Pharmacology Update

Paliperidone Extended-Release Tablets (Invega™)

By William T. Elliot, MD, FACP, and James Chan, PhD, PharmD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.

The FDA has approved a new atypical antipsychotic agent. Paliperidone is the active metabolite of risperidone. The drug is formulated in an osmotic drug delivery system (OROS) developed by ALZA. Invega is manufactured by ALZA Corp and marketed by Janssen.

Indications

Paliperidone is indicated for the treatment of schizophrenia.1

Dosage

The recommended dose is 6 mg once daily, taken in the morning. Dose titration is generally not required. Doses above 6 mg should be evaluated based on balancing potential benefit and adverse events. Increases of 3 mg/day should be made at intervals of greater than 5 days. The maximum dose is 12 mg daily. Tablets should be taken whole, not chewed or crushed and without regard to meals.1 No dosage adjustment of mild to moderate hepatic dysfunction. Dose reduction is recommended for moderate to severe renal dysfunction.

Paliperidone is available as 3 mg, 6 mg, and 9 mg tablets.

Potential Advantages

The combination of the active metabolite and extended-release technology of the OROS system minimizes fluctuation in the plasma level of the drug. This may facilitate treatment initiation. Since paliperidone does not undergo hepatic metabolism, drug-drug interactions involving hepatic enzyme systems are unlikely. Paliperidone also has minimal effect on p-glycoprotein.

Potential Disadvantages

Paliperidone shares the adverse effects associated with atypical antipsychotics in general and risperidone in particular. These include increased mortality in elderly patients with dementia related psychosis, prolonged QTc, neuroleptic malignant syndrome, tardive dyskinesia, hyperglycemia and diabetes mellitus, hyperprolactemia, esophageal dysmotility, and orthostatic hypotension. Most common adverse events are tachycardia or palpitation (12% vs 7% placebo). Less frequent adverse events include akathisia and extrapyramidal side effects. Due to the extended drug delivery system, it should be avoided in patients with rapid gastrointestinal transit time.1 Treatment greater than 6 weeks has not been studied.

Comments

Paliperidone is the primary active metabolite of isperidone. After administration of risperdone, levels of paliperidone are about 22 times higher than the parent compound. The efficacy of paliperidone was demonstrated in three 6-week, placebo-controlled, multinational trials (n = 1665).1 In a published study, 628 subjects were randomized to paliperidone 6 mg, 9 mg, 12 mg, placebo, and olanzapine 10 mg daily (active control).3 Primary endpoints were a decrease in the Positive and Negative Syndrome Scale (PANSS) that includes 5 factors (positive symptoms, negative symptoms, disorganized thought, uncontrolled hostility/excitement and anxiety/depression) and clinician rating of personal and social functioning (PSP). Paliperidone 6 mg reduced PANSS by 17.9 22.2 compared to -4.1 23.2 for placebo and -19.9 10 for olanzapine. A 30% or greater reduction was achieved with 56% of the paliperidone 6 mg arm, 52% for olanzapine and 30% for placebo. Improvement was observed at day 8 of therapy. For change in PSP, 60.5% of the paliperidone 6 mg arm had a 10-point improvement (on a 100-point scale) compared to 32.5% for placebo and 62.7% for olanzapine. All treatments were statistically better than placebo. The 6 mg dose appears to be the optimal dose. The 12 mg dose was associated with a marginal gain in efficacy (12 mg) but with a greater incidence of movement disorder related adverse effects as well as other adverse events. Frequency of gain of 7% of body weight occurred in 2% of placebo, 5% for paliperidone 6 mg, and 13% for olanzapine. Somnolence was more common with olanzapine. Increase in prolactin levels occurred with paliperidone but decreased with placebo and olanzapine. The 30-day wholesale cost of paliperidone 6 mg is $292.80.

Clinical Implications

Paliperidone is the primary metabolite of risperidone and is expected to share very similar pharmacological characteristics. This along with established drug delivery systems offers once daily dosing, more constant release of the drug, and lower potential for drug interactions. However, no clear clinical advantages have been demonstrated by direct comparisons to risperidone or other atypical antipsychotics.

References

1. Invega Product Information. December 2006. Janssen.

2. Zhu HJ, et al. Neuropsychopharmacology. 2006; Epub.

3. Kane J, et al. Schizophrenia Research. 2006; Epub.