Merck Receives Approval from FDA for Expanded Indications for Atypical Antipsychotic Medication Saphris (asenapine) Sublingual Tablets
WHITEHOUSE STATION, N.J., September 7, 2010 – Merck today announced that the U.S. Food and Drug Administration (FDA) has approved two supplemental new drug applications (sNDA's) for Saphris (asenapine) sublingual tablets to expand the product's indications. Saphris is now indicated for 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. Saphris was initially approved in the United States on August 13, 2009 for the acute treatment of schizophrenia in adults and as monotherapy for the acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults.
"These FDA approvals demonstrate our active commitment to further understand how our medicines can be used to help physicians help their patients, and we look forward to discussing these new uses for Saphris with the mental health community," said David Michelson, M.D., vice president of Neuroscience Clinical Research, Merck.
Important Safety Information about 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 [see Warnings and Precautions (5.1)].
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 Bipolar I Disorder and Schizophrenia
Bipolar I disorder (also known as manic-depressive disorder) is a chronic, episodic illness characterized by mania (episodes of elevated moods, extreme irritability, decreased sleep and increased energy), depression (overwhelming feelings of sadness, suicidal thoughts), or a combination of both.
Schizophrenia is an often chronic and disabling brain disorder. It's characterized by various symptom domains, such as so-called positive symptoms (including hallucinations, delusions and disordered thinking) as well as negative symptoms, cognitive impairment and other general psychopathological symptoms (such as anxiety or depression).
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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).
Saphris is a registered trademark of N.V. Organon, a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A.
Prescribing Information for Saphris is attached and is also available at http://www.spfiles.com/pisaphrisv1.pdf
Posted: September 2010
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