Paliperidone ER: Reformulated antipsychotic for schizophrenia Tx
Risperidone’s metabolite behaves well but differently in once-daily delivery.
In the 9 months since paliperidone extended-release was FDA-approved for schizophrenia, the 3 acute pivotal trials supporting its approval have been published.1-3 They join a handful of post hoc analyses of this second-generation antipsychotic (SGA) in schizophrenia subgroups, including patients over age 65, recently diagnosed patients, and those with predominant negative symptoms.
This article discusses the evidence and paliperidone ER’s probable clinical benefits and adverse effects, with focus on its:
- pharmacodynamics and pharmacokinetics
- potential efficacy in schizophrenia and for specific patients and symptoms
- safety and tolerability.
How does paliperidone ER work?
Paliperidone ER was approved for schizophrenia treatment in December 2006 based on three 6-week, randomized, placebo-controlled trials. Paliperidone ER is the active metabolite of risperidone (9-OH risperidone) delivered in a once-daily, time-released formulation (Table 1).
Pharmacodynamics. Similar to risperidone, paliperidone ER has high binding affinity for dopamine (D2) and serotonin (5-HT2A) receptors, with additional affinity for histaminic (H1) and adrenergic receptors (alpha1 and alpha2) but not for muscarinic-cholinergic receptors.
Pharmacokinetics. After oral administration, the medication is widely and rapidly distributed. The drug’s terminal half-life is about 23 hours, and steady-state concentration is reached in 4 to 5 days.4,5
Approximately 60% of the medication is eliminated renally and 11% is eliminated in the feces unchanged, with very limited hepatic metabolism.6 As a result, paliperidone ER appears to lack enzyme-inducing or inhibiting properties and does not substantially affect drugs that undergo cytochrome P-450 metabolism in the liver.
Thus paliperidone ER—when compared with risperidone and other antipsychotics that are metabolized primarily in the liver—is less likely to be involved in hepatic drug-drug or drug-disease interactions. However, some drugs that can induce CYP-450 enzymes—such as carbamazepine—may affect paliperidone’s metabolism.7
Paliperidone has an osmotic controlled-release oral delivery system (OROS®) for steady medication delivery across 24 hours8 (Table 2).1-3 The tablet consists of an osmotically active tri-layer core surrounded by a semipermeable membrane. When the tablet is swallowed, the membrane controls the rate of water reaching the tablet core, which determines the rate of drug delivery.6 The result is less variation between peak and trough drug concentrations, compared with immediate-release formulations.
How paliperidone ER compares with risperidone
Risperidone plus 9-OH risperidone
Primarily through cytochrome P-450 enzyme 2D6
Start at target dose
Titrate to target dose
OROS: osmotic controlled-release oral delivery system
Paliperidone ER’s clinical characteristics
Second-generation antipsychotic approved for schizophrenia
9-OH active metabolite of risperidone
Osmotic controlled-release system provides steady-state drug delivery over 24 hours
Terminal half-life (time for 50% of drug to be eliminated from the body) ~23 hours
Available in 3-mg, 6-mg, and 9-mg tablets; recommended starting dose is 6 mg/d, and labeled dose range is 3 to 12 mg/d
Excreted primarily by the kidney; maximum recommended dose for patients with oderate to severe renal impairment is 3 mg/d
Patient selection. Because of its slow-release formulation and relatively stable plasma concentrations, paliperidone ER might be useful for patients who are highly sensitive to antipsychotics’ side effects. In particular, paliperidone ER might be ideal for patients who respond to but may not tolerate risperidone.
Paliperidone ER appears to be safe in patients with liver disease. Its primary renal excretion should minimize the risk of hepatic-related drug interactions in patients taking multiple medications.
