Paliperidone

ADIS DRUG EVALUATION
Drugs 2010; 70 (10): 1295-1317 0012-6667/10/0010-1295/$55.55/0
2010 Adis Data Information BV. All rights reserved.
Paliperidone Extended Release

A Review of its Use in the Management of Schizophrenia
Claudine M. Chwieduk and Gillian M. Keating
Adis, a Wolters Kluwer Business, Auckland, New Zealand
Various sections of the manuscript reviewed by: M.D. Jibson, Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, USA; A.M. Mortimer, Department of Psychiatry, University of Hull, Hull, England; J. Peuskens, Universitair Psychiatrisch Centrum KU Leuven, Kortenberg, Belgium; E.K.G. Syvalahti, Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland.
Data Selection Sources: Medical literature published in any language since 1980 on paliperidone, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug. Search strategy: MEDLINE, EMBASE and AdisBase search terms were paliperidone and schizophrenia. Searches were last updated 9 June 2010. Selection: Studies in patients who received paliperidone extended release as acute or maintenance treatment for schizophrenia. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Index terms: Paliperidone, extended release, schizophrenia, pharmacodynamics, pharmacokinetics, pharmacoeconomics, therapeutic use, tolerability.
Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Receptor Binding and Occupancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Endocrine and Metabolic Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 General Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Acute Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1 Treatment of Acute Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2 Prevention of Acute Symptom Recurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Non-Acute Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1 Compared with Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2 In Patients Previously Unsuccessfully Treated with an Oral Antipsychotic . . . . . . . . . . . . . 5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 General Tolerability Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Extrapyramidal Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Endocrine and Metabolic Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1296 1297 1297 1297 1298 1299 1299 1299 1300 1300 1301 1301 1301 1305 1306 1306 1306 1307 1307 1309 1309
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5.4 Cardiac Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1310 6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311 7. Place of Paliperidone Extended Release in the Management of Schizophrenia . . . . . . . . . . . . . . . . 1311
Abstract
Paliperidone, the major active metabolite of the atypical antipsychotic risperidone, is available in an oral extended-release (ER) formulation (Invega) and is indicated for the acute and maintenance treatment of schizophrenia in adults in the US and the EU. Once-daily paliperidone ER provides stable plasma drug concentrations over a 24-hour period and may be initiated at therapeutically effective dosages without the need for titration. Paliperidone ER 312 mg/day improved Positive and Negative Syndrome Scale (PANSS) total scores (primary endpoint) from baseline to study end to a significantly greater extent than placebo in 6-week, double-blind trials in patients with acute symptoms of schizophrenia. The significant improvement in PANSS total score was seen after 4 days of treatment in some trials and paliperidone ER was effective against both positive and negative symptoms of the disease. End of treatment clinical response rates were significantly higher in paliperidone ER recipients than in those who received placebo. The efficacy of paliperidone ER was maintained with longer-term treatment (up to 52 weeks) in open-label extensions of placebo-controlled trials. When compared with quetiapine, paliperidone ER was associated with significantly greater improvements in PANSS total scores from baseline at 2 weeks (primary endpoint) in patients with acute schizophrenia, and at 6 weeks. The two drugs did not significantly differ in terms of clinical response rates. In the only trial to evaluate paliperidone ER for the prevention of symptom recurrence, paliperidone ER recipients had a significantly longer time to recurrence than did placebo recipients, as well as significantly less deterioration of symptom severity. In a 6-month, open-label trial in patients with non-acute schizophrenia, PANSS total scores, PANSS subscale scores and all five Marder factor scores did not significantly differ between paliperidone ER and olanzapine, but were significantly reduced from baseline at endpoint in both treatment groups. In adults with non-acute schizophrenia who were previously unsuccessfully treated with other oral antipsychotics and switched to paliperidone ER, PANSS total scores, PANSS subscale scores and all five Marder factor scores were significantly decreased from baseline at week 26 or endpoint. Paliperidone ER was generally well tolerated during short- and longer-term use and had a tolerability profile generally similar to that of its parent drug, risperidone. There were no unexpected tolerability findings during treatment of up to 52 weeks in duration. Paliperidone ER appeared to have little proarrhythmic potential and little effect on plasma glucose, lipid or insulin levels, but increased plasma prolactin levels over both short- and longer-term treatment periods. Clinically significant gains in bodyweight were seen in 15% of patients treated with paliperidone ER during the extension phase of placebocontrolled trials. Pooled analyses revealed that extrapyramidal symptoms occurred in approximately a quarter of the patients treated with higher doses of paliperidone ER (9 and 12 mg/day) in 6-week trials, and in 25% of paliperidone ER (mean dosage 10 mg/day) recipients during the 52-week extension phases.
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Although additional active comparator trials would be of interest, paliperidone ER is a useful option in the treatment and prevention of the acute symptoms of schizophrenia and may also be of use in patients with non-acute disease, including those previously unsuccessfully treated with other oral antipsychotics.
1. Introduction Schizophrenia, the most common form of psychotic disorder, causes alterations to a persons perception, thoughts, behaviour and affect, and is a significant burden for individuals, carers and healthcare systems.[1] While the aetiology of schizophrenia remains incompletely elucidated, it is widely accepted that dopamine plays a prominent role in its biochemical basis.[1] Antipsychotic drugs have long been the mainstay of treatment for schizophrenia[1] and have therapeutic effects attributable to central antagonism of dopamine D2 receptors (firstgeneration antipsychotics) or both D2 and serotonin 5-HT2A receptors (atypical antipsychotics).[2] The goals of drug therapy in the acute phase are to prevent harm, control behavioural disturbances, decrease the severity of psychosis and other symptoms (such as aggression, agitation, and negative and affective symptoms), and to bring about rapid return to the fullest possible level of functioning.[2] In the stable phase of the disease, treatment goals are to sustain symptom remission or control, maintain or improve functioning and quality of life, and to treat symptom increases or relapses.[2] Both clinical response and adverse events should be taken into account when choosing the appropriate antipsychotic agent.[1,2] Poor tolerability is one possible contributor to inadequate medication adherence, which may severely limit achievable clinical improvements, or result in relapse, in patients with schizophrenia.[3] Paliperidone (9-hydroxyrisperidone) is the major active metabolite of the well established, atypical antipsychotic, risperidone.[4] Paliperidone is available as two extended-release (ER) formulations, one an injectable suspension formulation of paliperidone palmitate (previously reviewed in CNS Drugs[5]) [Invega Sustenna; available in the US] and the other an osmotic
controlled-release oral delivery system (hereafter called paliperidone ER) [Invega] which is the focus of this review. The paliperidone ER delivery system consists of a three-layered core, comprised of two drug layers and a push layer containing osmotically active components, which is surrounded by a subcoat and a semipermeable membrane.[6] Paliperidone ER is available in the US[6] and the EU[7] for the acute and maintenance treatment of schizophrenia in adults (previously reviewed in CNS Drugs[8]). In the US, paliperidone ER is also available for the acute treatment of schizoaffective disorder, as monotherapy or as an adjunct to mood stabilizers and/or antidepressants.[6] However, this indication is outside the scope of this review, which focuses on the use of paliperidone ER in the management of schizophrenia in adults. 2. Pharmacodynamic Properties This section focuses on the pharmacodynamic properties of paliperidone ER. Studies in healthy volunteers[9] or patients with schizophrenia,[10-22] discussed here, are fully published[10-18,22] or available as abstracts[9,20] or posters[19,21] and are supplemented with data from the EU summary of product characteristics[7] and the European Medicines Agency scientific discussion[23] for paliperidone ER.
2.1 Receptor Binding and Occupancy
Paliperidone acts as an antagonist at D2 receptors (affinity constant [Ki] of 0.220.25 nmol/L) and 5-HT2A receptors (Ki of 4.6 nmol/L); it is also an antagonist at a1-adrenoceptors, and binds, with lower affinity, to a2-adrenoceptors and histamine H1 receptors.[7,23] Paliperidone has no affinity for b1- or b2-adrenoceptors, nor for cholinergic muscarinic receptors. There are no qualitative or
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quantitative differences in the pharmacological activities of the (d )- and (l )-enantiomers of paliperidone in vitro.[7,23] Positron emission tomography (PET) studies,[9,10,23] suggest that paliperidone ER dosages between 6 and 9 mg/day result in a D2 receptor occupancy of 7080% (a range which is associated with optimal efficacy[24-26]). Paliperidone ER dosages above 19.6 ng/mL were associated with >80% D2 receptor occupancy[23] and are therefore more likely to be associated with extrapyramidal adverse events.[4] In a PET study in ten patients with schizophrenia,[10] the magnitude of D2 receptor occupancy in the striatum and temporal cortex was not significantly different at steady-state paliperidone concentrations, indicating an absence of regional selectivity. The dose of paliperidone required to induce 50% D2 receptor occupancy was 2.38 mg/day in the striatum and 2.84 mg/day in the temporal cortex.[10] D2 receptor occupancies in the striatum and the temporal cortex at paliperidone ER dosages of 3, 9 and 15 mg/day are shown in figure 1.
2.2 Endocrine and Metabolic Effects
Prolactin release is inhibited by dopamine secreted into the portal hypophyseal circulation, thus, antagonism of this action of endogenous dopamine by D2 receptor antagonists
90 Mean dopamine D2 receptor occupancy 80 70 60 50 40 30 20 10 0 3 9 15 Paliperidone ER dosage (mg/day)
Fig. 1. Striatal and extrastriatal dopamine D2 receptor occupancies during paliperidone extended release (ER) treatment in patients with schizophrenia (n = 13). D2 receptor occupancy was measured by positron emission tomography after 26 weeks of treatment with paliperidone ER 3, 9 or 15 mg/day.[10]
Temporal cortex Striatum
(such as paliperidone) acts to elevate the release of prolactin.[7,23] There was a significant correlation (r = 0.52, p = 0.008) between plasma paliperidone concentration and plasma prolactin levels in blood from risperidone-treated patients (n = 25).[11] Plasma prolactin levels were not significantly correlated with plasma risperidone levels, indicating that the 9-hydroxy metabolite of risperidone (paliperidone) plays the predominant role in prolactin level elevation during risperidone treatment.[11] In a randomized, double-blind, multicentre trial in 70 patients with schizophrenia, paliperidone ER 12 mg/day (administered for 6 days) was associated with plasma prolactin level elevations similar to those with immediate release (IR) risperidone 4 mg/day (a dosage resulting in a similar exposure to the pharmacologically active fraction of risperidone).[12] The magnitude of prolactin level peak/trough variation was less with paliperidone ER than with IR risperidone. The duration of this study was too short to allow observation of any manifestations of hyperprolactinaemia.[12] Prolactin-related adverse events are discussed in section 5. According to a pooled analysis of three[13-15] 6-week trials (safety population of 1318) changes in triglyceride, total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol levels seen in paliperidone ER recipients were not clinically significant. Changes from baseline in plasma glucose levels were similar in paliperidone ER and placebo recipients.[18] A pooled analysis of the 52-week open-label extension phases of these trials supported the 6-week observations; there were no clinically relevant changes in plasma glucose, lipid or insulin levels during the extension phase.[27] The metabolic effects of paliperidone ER 69 mg/day were compared with those of olanzapine 1015 mg/day in a phase IV, 6-month, randomized, open-label trial in patients with schizophrenia (462 randomized, 459 treated).[21] The trial enrolled adults (1865 [mean 38] years) with Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV)[28] diagnoses of schizophrenia and baseline Positive and Negative
