Lundbeck and Merck Sign Exclusive Commercialization Agreement for Sycrest (asenapine) Sublingual Tablets in All Markets Outside of the United States, China and Japan

  • SYCREST received European Union (EU) approval from the European Medicines Agency (EMA) on September 1, 2010 for the treatment of moderate to severe manic episodes associated with bipolar I disorder in adults.
  • The adult bipolar mania market in the European Union is still quite undertreated - asenapine represents another treatment option for appropriate patients within this undertreated population.
  • Lundbeck expects to launch SYCREST in the EU at the beginning of 2011.

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Oct 12, 2010 - H. Lundbeck A/S (Lundbeck) and Merck, known outside the U.S. and Canada as MSD, today announced a worldwide commercialization agreement for SYCREST® (asenapine) sublingual tablets (5 mg, 10 mg). Under the terms of the agreement, Lundbeck will pay an undisclosed fee as well as product supply payments in exchange for exclusive commercial rights to SYCREST in all markets outside the United States, China and Japan. Lundbeck expects to launch SYCREST in the European Union (EU), where it is already approved, at the beginning of 2011. Merck will retain exclusive commercial rights to asenapine in the U.S., China and Japan. Merck has launched asenapine in the United States under the brand name SAPHRIS® (asenapine) sublingual tablets (5 mg, 10 mg).

"We are very pleased to be collaborating with Lundbeck on this important commercial milestone. Lundbeck has extensive experience in psychiatry and is the ideal partner to provide physicians and their patients with access to this important medicine in the markets where they will commercialize SYCREST," said Beverly Lybrand, senior vice president and general manager, neuroscience and ophthalmology, Merck. "Merck will continue to focus our efforts on marketing SAPHRIS in the U.S. as part of our ongoing commitment to researching, developing and delivering medicines in the neurosciences disease area."

"This agreement highlights our strategic focus on late-stage specialty central nervous system (CNS) products and our ambition to provide long-term growth opportunities for Lundbeck," said Ulf Wiinberg, president & chief executive officer at Lundbeck. “We are very pleased to include SYCREST in our existing portfolio of specialty CNS products and see great opportunities to leverage our highly dedicated sales infrastructure.”

About SYCREST/SAPHRIS

SYCREST, an atypical antipsychotic medication, received marketing approval in the EU on September 1 for the treatment of moderate to severe manic episodes associated with bipolar I disorder in adults. The marketing approval applies to all 27 EU member states.

In the United States, asenapine is marketed as SAPHRIS. It was approved by the U.S. Food and Drug Administration (FDA) on August 13, 2009 for the acute treatment of schizophrenia in adults and for the acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults. On September 7, 2010, two supplemental new drug applications (sNDA's) for SAPHRIS were approved in the United States to expand the product's indications to the treatment of schizophrenia in adults, as monotherapy for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, and as adjunctive therapy with either lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.

Additional regulatory applications for asenapine are pending in other markets.

Important Safety Information about Asenapine Based on U.S. Prescribing Information for SAPHRIS

WARNING: 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 that seen 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 percent, compared to a rate of about 2.6 percent 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. SAPHRIS® (asenapine) is not approved for the treatment of patients with dementia-related psychosis.

Cerebrovascular Adverse Events: 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. SAPHRIS is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with administration of antipsychotic drugs, including SAPHRIS. NMS can cause hyperpyrexia, muscle rigidity, altered mental status, irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems.

Tardive Dyskinesia (TD): The risk of developing TD and the potential for it to become irreversible may increase as the duration of treatment and the total cumulative dose increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Prescribing should be consistent with the need to minimize TD. If signs and symptoms appear, discontinuation should be considered.

Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases associated with ketoacidosis, hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Patients with risk factors for diabetes mellitus who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of and 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 also 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 antipsychotic drug.

Weight Gain: Patients receiving SAPHRIS should receive regular monitoring of weight. There were differences in mean weight gain between SAPHRIS-treated and placebo-treated patients in short-term schizophrenia trials (1.1 kg vs. 0.1 kg) and in bipolar mania trials (1.3 kg vs. 0.2 kg). In a 52 week study, the proportion of patients with an equal to or greater than 7 percent increase in body weight was 14.7 percent.

Orthostatic Hypotension and Syncope and Other Hemodynamic Effects: SAPHRIS may induce orthostatic hypotension and syncope. SAPHRIS should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, conditions which would predispose them to hypotension and in the elderly. SAPHRIS should be used cautiously when treating patients who receive treatment with other drugs that can induce hypotension, bradycardia, respiratory or central nervous system depression. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs.