Dosage and titration. For treating schizophrenia, the suggested starting dose of paliperidone ER is 6 mg/d taken in the morning. In the 3 pivotal trials, 6 mg was the lowest dose to show broad efficacy with minimal adverse events.9
For many patients, the 6-mg starting dose will be the therapeutic dose. When needed, the dose may be increased in 3-mg increments every 1 to 2 weeks to a maximum 12 mg/d (a 15-mg dose was used in clinical trials, but the adverse effects out-weighed the benefits). Lower maximum doses are recommended for patients with renal impairment:
- 6 mg/d for those with creatinine clearance ≥50 to <80 mL/min (mild impairment)
- 3 mg/d for those with creatinine clearance 10 to <50 mL/min (moderate to severe impairment).10
In the pivotal trials, differences in the terminal elimination half-life between hepatically impaired and healthy patients were minimal (26.5 hours vs 23.6 hours, respectively). Unbound paliperidone levels were slightly lower in patients with hepatic impairment11 but not low enough to recommend dose adjustment.
Safety and tolerability. Pooled data from the 3 trials indicate that adverse events (AEs) occurred during treatment in 66% to 77% of patients receiving paliperidone ER vs 66% in placebo groups. The most common AEs were headache (11% to 18%), insomnia (4% to 12%), and anxiety (6% to 9%).9
EPS. Risk of EPS-related AEs (such as akathisia and parkinsonian symptoms) with 3-mg and 6-mg paliperidone ER doses (13% and 10%, respectively) was similar to placebo (11%) but increased with the 9-mg, 12-mg, and 15-mg doses (25%, 26%, and 24%, respectively). Should EPS occur, reduce the paliperidone ER dose or consider adding antiparkinsonian medications.
Lab values. No clinically relevant changes were noted in blood glucose, insulin, or lipids.12 Similar to risperidone, paliperidone ER elevated prolactin levels.
Weight gain with paliperidone ER is dose-dependent; in the clinical trials, mean body weight change for all doses was ≤1.9 kg, which is similar to the weight gain seen with risperidone and in the moderate range compared with other SGAs. When using paliperidone ER, follow the American Diabetes Association/American Psychiatric Association guidelines13 for monitoring weight gain and metabolic parameters with antipsychotics. Also monitor patients for clinical symptoms of hyperprolactinemia, and—if intolerable—adjust the dose or switch to another SGA.
Tachycardia. Advise patients that they may experience a rapid heart rate while taking paliperidone ER. In clinical trials, tachycardia occurred in ≤14% of patients—twice the rate with placebo—but did not contribute to more serious cardiac rhythm disturbances or to discontinuation. Incidence of prolonged corrected QT interval (QTc) was 3% to 5% in the paliperidone ER group vs 3% in the placebo group.
Cost. Paliperidone ER costs approximately $12 to $18 per daily dose, which is similar to risperidone. Cost may be a greater consideration for patients next year, when generic risperidone becomes available (see Related Resources).
Patient education. Because of paliperidone ER’s pharmacokinetic properties, counsel patients to:
- take 1 tablet each day in the morning
- not chew, split, or crush the tablets but swallow whole to preserve the controlled-release delivery.
Also inform patients that they may see the tablet’s nonabsorbable shell in their stool as undigested residue.
Paliperidone ER’s potential benefits and risks in clinical practice
Data support acute (6 weeks) and chronic (up to 24 weeks) improvement in schizophrenia symptoms, patient function, and quality of life
Primarily renal excretion decreases risk of hepatic drug-drug or drug-disease interactions
Once-daily dosing simplifies treatment and may improve adherence
Risk similar to placebo at 3-mg and 6-mg doses, but increased at higher doses
Similar to risperidone
Similar to risperidone
Occurred in up to 14% of patients in clinical trials (twice the rate of placebo [7%])
Increase up to 12 msec on average, with no patients exceeding 500 msec and no clinically adverse events during trials; use paliperidone with caution in patients with arrhythmias or cardiovascular disease or who are taking other medication that can prolong the QT interval
EPS: extrapyramidal symptoms
Efficacy trials in schizophrenia
Three 6-week trials1-3 examined paliperidone ER’s efficacy in a total of 1,692 patients with chronic schizophrenia who were hospitalized ≥14 days with acute exacerbations. The trials were double-blind, randomized, fixed-dose, parallel-group, and placebo- and active-controlled (compared with olanzapine, 10 mg/d). Patients showed no significant differences in demographic or baseline characteristics or in the use of rescue medications.