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Syndrome Scale (PANSS; consisting of 30 items each rated from 1 = no symptoms to 7 = severe symptoms) total scores of 60100. Patients who had not previously been treated with antipsychotics, who were receiving treatment with a mood stabilizer or antidepressant, who had been treated with paliperidone ER, olanzapine or clozapine within the preceding 6 months, or who had received a depot antipsychotic within the preceding 3 months were amongst those excluded. As the primary objective of the trial was to compare the metabolic effects of paliperidone ER and olanzapine, patients with a history of diabetes mellitus or abnormal fasting glucose (>126 mg/dL) or fasting triglyceride (>400 mg/dL) levels at screening were also excluded. Participants were stratified to treatment according to the metabolic effects of their prior antipsychotic medication (weight-neutral or non-weight-neutral). Between-group differences at study endpoint in the change from baseline in the triglyceride : HDL ratio (a marker of insulin resistance) [-0.08 with paliperidone ER vs +0.42 with olanzapine, p < 0.0001] and the proportion of patients with new-onset metabolic syndrome (13.2% vs 23.3%, p < 0.05) were both significant in favour of paliperidone ER. Insulin resistance (assessed using the homeostasis model assessment of insulin resistance) significantly (p = 0.003 vs baseline) worsened with olanzapine, but not with paliperidone ER.[21]
2.3 Other Effects
3. Pharmacokinetic Properties The pharmacokinetic properties of paliperidone ER, which is the focus of this section, have been reviewed previously.[8] Information has been obtained from trials in healthy volunteers[29-34] and patients with schizophrenia,[32] most of which are available as abstracts.[29-32] Additional data were obtained from the manufacturers US prescribing information[6] and the EU summary of product characteristics[7] for paliperidone ER.
3.1 General Profile
Paliperidone ER 9 mg/day improved sleep architecture and continuity in a 2-week, randomized, double-blind, placebo-controlled, multicentre trial in patients with schizophrenia and concomitant insomnia.[22] Compared with placebo at endpoint, paliperidone ER improved (p < 0.10) a number of characteristics of sleep continuity including total sleep time, sleep period time, latency to sleep onset, latency to persistent sleep, sleep efficiency index, awakenings after sleep and the time awake during time in bed, as well as the durations and percentage of time spent in stages 1 and 2 sleep, and the time spent in rapid eye movement sleep.[22] Paliperidone ER was associated with decreased slow wave sleep, although this was not statistically significant.[22]
Paliperidone ER provides stable plasma paliperidone concentrations over a 24-hour period.[33] The fluctuation index (the variation between peak and trough plasma paliperidone concentrations at steady state) for paliperidone ER is 38%, while that for IR risperidone is 125%.[7] Paliperidone ER had an absolute oral bioavailability of 28% in healthy volunteers and displayed a slow ascending concentration-time profile.[31] Pharmacokinetic data for oral paliperidone ER after single and multiple 3 mg doses, and single 6, 9 or 12 mg doses, in healthy volunteers are shown in table I. The pharmacokinetics of paliperidone ER were dose-proportional over the approved dosage range of 312 mg/day and maximum plasma concentrations were reached in approximately 24 hours.[33] After multiple-dose (3 mg once daily) administration, the peak-to-trough ratio was 1.68 and the accumulation ratio was 3.47; steady state was achieved after four doses.[33] Both the maximum plasma concentration (Cmax) and area under the plasma concentrationtime curve (AUC) values for paliperidone are increased by up to 5060% when the drug is taken with a high-fat/high-calorie meal compared with in the fasting state.[7] Nevertheless, paliperidone ER may be administered without regard to meals, but its administration should not be switched between the fed and fasting states (section 6).[7] Paliperidone had an apparent volume of distribution of 487 L.[32] Racemic paliperidone is 74% protein bound, primarily to a1-acid glycoprotein and albumin.[7]
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Table I. Pharmacokinetics of oral paliperidone extended release after single and multiple 3 mg doses, and single 6, 9 and 12 mg doses, in healthy volunteers[33] Parametera Cmax (ng/mL) tmax (h) [median] AUC24 (ng h/mL) AUClast (ng h/mL) AUC (ng h/mL) CL/F (mL/min) tb (h) a 211 272 20.9 270 28.4 Dose 3 mg SD 5.5 24.0 67.5 3 mg MD 10.7 22.0 199 368 401 292 23.4 525 567 337 22.0 720 778 313 22.1 6 mg SD 10.2 24.0 9 mg SD 14.8 24.0 12 mg SD 19.6 24.0
Mean values unless otherwise stated.
AUC24 = area under the plasma paliperidone concentration-time curve between time zero and 24 h; AUClast = area under the plasma paliperidone concentration-time curve between time zero and the last quantifiable plasma concentration measurement; AUC = area under the plasma paliperidone concentration-time curve between time zero and infinity; CL/F = apparent total oral clearance; Cmax = maximum plasma paliperidone concentration; MD = multiple dose; SD = single dose; tb = terminal elimination half-life; tmax = time to Cmax.
Paliperidone ER is only metabolized to a small extent and is primarily eliminated via renal clearance.[7] In healthy volunteers given a single oral 1 mg dose of radiolabelled paliperidone, 80% of the administered radioactivity was recovered in the urine and 11% was recovered in the faeces after 1 week.[29] Approximately 60% of the dose was excreted unchanged into the the urine.[29] Four primary metabolic pathways (each accounting for 10% of the dose) were identified as dealkylation, hydroxylation, dehydrogenation and benzisoxazole scission.[6,29] According to population pharmacokinetic analyses, paliperidone exposure and clearance (CL) do not differ between extensive or poor metabolizers of cytochrome P450 (CYP) 2D6 substrates.[7] Paliperidone had a terminal elimination halflife (tb) of approximately 23 hours in patients with normal renal function[7,33] (table I).
3.2 Special Populations
for tb were 24, 40 and 51 hours in the corresponding patient groups.[7] The apparent steady-state CL of paliperidone was 20% lower in subjects aged 65 years than in adults aged between 18 and 45 years.[7] However, age-related differences in the pharmacokinetics of paliperidone were not apparent after correction for age-related decreases in CLCR in patients with schizophrenia.[7] The pharmacokinetics of paliperidone were not affected to a clinically significant extent by mild-to-moderate hepatic impairment, race, gender or smoker status.[7]
3.3 Drug Interactions
The total CL of paliperidone is reduced in the presence of renal impairment. In patients with varying degrees of renal impairment, paliperidone CL was correlated with creatinine CL (CLCR), decreasing by 32%, 64% and 71% in subjects with mild (CLCR of 5079 mL/min [3.04.7 L/h]), moderate (3049 mL/min [1.82.9 L/h]) and severe (<30 mL/min [<1.8 L/h]) impairment.[7] Mean values
Limited data are available regarding drug interactions with paliperidone ER. However, paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9 and CYP2C19; thus, clinically important interactions between paliperidone and other drugs metabolized by CYP isoenzymes are not expected.[6,7] Interaction between paliperidone and organic transport inhibitors is not expected.[6,7] In studies in healthy male volunteers, the potent CYP2D6 inhibitor paroxetine[34] and the potent organic cation transporter trimethoprim[35] had no clinically relevant effects on the pharmacokinetics of paliperidone ER.
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The coadministration of carbamazepine 200 mg twice daily and paliperidone ER 6 mg once daily decreased the mean steady-state Cmax and AUC of paliperidone by 37%, mostly due to a 35% increase in the renal CL of paliperidone.[6,7] This was likely due to the induction of renal P-glycoprotein by carbamazepine,[7] for which in vitro studies have shown paliperidone to be a substrate.[6,7] A single 12 mg dose of paliperidone ER in subjects administered valproate semisodium (divalproex sodium) ER 1000 mg once daily resulted in 50% increases in the Cmax and AUC of paliperidone.[6] 4. Therapeutic Efficacy
4.1 Acute Schizophrenia
The efficacy of once-daily oral paliperidone ER in patients with acute schizophrenia has been investigated in six randomized, double-blind, parallel-group, multicentre trials,[13-17,36] which are the focus of this section. Five of the trials evaluated paliperidone ER for the treatment of acute schizophrenia symptoms over 6 weeks (114630 randomized patients)[13-17] [section 4.1.1], and one trial (n = 530) evaluated paliperidone ER for the prevention of acute symptom recurrence over a variable treatment duration[36] (section 4.1.2). Of the 6-week trials, one included a 24-week, open-label extension phase (modified intent-to-treat [mITT] population of 88 patients)[16] and three included 52-week, open-label extension phases[13-15] (pooled results for the latter are reported separately; n = 1077[27]). Of the six double-blind trials, all but one, which enrolled only elderly patients aged 65 (mean 70) years,[16] enrolled patients aged 18[13-15] or between 18 and 65[17,36] (mean 3642) years. Where specified, study participants met DSM-IV criteria[28] for schizophrenia,[13-17,36] diagnosed for 1 year,[13-16,36] and were experiencing a current acute schizophrenic episode as indicated by PANSS scores of 70120.[13-16,36] One trial did not specify the minimum duration of schizophrenia diagnosis and PANSS score for study entry, but required that patients had scores of 4 on at least two of the PANSS items for hosti 2010 Adis Data Information BV. All rights reserved.
lity, excitement, tension, uncooperativeness and poor impulse control, with a combined score for these items of 17.[17] Where stated, the majority of patients had paranoid schizophrenia[13,15,17,36] and were hospitalized for at least the first 10[17] or 14[13-16] days of the trial. Patients with any other DSM-IV axis I diagnosis, who posed a danger to themselves or others, who had a history of risperidone/antipsychotic treatment resistance, who had received depot antipsychotic agents within one cycle or 120 days prior to the start of the study, or who had any other concurrent clinically relevant disease were amongst those excluded. All but one study excluded participants with DSM-IV axis I diagnoses of substance abuse, although patients with psychotic symptoms explained by substance abuse were excluded from this trial.[17] Benzodiazepines for agitation, anxiety or sleep difficulties,[13-17,36] continuing stable-dose antidepressants,[13-16,36] and benzatropine or biperiden for movement disorders[13,14,16,17,36] were permitted in some trials.
4.1.1 Treatment of Acute Symptoms
All of the double-blind, 6-week, studies that evaluated paliperidone ER for the treatment of acute schizophrenia symptoms were placebocontrolled;[13-17] one also included quetiapine 600800 mg/day as the active comparator.[17] Three trials incorporated an olanzapine 10 mg/day treatment arm to confirm trial validity only and were not designed to support statistical comparisons of paliperidone ER and olanzapine.[13-15] Thus, efficacy data for olanzapine are presented in table II, but are not discussed. Efficacy data for all paliperidone ER dosages are presented in table II. However, only results pertaining to the approved paliperidone ER dosage range of 312 mg/day are discussed in the text. In three trials, patients received fixed-dose paliperidone ER 3, 9 or 15 mg,[14] 6, 9 or 12 mg,[13] or 6 or 12 mg,[15] once daily in the morning, without titration (except in one trial where those randomized to paliperidone ER 15 mg/day were given 12 mg/day for the first week[14]). In the other two trials, patients received flexible-dose paliperidone ER 9 or 12[17] or 312[16] mg/day.
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Table II. Efficacy of oral paliperidone extended release (PAL ER) in the treatment of acute symptoms of schizophrenia. Results from 6-wk randomized, double-blind, parallel-group, multicentre trials in which patients (pts) received once-daily, fixed-dose[13-15] or flexible-dose[16,17] PAL ER 315 mg/d, quetiapine (QUE) 600800 mg/d,[17] olanzapine (OLA) 10 mg/d[13-15] or placebo (PL). Trials including an OLA treatment arm did so to confirm trial validity and did not include OLA data in statistical analyses.[13-15] Results presented are in the modified intent-to-treat (mITT) pt populations (all randomized pts who received at least one dose of study medication and had at least one post-baseline efficacy assessment) Study Treatment regimen (mg/d) No. of pts (mITT) Mean PANSS total score baseline change from baseline at 6 wka -15.0*** -16.3*** -19.9*** -18.1 -2.8 -17.9*** -17.2 -23.3 -19.9 -4.1 -15.7** -17.5*** -18.4 -8.0 -31.2**(-23.4***--) -26.6 (-17.1) NR -14.6* -9.9 58 58 33 45
*** ***
% of pts with a CGI-S rating of marked or severe[13,14] or marked, severe or extremely severe[15,16] baseline 6 wk
Clinical response rate (% of pts)b
Mean change in PSP score from baseline at endpoint
Fixed-dose studies Davidson et al.[14] PAL ER 3 PAL ER 9 PAL ER 15 OLA 10 PL Kane et al.[13] PAL ER 6 PAL ER 9 PAL ER 12 OLA 10 PL Marder et al.[15] PAL ER 6 PAL ER 12 OLA 10 PL Flexible-dose studies Canuso et al.[17,37]c PAL ER 9 or 12 QUE 600 or 800 PL Tzimos et al.[16]d a b c PAL ER 312 PL 157 157 80 76 38 102.8 101.3 103.8 91.8 94.3 65* (40.1*) 60 (31.2) 50 (27.5) 4.8 4.7 123 123 113 126 120 123 122 129 128 126 111 111 105 105 91.6 93.9 92.4 93.3 93.9 94.3 93.2 94.6 93.0 94.1 92.3 94.1 94.9 93.6 53.7 52.1 56.6 NR 55.8 62.6 57.3 64.4 64.1 59.5 57.6 64.0 70.5 60.0 31.7*** 22.8*** 16.9 NR 49.2 21.3*** 23.0 16.3 23.5 50.8 26.1** 20.7*** 29.6 44.7
*** **
40** 46** 53** NR 18 56*** 51 61 52 30 50* 51* 46 34