Leukopenia, Neutropenia, and Agranulocytosis: In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including SAPHRIS. 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: SAPHRIS was associated with increases in QTc interval ranging from 2 to 5 msec compared to placebo. No patients treated with SAPHRIS experienced QTc increases of equal to or greater than 60 msec from baseline measurements, nor did any experience a QTc of equal to or greater than 500 msec. SAPHRIS should be avoided in combination with other drugs known to prolong QTc interval, in patients with congenital prolongation of QT interval or a history of cardiac arrhythmias, and in circumstances that may increase the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.

Hyperprolactinemia: Like other drugs that antagonize dopamine D2 receptors, SAPHRIS can elevate prolactin levels, and the elevation can persist during chronic administration. Galactorrhea, amenorrhea, gynecomastia and impotence have been reported in patients receiving prolactin-elevating compounds.

Seizures: SAPHRIS should be used cautiously in patients with a history of seizures or with conditions that lower seizure threshold, e.g., Alzheimer's dementia.

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. SAPHRIS is not indicated for the treatment of dementia-related psychosis, and should not be used in patients at risk for aspiration pneumonia.

Potential for Cognitive and Motor Impairment: Somnolence was reported in patients treated with SAPHRIS. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that SAPHRIS therapy does not affect them adversely.

Body Temperature Regulation: Appropriate care is advised when prescribing SAPHRIS for patients who will be experiencing conditions that 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.

Suicide: The possibility of suicide attempt is inherent in psychotic illnesses and bipolar disorder. Close supervision of high-risk patients should accompany drug therapy. Prescriptions for SAPHRIS should be written for the smallest quantity of tablets in order to reduce the risk of overdose.

Hepatic Impairment: SAPHRIS is not recommended in patients with severe hepatic impairment.

Drug Interactions: The risks of using SAPHRIS in combination with other drugs have not been extensively evaluated. Given the primary CNS effects of SAPHRIS, caution should be used when it is taken in combination with other centrally-acting drugs or alcohol. Co-administration of SAPHRIS with strong CYP1A2 inhibitors (fluvoxamine) or compounds which are both CYP2D6 substrates and inhibitors (paroxetine) should be done with caution.

Commonly Observed Adverse Reactions (incidence equal to or greater than five percent and at least twice that for placebo) were:

 

  • In short-term schizophrenia trials with SAPHRIS 5 or 10 mg BID vs. placebo: akathisia (6% vs. 3%), oral hypoesthesia (numbing of the tongue [5% vs. 1%]), and somnolence (13% vs. 7%). The safety profile of SAPHRIS in the maintenance treatment of schizophrenia was similar to that seen with acute treatment.
  • In short-term bipolar mania (monotherapy) trials with SAPHRIS 5 or 10 mg BID vs. placebo: somnolence (24% vs. 6%), dizziness (11% vs. 3%), extrapyramidal symptoms other than akathisia (7% vs. 2%) and weight increase (5% vs. less than 1%).
  • In the short term bipolar mania (adjunctive) therapy trial with SAPHRIS 5 or 10 mg BID vs. placebo: somnolence (22% vs. 10%) and oral hypoesthesia (5% vs. 0%).

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com.

About Lundbeck

H. Lundbeck A/S (LUN.CO, LUN DC, HLUKY) is an international pharmaceutical company highly committed to improve the quality of life for people suffering from central nervous system (CNS) disorders. For this purpose Lundbeck is engaged in the research and development, production, marketing and sale of pharmaceuticals across the world, targeted at disorders like depression and anxiety, schizophrenia, insomnia, Huntington's, epilepsies, Alzheimer's and Parkinson's diseases.

Lundbeck was founded in 1915 by Hans Lundbeck in Copenhagen, Denmark, and employs today approximately 5,900 people worldwide. Lundbeck is one of the world's leading pharmaceutical companies working with CNS disorders. In 2009, the company's revenue was DKK 13.7 billion (approximately EUR 1.8 billion or USD 2.6 billion). For more information, please visit www.lundbeck.com.

Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. The forward-looking statements may include statements regarding product development, product potential, the company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the impact of pharmaceutical industry regulation and health care legislation; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; the risk of new and changing regulation and health policies in the United States and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2009 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

Please see attached Full Prescribing Information for SAPHRIS. Full Prescribing Information is also available at http://www.spfiles.com/pisaphrisv1.pdf

SAPHRIS® and SYCREST® are registered trademarks of N.V. Organon, a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A.

