Phase III Study Demonstrates INVEGA(R) SUSTENNA(TM) (paliperidone palmitate) Statistically Similar to RISPERDAL(R) CONSTA(R) (ri

TITUSVILLE, N.J., Dec. 10  /PRNewswire/ -- Treatment with once-monthly INVEGA® SUSTENNA(TM) is not inferior to treatment with bi-weekly RISPERDAL® CONSTA®, according to new data from a comparative study of both treatments in patients with schizophrenia. Results of the 13-week clinical trial were released this week.

An estimated one percent of the world's population suffers from schizophrenia - a brain disorder that impairs a person's ability to think clearly, relate to others, and distinguish between reality and imagination. In the U.S., approximately 2.4 million Americans have schizophrenia, with men and women affected equally.(1) Non-adherence to medication treatment is a common problem encountered in patients with schizophrenia, which can lead to relapse (an increase in symptoms) and hospitalization.(2) Since both INVEGA SUSTENNA and RISPERDAL CONSTA are given by a healthcare professional, it offers the physician a way to monitor patient medication adherence and intervene when a patient misses a dose. Both products offer flexibility to physicians and patients, based on their dosing regimens, thereby offering an important option to those who may need it.

The objective of this study was to show that INVEGA SUSTENNA was statistically similar (non-inferior) to RISPERDAL CONSTA, as measured by the Positive and Negative Syndrome Scale (PANSS). INVEGA SUSTENNA, a once-monthly injectable atypical antipsychotic, was recently approved in the U.S. for the acute and maintenance treatment of schizophrenia in adults. RISPERDAL CONSTA, the first long-acting injectable atypical antipsychotic, was approved for the treatment of schizophrenia in adults in the U.S. in 2003, and recently was approved for use as maintenance therapy in the treatment of Bipolar I Disorder.

"Physicians need treatment options that match the needs of their patients, particularly when compliance is a significant issue. INVEGA SUSTENNA was non-inferior to RISPERDAL CONSTA in the treatment of schizophrenia in this trial, which validates that these are both good options," said George Simpson, M.D., professor of research at Keck School of Medicine, University of Southern California and clinical investigator for the INVEGA SUSTENNA program. "The differences between the two products, such as the shorter or longer dosing interval or the need for oral supplementation, provide options for physicians to decide what will work best for an individual patient."

About the Study

The 13-week, randomized, double-blind, double-dummy trial included 1220 adults with a diagnosis of schizophrenia and a PANSS total score of 60 to 120. Participants were randomly assigned to receive INVEGA SUSTENNA (IS) plus oral placebo or RISPERDAL CONSTA (RC) plus oral risperidone for the first three weeks.

Patients assigned to IS received an initiation dosing regimen of 234* mg on day 1 and 156 mg on day 8, followed by once-monthly dosing on day 36 (78 mg or 156 mg) and day 64 (78 mg, 156 mg, or 234 mg). Additional placebo injections were administered to match RC dosing. Patients assigned to RC received their first injection on day 8, followed by biweekly injections on day 22, 36, 50, 64 and 78. This was supplemented with placebo injections to match IS dosing. The 25 mg starting dose of RC could have been increased up to 37.5 mg starting on day 36 and up to 50 mg on day 64. Patients on RC received mandatory oral risperidone supplementation from days 1 to 28. Oral supplementation was optional with subsequent dose increases.

The primary endpoint of the trial was the change in the PANSS total score versus baseline. Non-inferiority would be concluded by calculation using a 95% confidence interval (CI) based on a pre-specified change in total PANSS score. Secondary efficacy measures included change from baseline for Clinical Global Impression-Severity (CGI-S) and Personal and Social Performance (PSP) Scale.

Results showed similar improvement in the mean change from baseline to endpoint in PANSS total score for IS (-18.6) and RC groups (-17.9). Because the lower limit of the 95% CI exceeded the pre-specified margin of -5, IS was concluded to be non-inferior to RC. Patients' severity of illness (CGI-S) and personal and social performance (PSP) improved similarly in both groups.

The overall incidence of treatment-emergent adverse events (TEAEs) were comparable in the IS group (57.9%) and in the RC group (52.8%). TEAEs that occurred in more than 5% in both treatment groups were: insomnia, headache, somnolence, and injection-site pain. The incidence of extrapyramidal symptom-related TEAEs was similar for both treatment groups. The mean increases in body weight at endpoint also were similar between treatment groups (IS: 1.1 [3.36] kg; RC: 1.0 [3.14] kg).

The study was sponsored by Johnson & Johnson Pharmaceutical Research and Development, L.L.C. (J&JPRD).  In the U.S., Janssen®, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. markets INVEGA SUSTENNA and RISPERDAL CONSTA.  Visit http://www.invegasustenna.com/ and http://www.risperdalconsta.com/ for full prescribing information.