*** ***
8.3*** 7.6*** 12.2*** NR -1.5 9.1*** 8.1*** 11.5*** 10.3 0.5 8.8** 6.6 7.6 2.9
Primary endpoint was the change in PANSS total score from baseline to wk 2[17] or 6.[13-15] Wk 2 results are shown in parentheses. Defined as a 30% decrease in PANSS total score from baseline to endpoint[13-15] or a 30% decrease in PANSS total score from baseline to endpoint plus a CGI-Improvement score of 1 or 2 (very much or much improved) [composite response rate].[17] This trial comprised an initial 2-wk monotherapy phase, after which additional psychotropic drugs could be added. Target dosages were 9 or 12 mg/d for PAL ER and 600 or 800 mg/d for QUE. Mean dosages during the monotherapy phase were 10.4 mg/d (PAL ER) and 690.9 mg/d (QUE) and across the 6-wk study duration were 9.8 mg/d (PAL ER) and 599.1 mg/d (QUE). Trial in elderly pts; median mean PAL ER dosage was 8.4 mg/d.
CGI-S = Clinical Global Impressions-Severity scale; NR = not reported; PANSS = Positive and Negative Syndrome Scale; PSP = Personal and Social Performance scale; * p < 0.05, ** p < 0.01, *** p < 0.001 vs PL; - p < 0.05, -- p < 0.001 vs QUE.
The 6-week treatment duration of one trial consisted of an initial 2-week paliperidone ER or quetiapine monotherapy phase, followed by a 4-week additive therapy phase during which patients received additional psychotropic medications to optimize treatment response (including antipsychotics,
anticonvulsants, anxiolytics, mood stabilizers, sedative/hypnotics and antidepressants, but not risperidone, additional paliperidone ER or quetiapine, or any drug known to interact with CYP3A4).[17] All patients received paliperidone ER during the open-label extension phases, administered
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as flexible doses between 3 and 12[13,15,16] or 15[14] mg/day. In four trials,[13-15,17] the primary endpoint was the change in PANSS total score from baseline to endpoint. Three trials specified the primary endpoint as being at the completion of the 6-week treatment duration; the primary comparison was that between paliperidone ER and placebo.[13-15] One trial specified the primary endpoint as being at the end of the initial monotherapy phase at 2 weeks, and the primary comparison as that between paliperidone ER and quetiapine (but also assessed efficacy at the 6-week timepoint).[17] The primary objective of the fifth study was not to assess efficacy but rather to assess the safety and tolerability of paliperidone ER.[16] Where specified, statistical analyses of the primary efficacy variable were performed in the mITT patient populations using last observation carried forward (LOCF) imputation.[13-15,17] Secondary measures of efficacy included the change from baseline to endpoint in Clinical and Global Impressions-Severity (CGI-S) scale scores (a 7-point scale from 1 = normal to 7 = extremely ill),[13-15,17] the change from baseline to endpoint in Personal and Social Performance (PSP) scores (a composite score where 110 = lack of autonomy in basic functioning and 90100 = excellent functioning, based on ratings of four domains: socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behaviours),[13-15] and rates of clinical response (defined as a 30% decrease from baseline to endpoint in PANSS total score)[13-15] or composite response (defined as a 30% decrease from baseline to endpoint in PANSS total score plus a CGI-Improvement score of 1 [much improved] or 2 [very much improved]).[17]
Compared with Placebo
Paliperidone ER was effective in the treatment of patients with an acute exacerbation of schizophrenia. Paliperidone ER 312 mg/day improved PANSS total scores from baseline by study end to a significantly greater extent than placebo in each of the 6-week trials[13-17] (primary endpoint in three trials;[13-15] table II). Decreases from baseline ranged from 14.6 to 31.2 with paliperidone ER 312 mg/day and, where reported, from 2.8 to
9.9 with placebo at the 6-week timepoint (table II). PANSS total scores had also improved to a significantly greater extent with paliperidone ER than with placebo at 2 weeks in the trial specifying the change in PANSS total score from baseline to the end of its monotherapy phase as the primary endpoint[17] (table II). Significant (p < 0.05) improvements in PANSS total scores with paliperidone ER versus placebo were evident within 415 days of the start of therapy.[13-17] All five individual PANSS factor scores were improved from baseline at 6 weeks to a significantly (p 0.05) greater extent with paliperidone ER 3 and 9 mg/day[14] and 612 mg/day[13] than with placebo in two of the fixed-dose trials; improvements at 6 weeks versus placebo were significant (p 0.05) for positive, negative and hostility/excitement factor scores with paliperidone ER 6 and 12 mg/day, and for disorganized thoughts factor scores with paliperidone ER 12 mg/day in the third.[15] In the trial that comprised a 2-week monotherapy phase followed by a 4-week additive therapy phase, all but the anxiety/ depression factor score were reduced to a significantly (p 0.05) greater extent with flexibledose paliperidone ER 9 or 12 mg/day than with placebo at both the 2- and 6-week endpoints.[17] End of treatment clinical response rates were significantly higher in paliperidone ER recipients (4061%) than in those who received placebo (1834%),[13-15] as were composite response rates in a separate trial (65% vs 50%)[17] [table II]. Paliperidone ER 312 mg/day was significantly more effective than placebo in reducing global severity of clinical impairment in three trials, based upon changes from baseline in the proportions of patients with CGI-S ratings of marked or severe illness,[13,14] or marked, severe or extremely severe illness[15] (table II). CGI-S scores were also significantly (p < 0.05) improved with paliperidone ER relative to placebo at the end of the 2-week monotherapy phase (between-group least squares mean [LSM] difference of -0.4) and at 6 weeks (-0.5) in the additive-therapy study.[17] Mean PSP scale scores at 6 weeks were improved from baseline by 6.611.5 points with fixed-dose paliperidone ER 312 mg/day; improvements were significantly greater than with
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placebo (-0.5 to 2.9) with paliperidone ER 39 mg/day,[13-15] and with paliperidone ER 12 mg/day in one study[13] but not the other[15] (table II). In three trials and across all paliperidone ER dosages between 3 and 12 mg/day,[13-15] 46.260.5% of paliperidone ER recipients and 30.337.5% of placebo recipients improved by one or more PSP scale category (which is considered a clinically relevant change in patient functioning). In the trial including a 4-week additive therapy phase as part of the 6-week total study duration, the proportions of patients receiving at least one additional psychotropic medication did not significantly differ between paliperidone ER (52.9%) and placebo (66.7%) recipients.[17] However, a significantly (p < 0.05) lower proportion of paliperidone ER recipients than placebo recipients received additional antipsychotic drugs during the additive therapy phase (42.0% vs 61.7%).[17] In the trial enrolling elderly patients only, there were no significant differences between paliperidone ER recipients and placebo recipients in terms of changes in psychotic severity or personal functioning (reflected by CGI-S and PSP scores) at 6 weeks (table II).[16] Results of this study should be interpreted with caution, given that it was not powered to evaluate efficacy. Improvements in PANSS subscale, CGI-S and PSP scores seen during the double-blind period of the trial were maintained during the 24-week long-term extension phase (no formal statistical analysis conducted).[16] Pooled data[27] from the 52-week open-label extensions of three[13-15] of the 6-week trials showed that improvements in PANSS and PSP scores seen during the double-blind phase were maintained with longer-term treatment with paliperidone ER. Furthermore, additional improvements in PANSS total scores were seen during the first 12 weeks of the open-label paliperidone ER extension phase. Mean changes in PANSS total score from the start to the end of the extension phase were -16.5 in those initially randomized to placebo, -5.3 in those who continued paliperidone ER treatment, and -4.2 in patients who had received olanzapine during the doubleblind period and then switched to paliperidone ER during the extension phase.[27] By the end of
the open-label extension phase, clinical response rates were 68%, 69% and 66%, in the corresponding treatment groups.[27] Improvements in personal and social functioning were also maintained with long-term paliperidone ER treatment. Changes in PSP scale scores from open-label extension baseline to endpoint were 10.3 in those initially randomized to placebo, 4.4 in those who continued paliperidone ER treatment and 3.6 in patients who had received olanzapine during the double-blind period; improvements of more than one category were seen in 58.7%, 47.5% and 43.7% of patients in the three respective treatment groups.[27] The proportions of patients considered markedly, severely or extremely severely ill (on the CGI-S scale) by the end of the open-label extension phase in the corresponding treatment groups were 12.6%, 16.4% and 17.4% (vs 50.0%, 57.5% and 59.9%, respectively, at baseline of the double-blind period).[27]
Compared with Quetiapine
PANSS total scores improved from baseline to a significantly greater extent with paliperidone ER 9 or 12 mg/day than with quetiapine 600 or 800 mg/day at both 2-week (primary endpoint) and 6-week timepoints[17] (table II). In terms of improvements in individual PANSS factor scores, LSM changes from baseline in the negative symptoms, positive symptoms, disorganized thoughts, and hostility/excitement factors of the PANSS after 2 weeks treatment were significantly (p 0.008) greater with paliperidone ER than with quetiapine.[17] At 6 weeks, there was a significant (p < 0.05) between-group difference (in favour of paliperidone ER) in three of five PANSS factor scores, but not for the positive symptoms or anxiety/depression scores.[17] Composite response rates at weeks 2 and 6 did not significantly differ between paliperidone ER recipients and quetiapine recipients (table II) and the proportions of patients receiving at least one additional psychotropic medication did not significantly differ between paliperidone ER recipients (52.9%) and quetiapine recipients (55.4%).[17] The change in CGI-S score significantly (p 0.05) favoured paliperidone ER versus quetiapine at both weeks 2 and 6.[17]
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4.1.2 Prevention of Acute Symptom Recurrence
The trial evaluating the efficacy of paliperidone ER in the prevention of acute symptom recurrence consisted of an 8-week, open-label run-in period (during which all patients received once-daily, flexible-dose paliperidone ER 315 mg [starting dosage of 9 mg/day] until they were deemed stable for 2 weeks) followed by a 6-week stabilization phase at the dose established during the run-in phase.[36] Patients were then randomized (in a double-blind manner) to continue paliperidone ER treatment or switch to placebo for a variable duration (until the time to first recurrence event, study withdrawal or study completion). During the double-blind phase, patients received paliperidone ER starting at the dosage maintained during the stabilization phase; the median duration of exposure in the final analysis set was 45 days for paliperidone ER and 29 days for placebo.[36] The modal paliperidone ER dosage during the run-in phase was 9 mg/day (45% of patients); 47% of patients required increases to 12 or 15 mg/day, while 8% of patients received dosages of 3 or 6 mg/day. During the stabilization phase, 33%, 26% and 30% of patients received paliperidone ER dosages of 9, 12 and 15 mg/day, respectively.[36] The primary endpoint was the time to the first recurrence event during the double-blind phase of the trial.[36] Recurrence was deemed to have occurred when: patients required psychiatric hospitalization; PANSS total scores increased (for 2 consecutive days) by 25% in patients with scores >40 at randomization or by 10 points in those who scored 40 at randomization; CGI-S scores increased (for 2 consecutive days) to 4 in patients who scored 3 at randomization or to 5 in those with CGI-S scores of 4 at randomization; prespecified individual PANSS scores increased (for 2 consecutive days) to 5 in patients with scores 3 at randomization or 6 for those with scores of 4 at randomization; or deliberate self-injurious or aggressive behaviour, suicidal or homicidal ideation, or clinically significant aggressive behaviour. Statistical analyses were performed using the mITT population and utilized LOCF imputation. A prespecified interim analysis was conducted