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use SAPHRIS® (asenapine) safely and effectively. See full prescribing information for SAPHRIS.
SAPHRIS (asenapine) sublingual tablets
Initial U.S. Approval: 2009

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

See full prescribing information for complete boxed warning.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. SAPHRIS is not approved for the treatment of patients with dementia-related psychosis. (5.1)

---------------------------RECENT MAJOR CHANGES---------------------------

Indications and Usage, Schizophrenia (1.1)     09/2010
Indications and Usage, Bipolar Disorder (1.2)     09/2010
Dosage and Administration, Schizophrenia (2.2)     09/2010
Dosage and Administration, Bipolar Disorder (2.3)     09/2010
---------------------------INDICATIONS AND USAGE-----------------------------

SAPHRIS is an atypical antipsychotic indicated for:

 

  • Treatment of schizophrenia. (1.1)
    Efficacy was established in two 6-week clinical trials and one maintenance trial in patients with schizophrenia in adults. (14.1)
  • Acute treatment, as monotherapy or adjunctive therapy, of manic or mixed episodes associated with bipolar I disorder. (1.2)
    Efficacy was established in two 3-week monotherapy trials and in one 3-week adjunctive trial in patients with manic or mixed episodes associated with bipolar I disorder in adults. (14.2)

-------------------------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
for one
week

 

      10 mg
sublingually
twice daily

 

      10 mg
sublingually
twice daily

 

                         
Bipolar mania –
adults:
monotherapy (2.3)

 

      10 mg
sublingually
twice daily

 

      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

 

Administration: Do not swallow tablet. SAPHRIS 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, 17.1)

-----------------------DOSAGE FORMS AND STRENGTHS--------------------

Sublingual tablets: 5 mg and 10 mg (3)
Sublingual tablets, black cherry flavor: 5 mg and 10 mg (3)

-----------------------------CONTRAINDICATIONS---------------------------------

None (4)

-----------------------WARNINGS AND PRECAUTIONS------------------------

 

  • 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. (5.2)
  • Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. (5.3)
  • Tardive Dyskinesia: Discontinue if clinically appropriate. (5.4)
  • 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. (5.5)
  • Weight Gain: Patients should receive regular monitoring of weight. (5.6)
  • 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. (5.7)
  • 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. (5.8)
  • 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. (5.9)
  • Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. (5.11)
  • Potential for Cognitive and Motor Impairment: Use caution when operating machinery. (5.12)
  • Suicide: The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder. Closely supervise high-risk patients. (5.14)

-------------------------------ADVERSE REACTIONS------------------------------

Commonly observed adverse reactions (incidence ‰¥5% and at least twice that for placebo) were (6.2):

 

  • 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.

-------------------------------DRUG INTERACTIONS------------------------------

 

  • Fluvoxamine (strong CYP1A2 inhibitor) and Paroxetine (CYP2D6 substrate and inhibitor): cautiously approach coadministration with SAPHRIS. (7.1, 7.2)

--------------------------USE IN SPECIFIC POPULATIONS---------------------

 

  • Pregnancy: Use SAPHRIS during pregnancy only if the potential benefit justifies the potential risk. (8.1)
  • Nursing Mothers: Breast feeding is not recommended. (8.3)
  • Pediatric Use: Safety and effectiveness have not been established. (8.4)
  • Renal Impairment: No dose adjustment needed. (8.6)
  • Hepatic Impairment: SAPHRIS is not recommended in patients with severe hepatic impairment (Child-Pugh C). (2.4, 8.7, 12.3)

See 17 for PATIENT COUNSELING INFORMATION

Revised: 09/2010

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

1

 

  INDICATIONS AND USAGE

 

    1.1   Schizophrenia
    1.2   Bipolar Disorder
2

 

  DOSAGE AND ADMINISTRATION

 

    2.1   Administration Instructions
    2.2   Schizophrenia
    2.3   Bipolar Disorder
    2.4   Dosage in Special Populations
    2.5   Switching from Other Antipsychotics
3

 

  DOSAGE FORMS AND STRENGTHS

 

4

 

  CONTRAINDICATIONS

 

5

 

  WARNINGS AND PRECAUTIONS

 

