC in the absence of other causative factors.
• 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.
• Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold.
• Potential for Cognitive and Motor Impairment: Use caution when operating machinery.
• Suicide: The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder. Closely supervise high-risk patients.

Schizophrenia: akathisia, oral hypoesthesia, and somnolence.
Bipolar Disorder (Monotherapy): somnolence, dizziness, extrapyramidal symptoms other than akathisia, and weight increased.
Bipolar Disorder (Adjunctive): somnolence and oral hypoesthesia.

To report SUSPECTED ADVERSE REACTIONS, contact Schering Corporation, a subsidiary of Merck & Co., Inc., at 1-800-526-4099 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Administration Instructions
SAPHRIS 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. SAPHRIS sublingual tablets should not be crushed, chewed, or swallowed. Patients should be instructed to not eat or drink for 10 minutes after administration .

Schizophrenia
Usual Dose for Acute Treatment in Adults: The recommended starting and target dose of SAPHRIS 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. The safety of doses above 10 mg twice daily has not been evaluated in clinical studies.

Maintenance Treatment: Efficacy was demonstrated with SAPHRIS in a maintenance trial in patients with schizophrenia. The starting dose in this study was 5 mg twice daily with an increase up to 10 mg twice daily after 1 week based on tolerability. While there is no body of evidence available to answer the question of how long the schizophrenic patient should remain on SAPHRIS, patients should be periodically reassessed to determine the need for maintenance treatment.

Bipolar Disorder
Usual Dose for Acute Treatment of Manic or Mixed Episodes Associated with Bipolar I Disorder in Adults:

Monotherapy: The recommended starting dose of SAPHRIS, and the dose maintained by 90% of the patients studied, is 10 mg twice daily. The dose can be decreased to 5 mg twice daily if warranted by adverse effects or based on individual tolerability.

In controlled monotherapy trials, the starting dose for SAPHRIS was 10 mg twice daily. On the second and subsequent days of the trials, the dose could be lowered to 5 mg twice daily, based on tolerability, but less than 10% of patients had their dose reduced. The safety of doses above 10 mg twice daily has not been evaluated in clinical trials.

Adjunctive Therapy: The recommended starting dose of SAPHRIS 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.

Maintenance Treatment: While there is no body of evidence available to answer the question of how long the bipolar patient should remain on SAPHRIS, whether used as monotherapy or as adjunctive therapy with lithium or valproate, it is generally recommended that responding patients be continued beyond the acute response. If SAPHRIS is used for extended periods in bipolar disorder, the physician should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Dosage in Special Populations
In a study of subjects with hepatic impairment who were treated with a single dose of SAPHRIS 5 mg, there were increases in asenapine exposures (compared to subjects with normal hepatic function), that correlated with the degree of hepatic impairment. While the results indicated that no dosage adjustments are required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, there was a 7-fold increase (on average) in asenapine concentrations in subjects with severe hepatic impairment (Child-Pugh C) compared to the concentrations of those in subjects with normal hepatic function. Therefore, SAPHRIS is not recommended in patients with severe hepatic impairment. Dosage adjustments are not routinely required on the basis of age, gender, race, or renal impairment status [see Use in Specific Populations and Clinical Pharmacology].

Switching from Other Antipsychotics
There are no systematically collected data to specifically address switching patients with schizophrenia or bipolar mania from other antipsychotics to SAPHRIS or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized

5-mg Tablets
Round, white to off-white sublingual tablets, with "5" on one side.
Child-resistant packaging
Box of 60 6 blisters with 10 tablets NDC 0052-0118-06
Hospital Unit Dose
Box of 100 10 blisters with 10 tablets NDC 0052-0118-90

10-mg Tablets
Round, white to off-white sublingual tablets, with "10" on one side.
Child-resistant packaging
Box of 60 6 blisters with 10 tablets NDC 0052-0119-06
Hospital Unit Dose
Box of 100 10 blisters with 10 tablets NDC 0052-0119-90

5-mg Tablets, black cherry flavor
Round, white to off-white sublingual tablets, with "5" on one side within a circle.
Child-resistant packaging
Box of 60 6 blisters with 10 tablets NDC 0052-2139-03
Hospital Unit Dose
Box of 100 10 blisters with 10 tablets NDC 0052-2139-04

10-mg Tablets, black cherry flavor
Round, white to off-white sublingual tablets, with "10" on one side within a circle.
Child-resistant packaging
Box of 60 6 blisters with 10 tablets NDC 0052-2142-03
Hospital Unit Dose
Box of 100 10 blisters with 10 tablets NDC 0052-2142-04

Storage
Store at 15°–30°C (59°–86°F) [see USP Controlled Room Temperature].

Manufactured by: Catalent UK Swindon Zydis Ltd., Blagrove, Swindon, Wiltshire, SN5 8RU, UK
U.S. Patent Nos. 5,763,476 and 7,741,358.
Copyright © 2009, 2011 N.V. Organon, a subsidiary of Merck & Co., Inc. All rights reserved.
Rev. 10/11
51310040

PRINCIPAL DISPLAY PANEL - 5 mg Bottle Carton
Rx only
NDC 0052-0118-06
Saphris® 5 mg
(asenapine) sublingual tablets

Fragile: Do not push tablet through
tablet pack.
Do not crush tablet. Do not chew or
swallow tablet.
60 Tablets