after 43 recurrence events had occurred. Based on the results of this interim analysis, the trial was halted prematurely and the interim analysis became the primary analysis per protocol.[36] Of the 530 patients enrolled in the run-in phase, 207 were randomized into the double-blind phase; of the 323 patients not randomized to the doubleblind phase, 91 had not completed the run-in or stabilization phases before the study was halted but were allowed to enter the open-label extension. In all, 179 patients completed the doubleblind phase of the study (of whom 75 experienced a recurrence event). For the interim analysis, the mITT population comprised 56 paliperidone ER recipients and 55 placebo recipients.[36] Paliperidone ER 315 mg/day was effective in the prevention of acute symptom recurrence.[36] At the time of the interim analysis, paliperidone ER recipients had a significantly (p = 0.005) longer time to recurrence than did placebo recipients (thus, the study was halted). Recurrence events occurred in 14 of 56 (25%) paliperidone ER recipients and 29 of 55 (53%) placebo recipients, most frequently increases in CGI-S and PANSS total scores. The timepoints at which recurrence occurred in 25% of patients were 83 days with paliperidone ER and 23 days with placebo.[36] According to final analysis results, recurrence events occurred in 23 of 104 (22%) paliperidone ER recipients and 52 of 101 (52%) placebo recipients. The time to symptom recurrence was also significantly (p < 0.001) longer with paliperidone ER than with placebo in the final analysis. Symptom severity improvements (measured by changes from baseline in mean PANSS total score) achieved with paliperidone ER during the open-label phase of the study were maintained in those patients who continued paliperidone ER treatment, but symptom severity significantly (p < 0.001) worsened in those randomized to receive placebo during the double-blind phase.[36] Other secondary efficacy assessments indicated significantly less deterioration of other measures of symptom severity and patient functioning with paliperidone ER treatment than with placebo.[36] At the end of the double-blind treatment period, changes from baseline in key secondary efficacy measures significantly (p 0.003) differed between
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paliperidone ER recipients and placebo recipients (final analysis data set: median CGI-S scores 0 vs 1.0, and mean PSP scale scores -3.0 vs -8.0).[36]
4.2 Non-Acute Schizophrenia
4.2.2 In Patients Previously Unsuccessfully Treated with an Oral Antipsychotic
The efficacy of once-daily oral paliperidone ER in patients with non-acute schizophrenia has been investigated in two open-label, multicentre trials, results of which are available as posters.[21,38-40]
4.2.1 Compared with Olanzapine
Significant improvements in psychotic symptoms were seen at endpoint in a phase IV, 6-month, randomized, open-label, parallel-group, multicentre trial in patients with non-acute schizophrenia (baseline PANSS scores between 60 and 100) who received paliperidone ER 69 mg/day (n = 239) or olanzapine 1015 mg/day (n = 220)[21,38] [see section 2.2 for further trial details]. Approximately 70% of paliperidone ER recipients and 81% of olanzapine recipients completed 6 months of study treatment.[21] Changes from baseline to endpoint in PANSS total and PANSS subscale (positive, negative and general psychopathology) scores did not significantly differ between paliperidone ER and olanzapine, but were significant versus baseline in each treatment group.[21] PANSS total scores decreased from 79.2 at baseline to 65.7 at endpoint in paliperidone ER recipients and from 81.4 to 64.8 in olanzapine recipients (both p < 0.0001).[38] The noninferiority of paliperidone ER versus olanzapine was confirmed as the between-treatment difference (3.1) was lower than the prespecified minimum clinically relevant difference (6.0; p < 0.0242).[21] Decreases from baseline to endpoint in all five Marder factor scores were also significant (p < 0.0001) for both paliperidone ER and olanzapine, but did not significantly differ between treatments.[21] The proportion of patients meeting CGI-S criteria for being not at all ill or mildly ill increased from 17.0% at baseline to 51.1% at endpoint in paliperidone ER recipients, and from 11.3% at baseline to 56.8% at endpoint in olanzapine recipients (p-values not reported).[21]
The efficacy of paliperidone ER in the treatment of adults with non-acute schizophrenia previously unsuccessfully treated with an oral antipsychotic has been evaluated in a phase IIIb, noncomparative, multicentre, 6-month trial.[39,40] Enrollees (n = 1812) were aged 18 (mean 40.1) years, had DSM-IV diagnoses of schizophrenia (mean duration 10.1 years), and were either inpatients or outpatients. Participants were required to have non-acute schizophrenia, having been previously treated with an oral antipsychotic drug, at an adequate dosage and for an adequate treatment period (based on investigator judgement), with a change in CGI-S score of 1 during the preceding 4 weeks. Those treated with clozapine or a long-acting injectable antipsychotic drug in the 3 months prior to study enrolment, who had significant other medical illness, tardive dyskinesia or neuroleptic malignant syndrome, or who had a high risk for self harm or adverse events were amongst those excluded.[39] Patients received flexible-dose paliperidone ER 3, 6, 9 or 12 mg once daily for a period of 6 months, having been transitioned to the effective dose, without titration, based on clinical response and tolerability.[39] The primary efficacy outcome was based upon the primary reason for switching antipsychotic (either lack of efficacy [56.6% of patients], lack of tolerability [27.0%], lack of compliance [9.1%] or other reason [7.3%]), and was specified as a 20% improvement from baseline in PANSS total score for those switching primarily due to a lack of efficacy, and the change from baseline in PANSS total score for those switching for other reasons, at week 26. Additional efficacy measures included the changes from baseline in PANSS total, subscale and Marder factor scores, CGI-S score and PSP scale score at week 26 or endpoint.[39] The initial mean paliperidone ER dosage was 5.3 mg/day, the mean modal dose was 7.1 mg/day and the mean duration of treatment exposure was 149.6 days.[39] A total of 1281 (70.7%) patients completed 6 months of paliperidone ER treatment; the most frequent reasons for treatment
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discontinuation were withdrawal of consent (8.8% of patients), adverse events (5.0%), lack of efficacy (5.0%) and adverse events plus lack of efficacy (4.0%).[40] At the 26-week timepoint, 71.7% of patients who had switched from their previous antipsychotics because of a lack of efficacy had a 20% improvement from baseline in total PANSS scores, as did 61.3% of patients at endpoint.[39] Amongst those who switched antipsychotics because of reasons other than lack of efficacy, the decreases in PANSS total scores from baseline at endpoint were significant regardless of reason for switching antipsychotic: -8.4 in those switched because of lack of tolerability, -18.4 in those switched due to lack of compliance and -9.5 in those switched for other reasons (all p < 0.0001).[39] Across all patients (n = 1756), the mean PANSS total score was significantly decreased (from 79.4 at baseline to 66.1 at endpoint) with paliperidone ER treatment, as were PANSS subscale (positive, negative and general psychopathology) scores and all five Marder factor scores (all p < 0.0001).[39] The proportion of patients with CGI-S scores of mildly ill or less increased from 27% at baseline to 52% at endpoint, and those with PSP-defined mild functional impairment increased from 16% at baseline to 35% at endpoint.[39] In terms of the two PSP domains mostly driving functional impairment, the proportion of patients with marked to very severe impairments in socially useful activities decreased from 47% at baseline to 31% at endpoint and the proportion of patients with marked to very severe impairments in personal and social relationships decreased from 36% to 23% (p-values not reported).[40] According to a prespecified subgroup analysis of patients transitioned from risperidone to flexible-dose paliperidone ER (n = 694), 62% of patients switched because of lack of efficacy showed improvements from baseline in PANSS total scores of 20% at endpoint, and PANSS total scores were also significantly improved (p < 0.0001 vs baseline) in patients switched for reasons other than a lack of efficacy.[41]
5. Tolerability Data pertaining to the tolerability of paliperidone ER in patients with schizophrenia have been obtained from the well designed trials discussed in section 4,[13-17,36] as well as pooled analyses of 6-week[18] and longer-term[27] data from the three fixed-dose, placebo-controlled trials[13-15] that evaluated paliperidone ER 315 mg/day for the treatment of the acute symptoms of schizophrenia (6-week results shown in figure 2).
5.1 General Tolerability Profile
Paliperidone ER was generally well tolerated in 6-week trials and during longer-term treatment (for up to 52 weeks) in adults with schizophrenia.[13-17,36] Seventy-two percent of paliperidone ER recipients and 66% of placebo recipients reported treatment-emergent adverse events over the initial 6-week treatment period in the three[13-15] pivotal trials for which pooled tolerability analyses are available.[18] Rates of serious adverse events (56%) and discontinuation due to adverse events (27%) in paliperidone ER recipients were similar to those seen in placebo recipients (6% and 5%). The most common serious adverse events in recipients of paliperidone ER were psychotic disorder and schizophrenia; there were no deaths or reports of neuroleptic malignant syndrome in any of the three trials.[18] Excluding extrapyramidal symptoms (EPS), treatmentemergent adverse events most commonly reported (in 5% of all paliperidone ER recipients) were headache, insomnia, anxiety, tachycardia, sinus tachycardia, agitation, dizziness and somnolence[18] (figure 2a). There were no differences between paliperidone ER and placebo in terms of treatment-emergent adverse events suggestive of pro-arrhythmic potential[18] (the cardiac effects of paliperidone ER are discussed in section 5.4). In the 6-week trial enrolling only elderly patients,[16] nearly half of whom had a history of cardiovascular disease, rates of treatmentemergent adverse events (67%) and discontinuation due to adverse events (7%) in paliperidone ER recipients were similar to those seen in placebo
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a 16 14 12 10 8 6 4 2 Percentage of pts 0 Headache Insomnia Anxiety Sinus tachycardia
PAL 3 (n = 127) PAL 6 (n = 235) PAL 9 (n = 246) PAL 12 (n = 242) OLA (n = 364) PL (n = 355)
Agitation
Dizziness
Somnolence Tachycardia
b 16 14 12 10 8 6 4 2 0 Extrapyramidal disorder Akathisia Tremor Hypertonia Dystonia
Fig. 2. Adverse events profile of oral paliperidone extended release (PAL ER). Pooled tolerability data[18] from three 6-week, randomized, double-blind, placebo (PL)-controlled, multicentre trials[13-15] evaluating fixed-dose PAL ER 3, 6, 9, 12 or 15 mg/day for the treatment of acute symptoms in patients (pts) with schizophrenia. The three trials[13-15] incorporated an olanzapine 10 mg/day (OLA) treatment arm to confirm trial validity only, thus, data for olanzapine are presented in figure 2, but are not discussed. Shown are (a) treatment-emergent adverse events (excluding extrapyramidal symptoms [EPS]) occurring in 5% of all PAL ER recipients (shown as % of pts) and (b) treatment-emergent EPS occurring in 1% of pts in all treatment groups (shown as % of pts). Dystonia includes dystonia, muscle spasms, oculogyration and trismus. Results for the non-approved PAL ER 15 mg/day dosage are not shown.