    5.1   Increased Mortality in Elderly Patients with Dementia-Related Psychosis
    5.2   Cerebrovascular Adverse Events, Including Stroke, In Elderly Patients with Dementia-Related Psychosis
    5.3   Neuroleptic Malignant Syndrome
    5.4   Tardive Dyskinesia
    5.5   Hyperglycemia and Diabetes Mellitus
    5.6   Weight Gain
    5.7   Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects
    5.8   Leukopenia, Neutropenia, and Agranulocytosis
    5.9   QT Prolongation
    5.10   Hyperprolactinemia
    5.11   Seizures
    5.12   Potential for Cognitive and Motor Impairment
    5.13   Body Temperature Regulation
    5.14   Suicide
    5.15   Dysphagia
    5.16   Use in Patients with Concomitant Illness
6

 

  ADVERSE REACTIONS

 

    6.1   Overall Adverse Reactions Profile
    6.2   Clinical Studies Experience
7

 

  DRUG INTERACTIONS

 

    7.1   Potential for Other Drugs to Affect SAPHRIS
    7.2   Potential for SAPHRIS to Affect Other Drugs
8

 

  USE IN SPECIFIC POPULATIONS

 

    8.1   Pregnancy
    8.2   Labor and Delivery
    8.3   Nursing Mothers
    8.4   Pediatric Use
    8.5   Geriatric Use
    8.6   Renal Impairment
    8.7   Hepatic Impairment
9

 

  DRUG ABUSE AND DEPENDENCE

 

    9.1   Controlled Substance
    9.2   Abuse
10

 

  OVERDOSAGE

 

11

 

  DESCRIPTION

 

12

 

  CLINICAL PHARMACOLOGY

 

    12.1   Mechanism of Action
    12.2   Pharmacodynamics
    12.3   Pharmacokinetics
13

 

  NONCLINICAL TOXICOLOGY

 

    13.1   Carcinogenesis, Mutagenesis, Impairment of Fertility
14

 

  CLINICAL STUDIES

 

    14.1   Schizophrenia
    14.2   Bipolar Disorder
16

 

  HOW SUPPLIED/STORAGE AND HANDLING

 

17

 

  PATIENT COUNSELING INFORMATION

 

    17.1   Tablet Administration
    17.2   Increased Mortality in Elderly Patients with Dementia-Related Psychosis
    17.3   Neuroleptic Malignant Syndrome
    17.4   Hyperglycemia and Diabetes Mellitus
    17.5   Weight Gain
    17.6   Orthostatic Hypotension
    17.7   Leukopenia/Neutropenia
    17.8   Interference with Cognitive and Motor Performance
    17.9   Heat Exposure and Dehydration
    17.10   Concomitant Medication and Alcohol
    17.11   Pregnancy and Nursing
*Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING: 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 that seen 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. SAPHRIS® (asenapine) is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

1.1 Schizophrenia

SAPHRIS is indicated for the treatment of schizophrenia. The efficacy of SAPHRIS was established in two 6-week trials and one maintenance trial in adults [see Clinical Studies (14.1)].

1.2 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 [see Clinical Studies (14.2)].

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 [see Clinical Studies (14.2)].

2 DOSAGE AND ADMINISTRATION

2.1 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 [see Clinical Pharmacology (12.3)]. Patients should be instructed to not eat or drink for 10 minutes after administration [see Clinical Pharmacology (12.3) and Patient Counseling Information (17.1)].

2.2 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 [see Clinical Studies (14.1)]. 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.

2.3 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.

2.4 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 [see Use in Special Populations (8.7)]. Dosage adjustments are not routinely required on the basis of age, gender, race, or renal impairment status [see Use in Specific Populations (8.4, 8.5, 8.6) and Clinical Pharmacology (12.3)].

2.5 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.

3 DOSAGE FORMS AND STRENGTHS

 

  • SAPHRIS 5-mg tablets are round, white to off-white sublingual tablets, with “5” on one side.
  • SAPHRIS 10-mg tablets are round, white to off-white sublingual tablets, with “10” on one side.
  • SAPHRIS 5-mg tablets, black cherry flavor, are round, white to off-white sublingual tablets, with “5” on one side within a circle.
  • SAPHRIS 10-mg tablets, black cherry flavor, are round, white to off-white sublingual tablets, with “10” on one side within a circle.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

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. SAPHRIS is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

5.2 Cerebrovascular Adverse Events, 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. SAPHRIS is not approved for the treatment of patients with dementia-related psychosis [see also Boxed Warning and Warnings and Precautions (5.1)].

5.3 Neuroleptic Malignant Syndrome

A potentially

Posted: October 2010


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