6-4. Paliperidone: a review of clinical trial data and clinical implications.
Wang SM ; Han C ; Lee SJ ; Patkar AA ; Pae CU ; Fleischhacker WW
Clinical Drug Investigation [Clin Drug Investig] 2012 Aug 1; Vol. 32 (8), pp. 497-512.
Paliperidone, 9-hydroxy-risperidone, is the major metabolite of the atypical antipsychotic
risperidone and is available in an oral extended-release (ER) formulation. Paliperidone ER was
approved for treating schizophrenia in 2006, and in 2009 it became the first atypical antipsychotic
licensed for treating schizoaffective disorder. The short-term efficacy, safety and tolerability of
paliperidone ER for patients with schizophrenia were demonstrated in three pivotal 6-week,
randomized, double-blind, placebo-controlled studies. Data from the long-term trial showed that
paliperidone ER is also effective in preventing relapse of schizophrenia. Two randomized,
placebo-controlled, short-term studies have documented the efficacy and tolerability of
paliperidone ER in the treatment of schizoaffective disorder, but no long-term or maintenance
study has been conducted in patients with schizoaffective disorder. Two 3-week, randomized,
double-blind, placebo-controlled studies showed that paliperidone ER is significantly superior to
placebo for treating patients with bipolar disorder, but the results were driven by certain
subpopulations. Limited evidence suggests that paliperidone ER can potentially be superior to
quetiapine and risperidone. However, few direct head-to-head comparisons between
paliperidone ER and other antipsychotics have been conducted to confirm these results. The
distinctive pharmacological characteristics of paliperidone ER, including smooth fluctuations in
plasma drug concentrations, predominantly renal excretion, low risk of causing hepatic
impairment and low drug-drug interaction, might provide important clinical advantages
compared with risperidone. However, certain side effects require clinical attention. The rate of
extrapyramidal side effects was considerably higher than that of a placebo at doses ≥9 mg/day.
The risks for orthostatic hypotension, prolongation of the corrected QT interval and
hyperprolactinaemia are also concerns. This review summarizes the currently published data on
paliperidone ER for treating patients with schizophrenia, schizoaffective disorder and bipolar
disorder, and suggests its appropriate use in clinical practice.
6-5. Paliperidonepalmitate - review of the efficacy, safety and cost of a new second-generation
depot antipsychotic medication
Citrome L
International Journal Of Clinical Practice [Int J ClinPract] 2010 Jan; Vol. 64 (2), pp. 216-39. Date of
Electronic Publication: 2009 Nov 03.
Objective: To describe the efficacy, safety and cost of paliperidonepalmitate, a depot
antipsychotic medication recently approved for the treatment of schizophrenia.
Data Sources: A literature search was conducted by querying the websites
http://www.pubmed.gov,
http://www.fda.gov,
http://www.accessdata.fda.gov/scripts/cder/drugsatfda and http://www.clinicaltrials.gov for the
search term 'paliperidonepalmitate'. Cost information was obtained from the pharmaceutical
vendor servicing a local state-operated psychiatric facility.
Study Selection: All available reports of studies were identified. Product labelling provided
additional information.
Data Extraction: Descriptions of the principal results and calculation of the number needed to
treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were
extracted from the study reports and synopses. Additional safety outcomes subject to NNH
analysis were obtained from product labelling.
Data Synthesis: Paliperidonepalmitate is a newly available depot formulation of paliperidone (the
9-OH metabolite of risperidone). Upon injection into the deltoid or gluteal muscle, the release of
the drug starts as early as day 1, reaches maximum plasma concentrations at 13 days and lasts for
as long as 126 days. Maximum concentration following deltoid injection is approximately 28%
higher compared with injection into the gluteal muscle, and thus paliperidonepalmitate requires
initiation by two initial deltoid injections spread 1 week apart to achieve therapeutic
concentrations rapidly. Subsequent injections are at 4-week intervals. Acute efficacy was
evidenced by four short-term double-blind, randomised, placebo-controlled, fixed-dose studies of
acutely relapsed adult inpatients who met DSM-IV criteria for schizophrenia. NNT for a 30% or
greater decrease in the Positive and Negative Syndrome Scale total score compared with placebo
was consistently lower for the higher dose strengths of 156 and 234 mg, suggesting a therapeutic
dose-response. Treatment with paliperidonepalmitate at doses between 39 and 156 mg
significantly delayed the time to recurrence of symptoms of schizophrenia after 24 weeks of
maintained symptom stability. The NNT vs. placebo to avoid a recurrence of symptoms was 5
(95% CI 4-7). Overall, paliperidonepalmitate was reasonably well tolerated, with low rates of
extrapyramidal symptoms or body weight gain; however, these may be more common at higher
doses. Injection site reactions occurred at a rate ranging from 4% to 10%, depending on the dose
regimen, compared with 2% for the pooled placebo arms. The acquisition cost of a maintenance
dose of paliperidonepalmitate calculated on a per day basis is similar to that for risperidone
microspheres, but about double the cost for oral paliperidone and approximately 19 times the
cost of oral generic risperidone.
Conclusions: Paliperidonepalmitate is efficacious for the acute and maintenance treatment of
schizophrenia and is reasonably well tolerated. It offers several advantages over other available
second-generation depot antipsychotics: it comes in prefilled syringes in a number of different
dosage strengths; it does not require refrigeration; it does not require supplementation with oral
antipsychotics; it can be administered once monthly; it can be administered with a very small
bore needle; the injection volume is small; the injection site can be either the deltoid or gluteal
muscles; it does not require an additional precautionary observation period after the injection.
For patients for whom oral risperidone or paliperidone is otherwise effective,
paliperidonepalmitate offers a guaranteed delivery system that enhances adherence. However,
the high acquisition cost of paliperidonepalmitate will likely be an important obstacle to its
routine use.