recipients (71% and 8%). Three percent of paliperidone ER recipients and 8% of placebo recipients experienced serious adverse events. Tolerability results during the open-label extension phase of the trial were consistent with those of the double-blind phase. The incidence of somnolence and increased pulse rates (but not other safety measures) appeared to increase with age. Treatment-emergent tachycardia or sinus tachycardia occurred in 16% of paliperidone ER recipients (but no placebo recipients) during the double-blind phase of the study. Consistent
changes in other cardiovascular measures were also seen with paliperidone ER versus placebo, such as a higher incidence of heart rate 100 beats per minute (25% vs 5%) and a higher incidence of abnormal increases in standing (12% vs 5%) and supine (7% vs 0%) pulse rates; increases in pulse rates were more pronounced in patients within the 7075 years age group than in those within the 6469 years age group.[16] In the trial comparing the short-term safety of paliperidone ER and quetiapine, tremor, somnolence, insomnia and headache were the most
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common adverse events occurring during the 2-week monotherapy phase and tremor, somnolence, sedation, insomnia, hypertonia, dizziness and headache were the most common events over the full 6-week study period.[17] Over the 6 weeks, serious adverse events occurred in 13 of 158 (8.2%) paliperidone ER recipients, 7 of 159 (4.4%) quetiapine recipients and 2 of 80 (2.5%) patients who received placebo.[17] According to a pooled analysis of the longerterm tolerability results of the three similarly designed trials, paliperidone ER was generally well tolerated over the 52-week treatment duration and there were no unexpected findings.[27] The most common treatment-emergent adverse events (occurring with an incidence of 10%) were insomnia (14% of paliperidone ER recipients), headache (12%) and akathisia (11%). Seventysix percent of patients experienced treatmentemergent adverse events during the open-label extension phases, 16% experienced 1 serious adverse event, 7% experienced an adverse event leading to study withdrawal and two patients committed suicide. Serious adverse events reported in 1% of patients include psychotic disorder (5%), schizophrenia (5%), and agitation, aggression, depression, suicidal ideation and suicide attempt (1% each).[27]
5.2 Extrapyramidal Symptoms
EPS-related adverse events occurred in 16 of 127 (13%), 24 of 235 (10%), 62 of 246 (25%) and 63 of 242 (26%) paliperidone ER 3, 6, 9 and 12 mg recipients and 39 of 355 (11%) placebo recipients during three 6-week trials.[18] The most common events were extrapyramidal disorder, akathisia, tremor, hypertonia and dystonia (figure 2b). There were no clinically relevant differences between paliperidone ER and placebo with respect to median changes from baseline at 6 weeks in Barnes Akathisia Rating Scale (BARS) scores (for akathisia), Abnormal Involuntary Movement Scale (AIMS) scores (for tardive dyskinesia), or Simpson-Angus Rating Scale (SAS) scores (for parkinsonism).[18] SAS global scores did not change in the majority of patients across trials. However, of the patients with SAS global
score increases, a numerically higher proportion had received paliperidone ER at dosages exceeding 6 mg/day. Also, a numerically higher proportion of patients treated with paliperidone ER >6 mg/day reported EPS-related adverse events.[18] Tardive dyskinesia was reported in one patient after 4 days treatment with paliperidone ER 9 mg/day, although a causal relationship could not be established.[18] The incidence of EPS-related events with paliperidone ER was low in elderly patients treated for an initial 6-week period and remained low throughout the 24-week extension phase of the trial.[16] EPS reported by paliperidone ER and placebo recipients during the double-blind phase were hypertonia (2 vs 0 patients), tremor (2 vs 0), akathisia (2 vs 1) and extrapyramidal disorder (4 vs 4); during the extension phase, hypertonia, tremor, akathisia and extrapyramidal disorder occurred in 1, 2, 1 and 5 patients, respectively. Median scores on movement disorder scales did not change from baseline to endpoint of either study phase.[16] In the active comparator trial, EPS ratings according to the SAS were significantly (p < 0.001) higher in paliperidone ER recipients than in quetiapine recipients at the end of the 2-week monotherapy phase, but neither significantly differed from placebo in this regard, nor were between-group differences in BARS or AIMS scores seen at this timepoint.[17] At the 6-week endpoint, no significant between-group differences were observed for any of these three rating scale scores.[17] Over the 52-week, open-label extension phases of three trials for which pooled tolerability results are available, EPS-related adverse events were reported by 25% of paliperidone ER recipients (mean modal dosage 10 mg/day), but median maximum movement disorder ratings showed no change in severity.[27]
5.3 Endocrine and Metabolic Effects
Paliperidone ER elevated mean plasma prolactin levels to above the normal range in 6-week trials (see section 4); in general, plasma prolactin levels were elevated to a greater extent in female
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patients than in males, remained elevated throughout treatment, and increased with increasing paliperidone ER dosage.[13-17] Among patients receiving paliperidone 315 mg/day in three of the 6-week trials,[13-15] plasma prolactin levels were increased by a median 81 ng/mL in women and 24 ng/mL in men.[18] Median increases in plasma prolactin levels peaked on day 15 and subsequently decreased slightly, although plasma prolactin levels remained above the upper limit of normal (normal range 1.424.2 ng/mL in women and 1.618.8 ng/mL in men).[18] Moreover, mean plasma prolactin levels remained outside the normal range in patients receiving paliperidone ER in the longer term, according to the results of the pooled analysis of the 52-week extension phases.[27] Across the same three 6-week trials,[13-15] potential prolactin-related adverse events were reported in 12% of paliperidone ER or placebo recipients, and included impotence or other sexual dysfunction, gynaecomastia, galactorrhoea, amenorrhoea or menstrual irregularity (none resulted in treatment discontinuation).[18] During the 52-week extension phases, 1% of patients reported potential prolactin-related adverse events (this excluded reports of amenorrhoea [4% of females in each treatment group], irregular menstruation [5% of females in the group originally randomized to receive placebo during the doubleblind phase] and erectile dysfunction [3% of males in the group originally randomized to receive olanzapine]).[27] There were no prolactinrelated adverse events in the 6-week trial in elderly patients.[16] One percent of paliperidone ER recipients and 1% of placebo recipients in the three 6-week, fixeddose, placebo-controlled trials[13-15] reported potentially glucose-related adverse events (most commonly increased blood glucose levels), two of which (in paliperidone ER recipients) were considered serious.[18] There were no glucose-related adverse events, nor any noteworthy changes in mean bodyweight in the 6-week trial in elderly patients.[16] Longer-term data[27] from the 52-week extension phases of three trials[13-15] supported the 6-week findings, with 1% of patients across treatment groups reporting potentially glucose-related
adverse events (increased blood glucose, diabetes, glucosuria and hyperglycaemia). In the three 6-week, fixed-dose, placebocontrolled trials,[13-15] mean bodyweight changes over the 6-week treatment period were <2 kg across all paliperidone ER treatment groups and appeared to be dose-related: +0.6, +0.6, +1.0, +1.1 and +1.9 with paliperidone ER 3, 6, 9, 12 and 15 mg/day, respectively (vs -0.4 kg with placebo and +2.0 kg with olanzapine; statistical analyses not reported).[18] Increases in bodyweight were significantly (p 0.028) higher in quetiapine recipients than in either paliperidone ER or placebo recipients in the active comparator trial; at the 2-week monotherapy phase endpoint, LSM changes in bodyweight were 0.4, 0.8 and 0.2 kg in paliperidone ER, quetiapine and placebo recipients, respectively. Corresponding values at the 6-week endpoint were 0.4, 1.1 and 0.3 kg.[17] During the 52-week extension phases of three trials,[13-15] the mean increase in bodyweight (across all treatment groups; mean modal paliperidone ER dosage of 10 mg/day) from the baseline of the open-label extension phase to endpoint was 1.1 kg and 15% of patients had weight increases of 7%.[27] Mean bodyweight increased to a significantly (p < 0.0001) greater extent in olanzapine recipients (from 77.9 to 81.7 kg at endpoint) than in paliperidone ER recipients (from 75.8 to 76.9 kg) in the phase IV, 6-month, randomized, openlabel, parallel-group, multicentre trial in patients with non-acute schizophrenia (both p < 0.0001 vs baseline).[21]
5.4 Cardiac Effects
The pooled analysis of the three 6-week trials[13-15] revealed that none of the paliperidone ER recipients had a linear-derived (LD) corrected QT (QTc) interval (QTcLD) of 480 msec during the double-blind treatment period.[18] During 52-week, open-label extension phases of the same three 6-week trials (safety population of 1083 patients), 11 (1%) patients had a maximum post-baseline QTcLD 450 and <480 msec and one patient had a maximum post-baseline QTcLD 480 msec.[27]
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A post-baseline QTc interval prolongation of 500 msec occurred in 2 of 76 paliperidone ER recipients during the 6-week, double-blind period of a trial enrolling elderly patients with schizophrenia (both withdrawn from the study) and a further patient experienced QTc prolongation during the 24-week, open-label extension phase of the study.[16] All three patients had a cardiovascular history that included QTc prolongation.[16] No prolongations of QTcLD or the Fridericacorrected QT interval were seen in paliperidone ER or quetiapine recipients during a 6-week treatment period in one flexible-dose, comparative study.[17] 6. Dosage and Administration Paliperidone ER is available in the US[6] and the EU[7] for the acute and maintenance treatment of schizophrenia in adults. The recommended starting dosage of paliperidone ER is 6 mg, given once daily in the morning and without regard to meals[6,7] (although it is recommended that alternation between administration in the fed and fasting states be avoided).[7] Initial dosage titration is not necessary. However some patients may benefit from a lower (3 mg/day) dosage, or require a higher dosage (up to a maximum of 12 mg/day); where required, dosage adjustments in 3 mg/day increments at intervals of >5 days are recommended.[6,7] Paliperidone ER dosage adjustment is not required for patients with mild-to-moderate (ChildPugh class A and B) hepatic impairment. There have been no studies of paliperidone ER in patients with severe (Child-Pugh class C) hepatic impairment.[6,7] A lower initial dosage of paliperidone ER (3 mg once daily) is recommended in patients with mild renal impairment (CLCR 50 to <80 mL/min [3.0 to <4.8 L/h]), increasing to a maximum of 6 mg once daily based on clinical response and tolerability.[6,7] A starting dosage of 1.5 mg once daily (increasing to a maximum of 3 mg once daily after clinical assessment) is recommended for patients with moderate to severe renal impairment (CLCR 10 to <50 mL/min [0.6 to <3.0 L/h]).[6,7] Paliperidone ER is not recommen 2010 Adis Data Information BV. All rights reserved.
