Med Check

• The Food and Drug Administration (FDA) is requiring manufacturers to add a precaution on the labels of all antipsychotics about the risks of leukopenia, neutropenia, and agranulocytosis associated with the entire drug class. These adverse events related to white-blood-cell counts have been reported to the agency in clinical trials or postmarketing reports. Patients with an already low white blood-cell count and a history of drug-induced leucopenia/neutropenia may be at a higher risk for developing such problems if they are taking antipsychotics. Clinicians should carefully monitor patients for symptoms of infection if neutropenia develops and discontinue the drug if neutrophil count falls below 1000/mm³. The labeling change applies to both first- and second-generation antipsychotics.

• The FDA and the European Medicines Agency have launched a collaborative initiative to share standards and information for the regulation of clinical-trial practices, the FDA announced on August 3. The initiative includes sharing the agencies' reports from routine inspection and monitoring of clinical-trial sites, streamlining procedures, and communicating regulatory legislation and guidelines with each other. As more pharmaceutical and medical-device companies conduct global trials and seek marketing approval with clinical data collected abroad, the two agencies hope to share the inspection resources in monitoring compliance and assessing ethical conduct of clinical trials.

• The FDA approved paliperidone extended-release oral tablets for acute treatment of schizoaffective disorder as either monotherapy or adjunctive therapy to mood stabilizers and/or antidepressants, according to a July 31 announcement by Ortho-McNeil-Janssen Pharmaceuticals, a subsidiary of Johnson and Johnson. Two randomized, double-blind, placebo-controlled trials were conducted in patients with schizoaffective disorder for six weeks to support the approval.

In these trials patients either received paliperidone alone or were given paliperidone along with a mood stabilizer with or without an antidepressant. Patients on a dosage of 12 mg/day (with the option of reducing to 9 mg/day) of paliperidone showed statistically significant improvement over placebo patients on Positive and Negative Syndrome Scale (PANSS) total scores. A lower dosage (6 mg/day with the option of reducing to 3 mg/day) did not achieve significant difference in PANSS total score between the active treatment and placebo groups. Paliperidone had already been approved for acute and maintenance treatment of schizophrenia. It is currently the only medication carrying the approved indication for schizoaffective disorder.

• The FDA has approved the once-monthly, long-acting formulation of paliperidone palmitate injection for acute and maintenance treatment of schizophrenia, Ortho-McNeil-Janssen announced on August 4. The approval was based on four short-term clinical studies and one long-term study in which paliperidone palmitate was compared with placebo. In this formulation, paliperidone comes in prefilled syringes, and the first two intramuscular injections should be administered one week apart, followed by monthly injections thereafter. The company also manufactures risperidone long-acting injection, which is dosed once every two weeks. On August 27 Johnson and Johnson announced its decision to terminate the development of a once-every-four-week formulation of risperidone.

• The FDA has approved guanfacine extended-release tablets for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents aged 6 to 17, Shire announced on September 3. Also used to treat hypertension, guanfacine is an alpha_2A adrenergic receptor agonist. Shire developed this once-daily formulation specifically for the treatment of ADHD. The product, which is being marketed under the brand name of Intuniv, will not be a controlled medication.

In two randomized, double-blind, placebo-controlled clinical trials, children and adolescents treated with guanfacine improved in ADHD Rating Scale-IV total scores from baseline, and the difference between the active drug and placebo was statistically significant. The most common adverse events seen in the trials included somnolence, headache, fatigue, upper abdominal pain, and sedation. Adverse effects related to alpha agonists, such as hypotension, bradycardia, and syncope, were also observed in some patients. Prescribers are urged to assess patients' heart rate and blood pressure before starting the medication, followed by periodic monitoring.

• Labopharm Inc., a Canadian company, said on August 25 that the FDA accepted its response to a previous letter the agency had issued regarding the company's trazodone extended-release tablets, a once-daily formulation of the first-generation antidepressant developed by the company and currently awaiting FDA marketing approval. According to the company, the agency's letter had initially rejected the new drug application because of deficiencies discovered at a manufacturing plant but cited no safety or efficacy concerns about the medication. A final decision on the application will be made by February 2010.

• Dainippon Sumitomo Pharma, a Japanese pharmaceutical company, announced on August 26 positive results from a phase 3 clinical trial of lurasidone, a second-generation antipsychotic in development. Lurasidone binds to dopamine D₂, serotonin 5-HT₇, 5-HT_2A, 5-HT_1A, and noradrenalin alpha_2c receptors. In the randomized, double-blind, controlled trial, 478 patients with schizophrenia were given lurasidone 40 mg/day or 120 mg/day, placebo, or olanzapine 15 mg/day for six weeks. Olanzapine was included as an active comparator to determine whether the trial was conducted with enough sensitivity to be able to detect a difference between active treatment and the placebo effect.

At both dosage levels, lurasidone was more effective in reducing patients' psychotic symptoms as measured by the PANSS total score. Lurasidone did not beat olanzapine in the primary efficacy endpoint. The most common adverse events associated with lurasidone were akathisia, somnolence, sedation, extrapyramidal effects, nausea, and dystonia. The median weight gain after the six-week study was 0.9 kg in the 40 mg/day lurasidone group, 0.5 kg in the 120 mg/day group, 0 kg in the placebo group, and 3.1 kg in the olanzapine group. The company said it plans to file a new drug application for lurasidone with the FDA in early 2010.

• The investigational drug pimavanserin, which is being studied for Parkinson's disease psychosis, failed to meet the primary efficacy endpoint in a phase 3 trial conducted by its maker, Acadia Pharmaceuticals, according to a September 1 company announcement. In a double-blind, placebo-controlled trial, 298 patients diagnosed with psychosis related to Parkinson's disease were randomly assigned to pimavanserin 10 mg/day or 40 mg/day or to placebo. After six weeks of treatment, symptoms improved from baseline in all three groups, as indicated by the Scale for the Assessment of Positive Symptoms (SAPS) score. The SAPS score decreased by 5.8 points and 6.7 points in the pimavanserin 10 mg and 40 mg groups, respectively. Neither change differed significantly from the 5.9-point reduction in the placebo group.

Pimavanserin is a serotonin 5-HT_2A receptor inverse agonist being developed for psychosis associated with Parkinson's and Alzheimer's diseases. The company said it plans to continue the phase 3 development.▪