INVEGA SUSTENNA was approved in July 2009 in the U.S. for the acute and maintenance treatment of schizophrenia in adults and utilizes the NanoCrystal® Technology, which is a proprietary technology developed by Elan Drug Technologies through Elan Pharma International Limited and other Elan affiliates.

RISPERDAL CONSTA was approved in 2003 for the treatment of schizophrenia and was approved in May 2009 for monotherapy and adjunctive therapy in the maintenance treatment of Bipolar I Disorder in adults.

IMPORTANT SAFETY INFORMATION FOR INVEGA® SUSTENNA(TM)

INVEGA® SUSTENNA(TM) is not approved for the treatment of dementia-related psychosis in elderly patients. Elderly patients who were given oral antipsychotics like INVEGA® SUSTENNA(TM) in clinical studies for psychosis caused by dementia (memory problems) had a higher risk of death.

Neuroleptic Malignant Syndrome (NMS) is a rare, but serious side effect that could be fatal and has been reported with INVEGA® SUSTENNA(TM) and similar medicines. Call the doctor right away if you develop symptoms such as a high fever, rigid muscles, shaking, confusion, sweating more than usual, increased heart rate or blood pressure, or muscle pain or weakness. Treatment should be stopped if you are being treated for NMS.

Tardive Dyskinesia (TD) is a rare, but serious and sometimes permanent side effect reported with INVEGA® SUSTENNA(TM) and similar medicines. Call your doctor right away if you start to develop twitching or jerking movements that you cannot control in your face, tongue, or other parts of your body. The risk of developing TD and the chance that it will become permanent is thought to increase with the length of therapy and the total dose received. This condition can also develop after a short period of treatment at low doses but this is less common. There is no known treatment for TD but it may go away partially or completely if the medicine is stopped.

One risk of INVEGA® SUSTENNA(TM) is that it may change your heart rhythm. This effect is potentially serious. You should talk to your doctor about any current or past heart problems. Because these problems could mean you're having a heart rhythm abnormality, contact your doctor IMMEDIATELY if you feel faint or feel a change in the way that your heart beats (palpitations).

High blood sugar and diabetes have been reported with INVEGA® SUSTENNA(TM) and similar medicines. If you already have diabetes or have risk factors such as being overweight or a family history of diabetes, blood sugar testing should be done at the beginning and during the treatment. The complications of diabetes can be serious and even life-threatening. Call your doctor if you develop signs of high blood sugar or diabetes, such as being thirsty all the time, having to urinate or "pass urine" more often than usual, or feeling weak or hungry.

Weight gain has been observed with INVEGA® SUSTENNA(TM) and other atypical antipsychotic medications. If you notice that you are gaining weight, please notify your doctor.

Some people may feel faint, dizzy, or may pass out when they stand up or sit up suddenly. Be careful not to get up too quickly. It may help if you get up slowly and sit on the edge of the bed or chair for a few minutes before you stand up. These symptoms may decrease or go away after your body becomes used to the medicine.

INVEGA® SUSTENNA(TM) and similar medicines have been associated with decreases in the counts of white cells in circulating blood. If you have a history of low white blood cell counts or have unexplained fever or infection, then please contact your doctor right away.

INVEGA® SUSTENNA(TM) and similar medicines can raise the blood levels of a hormone called prolactin and blood levels of prolactin remain high with continued use. This may result in some side effects including missed menstrual periods, leakage of milk from the breasts, development of breasts in men, or problems with erection. If you have a prolonged or painful erection lasting more than 4 hours, seek immediate medical help to avoid long-term injury. Call your doctor right away if you start thinking about suicide or wanting to hurt yourself.

INVEGA® SUSTENNA(TM) can make some people feel dizzy, sleepy, or less alert. Until you know how you are going to respond to INVEGA® SUSTENNA(TM), be careful driving a car, operating machines, or doing things that require you to be alert.

This medicine may make you more sensitive to heat. You may have trouble cooling off or be more likely to become dehydrated. Be careful when you exercise or spend time doing things that make you warm.

Some medications interact with INVEGA® SUSTENNA(TM). Please inform your healthcare professional of any medications or supplements that you are taking. INVEGA® SUSTENNA(TM) should be used cautiously in people with a seizure disorder, who have had seizures in the past, or who have conditions that increase their risk for seizures.

Inform your healthcare professional if you become pregnant or intend to become pregnant during therapy with INVEGA® SUSTENNA(TM).

Do not drink alcohol while you are taking INVEGA® SUSTENNA(TM).

In a study of people taking INVEGA® SUSTENNA(TM), common side effects in the treatment of schizophrenia were reactions at the injection site, sleepiness, dizziness, feeling of inner restlessness, and abnormal muscle movements, including tremor (shaking), shuffling, uncontrolled involuntary movements, and abnormal movements of the eyes.

This is not a complete list of all possible side effects. Ask your doctor or treatment team if you have any questions or want more information.