ded for use in patients with CLCR <10 mL/min [0.6 L/h]).[6,7] No specific dosage adjustments are recommended based on gender, race or age,[7] although dose individualization may be required in the elderly based on renal function.[6,7] US product labelling for paliperidone ER contains a boxed warning regarding the increased risk of death with the use of antipsychotic drugs in elderly patients with dementia-related psychosis.[6] As such, paliperidone ER is not approved in the US for use in this patient group.[6] EU recommendations advise caution with the use of paliperidone ER in elderly patients with dementia and risk factors for stroke.[7] Local prescribing information for paliperidone ER should be consulted for details of contraindications, warnings and precautions, other indications, and use in special patient populations. 7. Place of Paliperidone Extended Release in the Management of Schizophrenia Antipsychotic drugs are the mainstay of schizophrenia treatment.[1,2] However, the overall effectiveness of antipsychotic drug treatment in patients with schizophrenia is not optimal; some patients do not respond to the available treatments, and others continue to have residual symptoms even with adequate treatment.[42] Furthermore, while a high proportion of patients with schizophrenia do respond to initial antipsychotic therapy, about 80% relapse within 5 years, which is partially explained by treatment discontinuation[1] often due to tolerability issues, complicated regimens or cognitive impairment typically associated with the disease.[3] For these reasons, novel agents are required to strengthen the pharmacological armamentarium available for the treatment of schizophrenia. In particular, agents with potential benefits in terms of improved tolerability or patient convenience, that may improve treatment adherence in a notoriously non-adherent patient population,[3] are required. Both clinical response and adverse events should be taken into account when choosing the appropriate antipsychotic agent.[1,2] Treatment guidelines generally do not recommend any one
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antipsychotic over another; rather, they recommend that the initial choice of drug be largely based upon the relative potential of an individual agent to cause EPS and other adverse events.[1,2] An antipsychotic drug may be more effective or better tolerated in one individual than another, so treatment should be individualized for the patient. The goals of schizophrenia treatment are rapid symptom elimination, relapse prevention and reduction of illness severity, as well as improving social functioning and relationships.[23] While the typical antipsychotic drugs are firmly established as being effective, they are generally associated with a high incidence and wide range of adverse events, including lethargy, sedation, weight gain and sexual dysfunction.[1] EPS (namely parkinsonism, akathisia and dystonia) are common and can be disabling and disturbing. Tardive dyskinesia is a serious adverse event which develops in around 20% of people treated with typical antipsychotic drugs. Consequently, considerable effort has been directed at the development of pharmacological treatments for schizophrenia that are more effective and associated with fewer or less disabling adverse events.[1] The atypical antipsychotics were introduced with the promise of improved efficacy and tolerability[43] and can be divided into three groups based upon their receptor affinity profiles: selective D2/D3 receptor antagonists (amisulpride); dopamine and 5-HT2A receptor antagonists (such as paliperidone, risperidone, iloperidone and ziprasidone); and those with affinities for a broad range of central receptors (such as clozapine, olanzapine, quetiapine and zotepine).[44] In general, the atypical antipsychotics are distinguished as having a lower liability for EPS[43] and tardive dyskinesia[45] than their typical counterparts.[1] Their lower relative propensity for EPS is thought to be due, in part, to their high binding affinity at 5-HT2A receptors, although it is also postulated that fast dissociation from the D2 receptor may better explain the difference in adverse event profile between typical and atypical antipsychotics.[44,46] Despite having a generally lower liability for EPS as a group, atypical antipsychotic drugs differ in their individual propensities for EPS.[1] Furthermore, other toler 2010 Adis Data Information BV. All rights reserved.
ability issues persist with atypical antipsychotics; some cause weight gain and alterations in glucose and lipid metabolism, which may increase the risks of type 2 diabetes and cardiovascular disease,[47] and some cause increased plasma prolactin levels which can lead to menstrual abnormalities, galactorrhoea and sexual dysfunction, as well as reduced bone mineral density in the longer-term.[1] While acknowledging limitations of the data available to examine relationships between atypical antipsychotics and obesity or diabetes, there is a consensus that risks are greatest with clozapine and olanzapine, intermediate for risperidone and quetiapine and least with aripiprazole and ziprasidone.[48] Risperidone has shown a higher propensity for increased plasma prolactin levels and related adverse events in patients with schizophrenia than olanzapine, quetiapine and ziprasidone.[43] Paliperidone ER, the major metabolite of the firmly-established atypical antipsychotic risperidone, is available in the US[6] and the EU[7] for the acute and maintenance treatment of schizophrenia in adults. The ER formulation allows once-daily administration with only small 24-hour peak-to-trough plasma paliperidone concentration fluctuations. Although it remains a theoretical construct, unstable D2 receptor occupancy by an antipsychotic drug may be associated with adverse events and an inconsistent therapeutic effect.[49] Studies in rats using models for antipsychotic efficacy (D-amfetamine-induced hyperlocomotion) and EPS liability (latency on-bar) suggested that more stable antipsychotic efficacy with reduced motor impairment may be achieved with continuous paliperidone than with repeated risperidone administration.[4] It has been proposed that striatal D2 receptor occupancy must exceed 6065% before therapeutic effects of an antipsychotic agent are seen in patients with schizophrenia.[4,25] However, the risk of EPS is increased at high levels of D2 receptor occupancy (i.e. over 8085%).[4] For paliperidone, D2 receptor occupancy of 7080% is achieved at paliperidone ER dosages between 6 and 9 mg/day[10] (section 2.1). The predictable pharmacokinetic
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profile and minimal peak-to-trough plasma concentration variability seen with paliperidone ER may represent an advantage in the treatment of schizophrenia in which continuous drug coverage appears important.[33] However, this remains to be established. Paliperidone ER demonstrated efficacy in the short-term treatment of adults with an acute exacerbation of schizophrenia, according to data from the five randomized, double-blind, multicentre, phase III trials discussed in section 4.1.1. In these well designed clinical trials, paliperidone ER 312 mg/day was associated with significantly greater improvements from baseline in PANSS total scores than placebo and was also associated with higher clinical response rates (table II). The significant improvements in PANSS total scores were seen as early as after 4 days of paliperidone ER treatment in three double-blind trials.[13-15] The drug generally showed efficacy in the treatment of both the positive and negative symptoms of schizophrenia (evidenced by significant improvements in individual PANSS factor scores for negative symptoms, positive symptoms, disorganized thoughts, depression/anxiety and hostility/excitement) and produced clinically relevant improvement in patient functioning (based on significant changes in mean PSP scores from baseline to the 6-week endpoint) [section 4.1.1]. Results from a separate mediation analysis showed that the significant effects of paliperidone ER on social functioning were independent of its effects on symptom improvement.[50] Longerterm (52 weeks) data from open-label extension phases of three pivotal trials have found the improvements in symptoms and functioning with initial treatment to be maintained with paliperidone ER[27] (section 4.1.1). When compared with quetiapine,[17] paliperidone ER was associated with significantly greater improvements from baseline in PANSS total scores, as well as in four of five individual PANSS factor scores at 2 weeks and three of five Marder factor scores at 6 weeks, but did not significantly differ in terms of clinical response rates (table II). Three double-blind trials that included an olanzapine treatment arm[13-15] did so to confirm trial validity only and used a 10 mg/day
dosage of olanzapine that may been too low to provide a clinically clear comparison. Additional active comparator trials are required in order to accurately place paliperidone ER in relation to other currently available antipsychotics for the management of acute schizophrenia. In particular, no well designed trials have directly compared paliperidone ER with risperidone; such trials would be of interest. Furthermore, data reflecting the use of paliperidone ER in the real world setting would be of value. Preliminary data are available (as a poster[51]) from a phase IV, noncomparative study enrolling 294 patients with acute schizophrenia treated for 6 weeks with flexible dose paliperidone ER 312 mg/day. At endpoint, 66.3% of patients met criteria for treatment response (defined as a 30% decrease in PANSS total scores from baseline; primary endpoint), and 34.7% of patients demonstrated improvements in PANSS total scores from baseline of 50%. The mean PANSS total score decreased by 27.5 at endpoint, with significant improvements (p < 0.0001 vs baseline) observed at the first post-treatment assessment on day 2.[51] There are no consistent, reliable predictors of prognosis or drug response in patients with schizophrenia. Therefore, it is generally recommended that pharmacological relapse prevention is considered for the majority of patients.[1] Relapse results in hospitalization and increased costs, plus a reduced quality of life for the patient.[36] Worse prognoses and progressively declining outcomes are linked with successive relapses.[36] In the only trial to evaluate paliperidone ER for the prevention of acute symptom recurrence,[36] paliperidone ER recipients had a significantly longer time to recurrence than did placebo recipients, as well as significantly less deterioration of symptom severity (section 4.1.2). However, limitations of this study included the large number of patient dropouts (52%) and the fact that a large majority of patients required a 9 mg/day dosage of paliperidone ER to control their symptoms.[52] A conservative summation could be that patients successfully treated with paliperidone ER may be more likely to experience symptom recurrence when paliperidone treatment is discontinued in comparison to continued treatment.[52] Further
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studies would be of interest, including those incorporating an active comparator. Individuals with non-acute schizophrenia are also an important population for treatment. In the 6-month, open-label trial that compared paliperidone ER 69 mg/day with olanzapine 1015 mg/day, PANSS total scores, PANSS subscale (positive, negative and general psychopathology) scores and all five Marder factor scores did not significantly differ between treatments but were significantly reduced from baseline at endpoint in both treatment groups.[21,38] In one 6-month, open-label trial in adults with non-acute schizophrenia who were switched from previously unsuccessful oral antipsychotic treatment, PANSS total scores, PANSS subscale scores and all five Marder factor scores were significantly decreased from baseline at week 26 or endpoint, and improvements in personal and social functioning were also evident[39,40] (section 4.2). Paliperidone ER was generally well tolerated in patients with schizophrenia in short- and longer-term trials (section 5), and no unexpected tolerability findings arose with longer-term treatment according to pooled results of openlabel extension periods of three trials.[27] Paliperidone ER had an adverse event profile similar to that previously reported with risperidone,[53] although prospective head-to-head trials are needed. Paliperidone ER appears to have little pro-arrhythmic potential (section 5.4) and has little effect on plasma glucose, lipid or insulin levels, but increases plasma prolactin levels over both short- and longer-term treatment periods (section 2.2). Although the prolactin-elevating effects of paliperidone ER were notable, potential prolactin-related adverse events were reported in only 12% of paliperidone ER or placebo recipients in three 6-week trials.[13-15] Clinically significant gains in bodyweight were seen in 15% of patients treated with paliperidone ER during open-label extension phases (of up to 52 weeks, mean modal dosage of 10 mg/day) of three placebo-controlled trials.[27] Pooled analyses revealed that dose-related EPS occurred in 1026% of patients receiving paliperidone ER 312 mg/day in 6-week trials,[18] and in 25% of