The primary outcome measure was mean change in Positive and Negative Syndrome Scale (PANSS) total score, which quantifies positive, negative, and global psychopathologic symptom severity. Secondary outcome measures included:
- PANSS Marder factor scores14 (derived from PANSS items that reflect positive and negative symptoms, anxiety and depression, hostility, and thought disorganization).
- Clinical Global Impressions-Severity (CGI-S) score, which measures overall illness severity.15
- Personal and Social Performance (PSP) scores, which rate socially useful activities, relationships, self-care, and disturbing and aggressive behaviors; improvement by 1 category (10 points) reflects a clinically meaningful change.16,17
The first study1 was conducted at 74 U.S. centers and enrolled 444 subjects (PANSS mean baseline score 94 ± 12). Patients were randomly assigned to fixed doses of paliperidone ER, 6 mg or 12 mg; placebo; or olanzapine, 10 mg/d. The olanzapine arm confirmed assay sensitivity and was not included in the efficacy analyses. Clinical response was defined as ≥30% improvement from baseline in total PANSS score.
A total of 43% of patients completed the study—34% taking placebo; 46% taking paliperidone ER, 6 mg; 48% taking paliperidone ER, 12 mg; and 45% taking olanzapine. Demographic and baseline characteristics of the 432 patients who received ≥1 dose were similar across all groups. Approximately 75% of patients in each group used rescue medications—primarily lorazepam—for agitation, restlessness, or insomnia for a mean of 8 days.
Patients taking either paliperidone ER dose showed statistically significant greater improvement in PANSS total score compared with those taking placebo (6 mg, P = 0.006; 12 mg, P <0.001).
Clinical response rates were similar with the 6-mg and 12-mg paliperidone ER doses—50% and 51%, respectively—and greater than with placebo (34%). The higher response rates with paliperidone ER were statistically significant compared with placebo (6 mg, P <0.03; 12 mg, P = 0.013).
Discontinuation rates for lack of efficacy were lower with paliperidone ER (6 mg, 23%; 12 mg, 14%) than with placebo (35%). A substantially lower percentage of patients taking this agent remained classified as “marked/severe/extremely severe” on the CGI-S score from baseline to endpoint, compared with the placebo group;
- 6 mg paliperidone ER, 58% to 26%
- 12 mg paliperidone ER, 64% to 21%
- placebo, 60% to 45%.
PSP scores improved in both paliperidone ER groups, but the difference compared with placebo was statistically significant only for the 6-mg dose (P <0.008).
The second study2 included U.S. and international sites and compared 3 fixed doses of paliperidone ER (6-, 9-, and 12-mg) with placebo. Among the 630 patients enrolled, 66% completed the study. Patients were randomly assigned to 6 mg, 9 mg, or 12 mg of paliperidone ER; 10 mg of olanzapine; or placebo. The number of patients who dropped out because of adverse events was comparable across the groups.
Patient groups assigned to paliperidone ER showed significant improvement when compared with placebo (P <0.001), based on mean change in PANSS total score and PANSS Marder factor scores. The percentage of patients with a >30% reduction in PANSS total score from baseline to endpoint included:
- 6 mg paliperidone ER, 56%
- 9 mg paliperidone ER, 51%
- 12 mg paliperidone ER, 61%
- placebo, 30%.
Discontinuation rates for lack of efficacy also were lower in the paliperidone ER groups vs placebo (6 mg, 16%; 9 mg, 16%; 12 mg, 10%; placebo, 40%). A substantially lower percentage of patients taking the drug remained classified as “marked/severe/extremely severe” by CGI-S score, compared with placebo:
- 6 mg paliperidone ER, 63% at baseline to 22% at endpoint
- 9 mg paliperidone ER, 58% to 23%
- 12 mg paliperidone ER, 64% to 16%
- placebo, 60% to 51%.
PSP scores improved significantly for all 3 paliperidone ER doses vs placebo.
The third study3 was a multicenter international trial that compared 3 fixed doses of paliperidone ER (3, 9, and 15 mg) with placebo. Among the 618 randomized patients, 365 (59%) completed the study: 70 of 127 (55%) on 3-mg paliperidone ER, 78 of 125 (62%) on 9-mg paliperidone ER, 82 of 115 (71%) on 15-mg paliperidone ER, and 47 of 123 (38%) on placebo.