If you have any questions about INVEGA® SUSTENNA(TM) or your therapy, talk with your doctor.

IMPORTANT SAFETY INFORMATION FOR RISPERDAL® CONSTA®

Elderly Patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared to placebo. RISPERDAL® CONSTA® (risperidone) is not approved for the treatment of patients with dementia-related psychosis.

Cerebrovascular Adverse Events (CAEs): CAEs, including fatalities, have been reported in elderly patients with dementia-related psychosis taking oral risperidone in clinical trials. The incidence of CAEs with risperidone was significantly higher than with placebo. RISPERDAL® CONSTA® 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 the use of antipsychotic medications, including RISPERDAL® CONSTA®. 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), including RISPERDAL® CONSTA®. 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.

Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors,

RISPERDAL® CONSTA® elevates prolactin levels and the elevation persists during chronic administration.  Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.

Orthostatic Hypotension: RISPERDAL® CONSTA® may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period. Monitoring should be considered in patients for whom this may be of concern. RISPERDAL® CONSTA® should be used with caution in patients with known cardiovascular disease, and conditions that would predispose patients to hypotension.

Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including risperidone.  Patients with a pre-existing low white blood cell count (WBC) or a history of leukopenia/neutropenia should have frequent complete blood cell counts during the first few months of therapy.  At the first sign of a decline in WBC and in the absence of other causative factors, discontinuation of RISPERDAL® CONSTA® should be considered.

Potential for Cognitive and Motor Impairment: RISPERDAL® CONSTA® has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that RISPERDAL® CONSTA® does not affect them adversely.

Seizures: RISPERDAL® CONSTA® should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold.

Dysphagia: Esophageal dysmotility and aspiration can occur. Use cautiously in patients at risk for aspiration pneumonia.

Priapism has been reported. Severe priapism may require surgical intervention.

Thrombotic Thrombocytopenic Purpura (TTP) has been reported.

Administration: RISPERDAL® CONSTA® should be injected into the deltoid or gluteal muscle, and care must be taken to avoid inadvertent injection into a blood vessel.

Suicide: The possibility of suicide attempt is inherent in schizophrenia or bipolar disorder.  Close supervision of high-risk patients should accompany drug therapy.

Increased sensitivity in patients with Parkinson's disease or those with dementia with Lewy bodies has been reported. Manifestations and features are consistent with NMS.

Use RISPERDAL® CONSTA® with caution in patients with conditions and medical conditions that could affect metabolism or hemodynamic responses (e.g. recent myocardial infarction or unstable cardiac disease).

Maintenance Treatment: Patients should be periodically reassessed to determine the need for continued treatment.

Commonly Observed Adverse Reactions for RISPERDAL® CONSTA®:  The most common adverse reactions in clinical trials in patients with schizophrenia (greater than or equal to 5%) were headache, Parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increase, pain in extremities, and dry mouth.

The most common adverse reactions in clinical trials in patients with bipolar disorder were weight increased (5% in monotherapy trial) and tremor and Parkinsonism (> 10% in adjunctive therapy trial).

If you have any questions about RISPERDAL® CONSTA® or your therapy, talk with your doctor.

About Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD) is headquartered in Raritan, New Jersey (USA), and has nine sites throughout Europe and the United States. J&JPRD employs approximately 3,500 people and is leveraging drug discovery, drug evaluation and drug development in a variety of therapeutic areas to address unmet medical needs worldwide. The company's major therapeutic areas of focus include hematology, oncology, infectious disease, obesity and metabolic disorders, neurology and psychiatry, pain and women's health.

About Janssen

Janssen®, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., is based in Titusville, N.J., and is the only large pharmaceutical company in the U.S. dedicated solely to mental health.  It currently has prescription medications for the treatment of schizophrenia, bipolar mania, and the treatment of symptoms associated with autistic disorders. Ortho-McNeil-Janssen Pharmaceuticals, Inc. is a member of the Johnson & Johnson family of companies.  For more information about Janssen, visit http://www.janssen.com/.

*Because doses of paliperidone palmitate can be expressed both in terms of milligram equivalents (mg eq.) of the pharmacologically active fraction of paliperidone and in milligrams of paliperidone palmitate, the doses expressed as 50, 100 and 150 mg eq. equate to 78, 156 and 234 mg respectively, of paliperidone palmitate.

(1)National Institutes of Mental Health Web site: http://www.nimh.nih.gov/health/publications/the-numbers-count-mental-disorders -in-america/index.shtml#Schizophrenia. Accessed  November 12, 2009.

(2)Sun SX, Liu GG, Christensen DB, Fu AZ. Review and analysis of hospitalization costs associated with antipsychotic nonadherence in the treatment of schizophrenia in the United States. Curr Med Res Opin. Oct. 2007; 23 (10): 2305-12. 

DATASOURCE: Janssen(R), Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.



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