paliperidone ER recipients during the 52-week extension phases.[27] With regards to specific patient populations, further trials would be of interest in both elderly and adolescent patients with schizophrenia. The elderly represent a challenging population to treat as they generally experience more severe movement disorder symptoms and higher tardive dyskinesia rates.[16] Paliperidone ER was effective and generally well tolerated in one 6-week trial enrolling patients aged 6481 years (section 4.1.1). The incidence of somnolence and increased pulse rates (but not other safety measures) appeared to increase with age in this study.[16] Longer-term data in elderly patients would be of interest. As schizophrenia can begin in childhood or adolescence, specific data relating to the use of paliperidone ER in patients younger than 18 years would also be of interest. Results from a recently completed double-blind trial in adolescent patients with schizophrenia are awaited.[54] Paliperidone ER may be an appropriate choice for patients with hepatic dysfunction, as impaired liver function does not impact upon its metabolism[49] (section 3). The negligible hepatic metabolism of paliperidone ER reduces drug interaction risk, which is a practical concern in patients with schizophrenia who often require multiple treatments for co-morbidities;[36] this represents an advantage over risperidone, which does undergo hepatic metabolism and has more potential for drug interactions.[52] However, the fact that a large proportion of a paliperidone dose is excreted unchanged via the kidneys has implications for those who are renally impaired.[49] Three cost-effectiveness analyses have shown paliperidone ER to be associated with better outcomes and lower costs than alternative antipsychotics in patients with schizophrenia in Greece,[55] the US[56] and Italy.[57] However, an important limitation of these analyses is that the pharmacoeconomic models were not based on the results of head-to-head trials. This makes it difficult to draw accurate conclusions regarding the cost effectiveness of paliperidone ER relative to other antipsychotics, including risperidone. More robust pharmacoeconomic analyses
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(i.e. analyses utilizing results of head-to-head trials) would be of interest. In recent National Institute for Health and Clinical Excellence (NICE) guidelines,[1] zotepine dominated all other treatments in a deterministic analysis (time horizons of 10 years and over a lifetime), with olanzapine and paliperidone ER the second and third most cost-effective options of the other six evaluated antipsychotics available for the prevention of schizophrenia relapse in the UK. However, the results of probabilistic analysis indicated that no one antipsychotic could be considered clearly more cost effective when compared with other assessed treatment options. In most cases, results relied upon for analyses were characterized by a high level of uncertainty and variable consistency, and did not include the complete range of drugs available in the UK for the management of schizophrenia.[1] In conclusion, paliperidone ER is an atypical antipsychotic that is administered once daily without the need for initial dosage titration and that undergoes minimal hepatic metabolism. The latter feature may be beneficial in patients with clinically relevant hepatic dysfunction. It has demonstrated efficacy in the reduction of acute schizophrenia symptoms in 6-week, placebocontrolled, double-blind trials and its efficacy was maintained in the longer term according to extension studies of up to 52 weeks in duration. Paliperidone ER also reduced acute schizophrenia symptoms to a similar extent to olanzapine in an open-label trial, to a significantly greater extent than quetiapine in a placebo-controlled, doubleblind trial, and was effective for the prevention of acute symptom recurrence in a third. The drug is generally well tolerated with a predictable adverse event profile. Additional active comparator trials examining efficacy, tolerability and cost effectiveness are needed in order to position paliperidone ER in relation to other currently available antipsychotics and, in particular, risperidone. Nonetheless, paliperidone ER is a useful option in the treatment and prevention of the acute symptoms of schizophrenia and may also be of use in patients with non-acute disease, including those previously unsuccessfully treated with other oral antipsychotics.
Disclosure
The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was also offered an opportunity to comment on this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.
References
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25. Kapur S, Zipursky R, Jones C, et al. Relationship between dopamine D2 occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 2000; 157 (4): 514-20 26. Kapur S, Zipursky RB, Remington G. Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy or clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 1999 Feb; 156 (2): 286-93 27. Emsley R, Berwaerts J, Eerdekens M, et al. Efficacy and safety of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 52-week open-label studies. Int Clin Psychopharmacol 2008 Nov; 23 (6): 343-56 28. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994 29. Vermeir M, Boom S, Naessens I, et al. Absorption, metabolism and excretion of a single oral dose of (14)C-paliperidone 1 mg in healthy subjects [abstract no. P.8.097]. Eur Neuropsychopharmacol 2005 Oct; 15 Suppl. 3: 648-649. Plus poster presented at the 18th European College of Neuropsychopharmacology Congress; 2005 Oct 22-26; Amsterdam 30. Cleton A, Rossenu S, Vermeulen A, et al. A pharmacokinetic model to document the interconversion between paliperidones enantiomers [abstract no. PII-72]. Clin Pharmacol Ther 2006 Feb 1; 79 (2): 55 31. Rossenu S, Crauwels H, Cleton A, et al. Evaluation of the pharmacokinetics of several formulations of paliperidone. AAPS J 2006; 8 Suppl. 2: 1042 32. Cirincione BB, Redman ML, Fiedler-Kelly J, et al. Population pharmacokinetics of paliperidone ER in healthy and schizophrenia patients. Clin Pharmacol Ther 2007 Mar; 81 Suppl. 1: 19 33. Boom S, Talluri K, Janssens L, et al. Single- and multipledose pharmacokinetics and dose proportionality of the psychotropic agent paliperidone extended release. J Clin Pharmacol 2009 Nov; 49 (11): 1318-30 34. Berwaerts J, Cleton A, Herben V, et al. The effects of paroxetine on the pharmacokinetics of paliperidone extendedrelease tablets. Pharmacopsychiatry 2009 Jul; 42 (4): 158-63 35. Thyssen A, Cleton A, Talluri K, et al. No pharmacokinetic interaction between paliperidone extended-release tablets and trimethoprim in healthy subjects. Hum Psychopharmacol 2009; 24: 532-9 36. Kramer M, Simpson G, Maciulis V, et al. Paliperidone extended-release tablets for prevention of symptom recurrence in patients with schizophrenia: a randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol 2007 Feb; 27 (1): 6-14 37. Canuso C, Carothers J, Dirks B, et al. A double-blind, placebo-controlled trial of paliperidone ER and quetiapine in patients with a recent acute exacerbation of schizophrenia [abstract]. 161st Annual Meeting of the American Psychiatric Association; 2008 May 3-8; Washington, DC, 166 38. Schreiner A, Tessier C, Hoeben D, et al. A prospective randomized controlled trial of paliperidone ER versus oral olanzapine in patients with schizophrenia [abstract]. 18th European Congress of Psychiatry; 2010 Feb 27-Mar 2; Munich
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39. Schreiner A, Hoeben D, Lahaye M, et al. A flexible-dose study of paliperidone ER in non-acute patients with schizophrenia previously unsuccessfully treated with other oral antipsychotics [abstract]. 18th European Congress of Psychiatry; 2010 Feb 27-Mar 2; Munich 40. Schreiner A, Hoeben D, Lahaye M, et al. Patient functioning with flexible doses of paliperidone ER: a 6-month prospective study [abstract]. 18th European Congress of Psychiatry; 2010 Feb 27-Mar 2; Munich 41. Schreiner A, Hoeben D, Lahaye M, et al. A flexible-dose study of paliperidone ER in non-acute patients with schizophrenia previously unsuccessfully treated with oral risperidone [abstract]. 18th European Congress of Psychiatry; 2010 Feb 27-Mar 2; Munich 42. Howland RH. Paliperidone extended-release tablets: a new atypical antipsychotic. J Psychosoc Nurs Ment Health Serv 2007 May; 45 (5): 15-8 43. Salimi K, Jarskog LF, Leiberman JA. Antipsychotic drugs for first-episode schizophrenia. CNS Drugs 2009; 23 (10): 837-55 44. Mortimer A. How do we choose between atypical antipsychotics? The advantages of amisulpride. Int J Neuropsychopharmacol 2004; 7 Suppl. 1: S21-5 45. Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry 2004 Mar; 161 (3): 414-25 46. Kapur S, Seeman P. Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 2001 Mar; 158 (3): 360-9 47. Falkai P. Limitations of current therapies: why do patients switch therapies? Eur Neuropsychopharmacol 2008; 18 Suppl.: S135-9 48. American Diabetes Association. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004 Feb; 27 (2): 596-601 49. Jones A. What are the nursing implications when using paliperidone prolonged release for people with schizophrenia. J Psychiatr Ment Health Nurs 2008 Dec; 15 (10): 792-9
50. Hough D, Nuamah IF, Lim P, et al. Independent effect of paliperidone extended release on social functioning beyond its effect on positive and negative symptoms of schizophrenia: a mediation analysis [letter]. J Clin Psychopharmacol 2009 Oct; 29 (5): 496-7 51. Schreiner A, Badescu GM, Jukic V, et al. Safety, tolerability and treatment response of flexible doses of paliperidone ER in acutely exacerbated patients with schizophrenia [abstract]. 9th World Congress of the World Federation of Societies of Biological Psychiatry; 2009 Jun 28-Jul 2; Paris 52. Kantrowitz J, Citrome L. Paliperidone: the evidence of its therapeutic value in schizophrenia. Core Evidence 2008; 2 (4): 261-71 53. Nussbaum A, Stroup TS. Oral paliperidone for schizophrenia. Cochrane Database Syst Rev 2009; (2): CD006369 54. US National Institutes of Health. A double-blind, placebocontrolled study of the safety and efficacy of paliperidone extended release (ER) in the treatment of schizophrenia in adolescent patients [online]. Available from URL: http://www.clinicaltrials.gov/ct2/show/record/NCT00518323 [Accessed 2010 May 3] 55. Geitona M, Kousoulakou H, Ollandezos M, et al. Costs and effects of paliperidone extended release compared with alternative oral antipsychotic agents in patients with schizophrenia in Greece: a cost effectiveness study. Ann Gen Psychiatry 2008; 7: 16 56. Edwards NC, Pesa J, Meletiche DM, et al. One-year clinical and economic consequences of oral typical antipsychotics in the treatment of schizophrenia. Curr Med Res Opin 2008 Dec; 24 (12): 3341-55 57. Berto P, Negrini C, Ferrannini L. Analisi costo-efficacia di paliperidone ER nel trattamento delle ricadute della schizofrenia, nella prospettiva del Sistema Sanitario Nazionale italiano. Farmeconomia e Percorsi Terapeutici 2008; 9 (2): 95-108
Correspondence: Claudine M. Chwieduk, Adis, a Wolters Kluwer Business, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand. E-mail: demail@adis.co.nz
Drugs 2010; 70 (10)
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Drugs 2010; 70 (10): 1295-1317 0012-6667/10/0010-1295/$55.55/0

