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Blood Levels of Paliperidone Extended-Release Tablets are Not Increased by Common Antidepressant

Study shows paroxetine produced no significant drug interaction with paliperidone ER

SAN DIEGO, May 22, 2007 /PRNewswire/ -- After administration of paliperidone extended-release (ER) tablets, blood levels of the drug were not affected when given with a common antidepressant, according to new data presented today at the 160th Annual Meeting of the American Psychiatric Association. Paroxetine, a selective serotonin reuptake inhibitor (SSRI), is an antidepressant known to interact with several antipsychotic medications. This new study showed there was no clinically significant increase in paliperidone exposure when paroxetine was administered with paliperidone ER.(1)

Many medications prescribed for psychiatric illnesses are metabolized in the liver by a specific enzyme called CYP2D6. Administering more than one drug metabolized by CYP2D6 may cause drug-drug interactions. Paroxetine is a potent inhibitor of the CYP2D6 enzyme, and can inhibit the metabolism of some atypical antipsychotic drugs. Approximately 50 percent of patients with schizophrenia have at least one other psychiatric or medical condition requiring medication, most commonly depression.(2)

"Drug interactions frequently occur in patients with schizophrenia because this population is often treated for multiple medical and psychiatric conditions," said Dr. Joseph Palumbo, Franchise Medical Leader for Psychiatry, Johnson & Johnson Pharmaceutical Research & Development, L.L.C. "Drug interactions are an under appreciated factor that can reduce optimal treatment outcomes in our patients. This study shows that paliperidone ER can be an important new option for patients with schizophrenia who also require treatment with an antidepressant metabolized through the CYP2D6 system."

    In this study 60 healthy male patients were randomized to receive either:

    -- Treatment A: 1 tablet of paliperidone ER 3mg (Day 1)

    -- or treatment B: 20mg of paroxetine daily (Day 1-13) with 1 tablet of

       paliperidone ER 3mg on Day 10.

After completing their first treatment the patients took no medication for 14 days. Then patients who had received treatment A received treatment B and vice versa.

Four days after paliperidone ER administration, the investigators measured the maximum concentration of the drug in the body and total exposure over time to paliperidone ER. No clinically significant increase in paliperidone exposure was seen when paliperidone ER was administered together with paroxetine compared with paliperidone ER given alone.

There were no serious adverse events or clinically important changes in laboratory values, vital signs or cardiac parameters.

"These results demonstrate that prescribers can administer a CYP2D6- inhibiting antidepressant, paroxetine, with paliperidone ER without having to adjust the dose of paliperidone ER," Palumbo said. "This, when combined with once-daily oral dosing and well demonstrated efficacy, safety, and tolerability, adds to paliperidone ER's usefulness as a new option for the treatment of schizophrenia."

The study was sponsored by Janssen, L.P. Janssen is exclusively dedicated to mental health and committed to providing new treatment options, such as paliperidone ER, to patients with psychiatric illnesses.

About Schizophrenia

Worldwide, it is estimated that 1 person in every 100 develops schizophrenia, one of the most serious types of mental illness. In the United States, there are currently 2,000,000 people with schizophrenia, with men and women affected equally. The disease is marked by positive symptoms (hallucinations and delusions) and negative symptoms (depression, blunted emotions, and social withdrawal), as well by disorganized thinking.

Janssen, L.P., based in Titusville, N.J., is the only pharmaceutical company in the U.S. dedicated solely to mental health. The company currently markets prescription medications for the treatment of schizophrenia, bipolar mania, and irritability associated with autistic disorder.

For more information about Janssen, L.P., visit www.janssen.com.

IMPORTANT SAFETY INFORMATION FOR PALIPERIDONE EXTENDED-RELEASE (ER) TABLETS

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks) in these patients 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. Neither paliperidone nor risperidone are approved for the treatment of patients with Dementia-Related Psychosis.

Commonly observed adverse events: The most commonly observed adverse events occurring at an incidence of .5% and at least 2 times placebo were akathisia and extrapyramidal disorder.

QT Prolongation: Paliperidone causes a modest increase in the corrected QT (QTc) interval. Paliperidone should be avoided in combination with other drugs that are known to prolong the QTc interval, in patients with congenital long QT syndrome or a history of cardiac arrhythmias. Certain circumstances may increase the risk of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.

Neuroleptic malignant syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with the use of antipsychotic medications, including Clinical manifestations include muscle rigidity, fever, altered mental status and evidence of autonomic instability (see full Prescribing Information). 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): TD is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic medications. The risk of developing TD and the likelihood that dyskinetic movements will become irreversible are believed to increase with duration of treatment and total cumulative dose. Elderly patients appeared to be at increased risk for TD. Prescribing should be consistent with the need to minimize the risk of TD. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

Hyperglycemia and Diabetes: Hyperglycemia, some cases extreme and associated with ketoacidosis, hyperosmolar coma or death has been reported in patients treated with atypical antipsychotics (APS). Patients starting treatment with APS who have or are at risk for diabetes, should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing.

Gastrointestinal: Paliperidone should ordinarily not be administered to patients with pre-existing severe gastrointestinal narrowing. Rare instances of obstructive symptoms have been reported in patients with known strictures taking non-deformable formulations. Paliperidone should only be used in patients who are able to swallow the tablet whole.

Cerebrovascular adverse events (CAEs): CAEs, including fatalities, have been reported in elderly patients with dementia-related psychosis taking atypical anti-psychotics in clinical trials. Paliperidone is not approved for treating these patients.

Orthostatic hypotension and Syncope: Paliperidone can cause orthostatic hypotension and syncope in some patients. Appropriate monitoring of orthostatic vital signs should be considered.

Seizures: Paliperidone should be used cautiously in patients with a history of seizures.

Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, paliperidone elevates prolactin levels and the elevation persists during chronic administration.

Suicide: The possibility of suicide attempt is inherent in psychotic illnesses and close supervision of high-risk patients should accompany drug therapy.

Maintenance treatment: Physicians who elect to use paliperidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Given the primary CNS effects of paliperidone, paliperidone should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists.

    References

    (1) Berwaerts J, Cleton A, et al. A randomized, open label, single center,

        crossover study of the potential effects of paroxetine on the

        pharmacokinetics of a single dose of paliperidone extended release

th        tablets in healthy subjects. Presented at the 160   Annual Meeting of

        the American Psychiatric Association, San Diego, May 22, 2007

    (2) Green AI, Canuso CM, et al. Detection and management of comorbidity in

        patients with schizophrenia. Psychiatric Clinics of North America 2003

        March; 26(1): 115-39

CONTACT: Ambre Morley of Janssen, L.P., +1-609-730-3429, or amorley1@gpcus.jnj.com

Web site: http://www.janssen.com/

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Posted: May 2007

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