2010 Adis Data Information BV. All rights reserved.

Paliperidone Extended Release

Chwieduk & Keating

2010 Adis Data Information BV. All rights reserved.

Drugs 2010; 70 (10)

Paliperidone Extended Release: A Review

Chwieduk & Keating

Temporal cortex Striatum

2010 Adis Data Information BV. All rights reserved.

Paliperidone Extended Release: A Review

Chwieduk & Keating

Mean values unless otherwise stated.

Paliperidone Extended Release: A Review

Chwieduk & Keating

Clinical response rate (% of pts)b

Mean change in PSP score from baseline at endpoint

40** 46** 53** NR 18 56*** 51 61 52 30 50* 51* 46 34

Paliperidone Extended Release: A Review

Chwieduk & Keating

Paliperidone Extended Release: A Review

4.1.2 Prevention of Acute Symptom Recurrence

Chwieduk & Keating

4.2.2 In Patients Previously Unsuccessfully Treated with an Oral Antipsychotic

Paliperidone Extended Release: A Review

Chwieduk & Keating

a 16 14 12 10 8 6 4 2 Percentage of pts 0 Headache Insomnia Anxiety Sinus tachycardia

b 16 14 12 10 8 6 4 2 0 Extrapyramidal disorder Akathisia Tremor Hypertonia Dystonia

Paliperidone Extended Release: A Review

Chwieduk & Keating

Paliperidone Extended Release: A Review

Chwieduk & Keating

Paliperidone Extended Release: A Review

Chwieduk & Keating

Paliperidone Extended Release: A Review

Drugs 2010; 70 (10)

Chwieduk & Keating

2010 Adis Data Information BV. All rights reserved.

Drugs 2010; 70 (10)

Paliperidone Extended Release: A Review

2010 Adis Data Information BV. All rights reserved.

Drugs 2010; 70 (10)

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