Other antipsychotics. ATC code:
Pharmacology: Pharmacodynamics: Mechanism of Action:
Paliperidone, the active ingredient in INVEGA SUSTENNA, is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives (atypical neuroleptic antipsychotic). INVEGA SUSTENNA contains a racemic mixture of (+) and (-)-paliperidone.
Paliperidone palmitate is hydrolyzed to paliperidone (see Toxicology as follows). Paliperidone is a centrally active dopamine D2 antagonist with predominant serotonergic 5-HT2A antagonistic activity. Paliperidone is also active as an antagonist at α1 and α2 adrenergic receptors and H1 histaminergic receptors. Paliperidone has no affinity for cholinergic muscarinic or β1- and β2-adrenergic receptors. The pharmacological activity of the (+)- and (-)-paliperidone enantiomers is qualitatively and quantitatively similar.
The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism. Antagonism at receptors other than D2 and 5HT2A may explain some of the other effects of paliperidone.
Effect on QT/ATc interval and cardiac electrophysiology: The effects of oral paliperidone on the QT interval were evaluated in two randomized, double-blind, multicenter, phase 1 studies in adults with schizophrenia and schizoaffective disorder, and in three placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia.
In the first phase 1 study (n=141), subjects were randomized to receive either 7 days of immediate-release oral paliperidone once daily (titrated from 4 to 8 mg) or a single dose of moxifloxacin (400 mg). The 8 mg once daily dose of immediate-release oral paliperidone (n=50, Cmax ss=113 ng/mL) achieved a mean steady-state maximum plasma concentration greater than 2-fold the exposure observed with the maximum recommended 150 mg dose of INVEGA SUSTENNA administered in the deltoid muscle (predicted median Cmax ss=50 ng/mL). In the model-adjusted day-averaged linear-derived QT correction (QTcLD), there was a mean increase of 5.5 msec (90% CI: 3.66; 7.25) in the INVEGA SUSTENNA treatment group (n=50).
In the second phase 1 study (n=109), subjects were randomized to receive either placebo, the maximum recommended dose of oral extended-release paliperidone (12 mg once daily), subsequently titrated to a dose above the recommended range (18 mg once daily), or an active control from the same pharmacologic class of drugs (400 mg quetiapine twice daily). The primary comparison in this 10-day noninferiority study was between extended-release paliperidone 12 mg and quetiapine. The least squares mean change from baseline in QTcLD at each individual's observed tmax was estimated to be 5.1 ms lower for 12 mg extended-release paliperidone (mean Cmax 34 ng/mL) compared with 400 mg quetiapine twice daily (mean Cmax 1183 ng/mL) (90% CI: -9.2; -0.9), meeting the prespecified noninferiority criterion of 10 ms. The mean change from baseline in QTcLD at each individual's observed tmax was estimated to be 2.3 ms lower for 18 mg extended-release paliperidone (mean Cmax 53 ng/mL) compared with 400 mg quetiapine twice daily (mean Cmax 1183 ng/mL) (90% CI: -6.8; 2.3).
The mean change from baseline in QTcLD at each individual's observed tmax was estimated to be 1.5 ms higher (90% CI: -3.3; 6.2) for 12 mg extended-release paliperidone and 8.0 ms higher (90% CI: 3.1; 12.9) for 400 mg quetiapine twice daily compared with the mean change from baseline in QTcLD at median observed tmax (of the active drug in the comparison) in the concurrent placebo arm. The mean change from baseline in QTcLD at each individual's observed tmax was estimated to be 4.9 ms higher (90% CI: -0.5; 10.3) for extended-release paliperidone 18 mg and 7.5 ms higher (90% CI: 2.5; 12.5) for quetiapine 400 mg twice daily compared with the mean change from baseline in QTcLD at median observed tmax (of the active drug in the comparison) in the concurrent placebo arm.
None of the subjects had a change from baseline exceeding 60 msec or a QTcLD exceeding 500 msec at any time during either of these studies.
In the three fixed-dose efficacy studies of oral extended-release paliperidone, extensive electrocardiography (ECG) measurements were taken at 15 times points on specified days (including the times of expected Cmax) using a standardized methodology. Mean QTcLD increase did not exceed 5 msec in any treatment group at any time point, based on pooled data from 836 subjects treated with extended-release paliperidone, 357 subjects treated with olanzapine, and 350 subjects treated with placebo. One subject each in the extended-release paliperidone 12 mg and olanzapine groups had a change exceeding 60 msec at one time-point during these studies (increases of 62 and 110 msec, respectively).
In the four fixed-dose efficacy studies of INVEGA SUSTENNA, no subject experienced a change in QTcLD exceeding 60 msec and no subject had a QTcLD value of >500 msec at any time point. In the long-term recurrence prevention study, no subject had a QTcLD change >60 msec, and one subject had a QTcLD value of 507 msec (Bazett's QT corrected interval [QTcB] value of 483 msec); this latter patient also had a heart rate of 45 beats per minute.
Schizophrenia: The efficacy of INVEGA SUSTENNA in the acute treatment of schizophrenia was evaluated in four short-term one 9-week and three 13-week) double-blind, randomized, placebo-controlled, fixed-dose studies of acutely relapsed adult inpatients who met DSM-IV criteria for schizophrenia. The fixed doses of INVEGA SUSTENNA in these studies were given on days 1, 8, and 36 in the 9-week study, and additionally on day 64 of the 13-week studies, i.e., at a weekly interval for the initial two doses and then every 4 weeks for maintenance.
Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. Functioning was evaluated using the Personal and Social Performance (PSP) scale. The PSP is a validated clinician rated scale that measures personal and social functioning in the domains of socially useful activities: work and study, personal and social relationships, self-care, and disturbing and aggressive behaviors. The severity of dysfunctioning in social, personal, and self-care is measured by level of difficulty (absent, mild, manifest, marked, severe) in performing such activities with and without the help of other people. Similarly, severity of dysfunctioning in aggressive behaviors is measured by the presence or absence of aggressive behaviors (e.g., rudeness, insulting others in public, breaking objects, verbal threats, physical assault) and the frequency in which these behaviors occur.
In a 13-week study (n=636) comparing three fixed doses of INVEGA SUSTENNA (initial deltoid injection of 150 mg followed by 3 gluteal or deltoid doses of either 25 mg/4 weeks, 100 mg/4 weeks or 150 mg/4 weeks) to placebo, all three doses of INVEGA SUSTENNA were superior to placebo in improving the PANSS total score. In this study, both the 100 mg/4 weeks and 150 mg/4 weeks, but not the 25 mg/4 weeks, treatment groups demonstrated statistical superiority to placebo for the PSP score. These results support efficacy across the entire duration of treatment and improvement in PANSS and was observed as early as day 4 with significant separation from placebo in the 25 mg and 150 mg INVEGA SUSTENNA groups by day 8.
In another 13-week study (n=349) comparing three fixed doses of INVEGA SUSTENNA (50 mg/4 weeks, 100 mg/4 weeks, and 150 mg/4 weeks) to placebo, only 100 mg/4 weeks of INVEGA SUSTENNA was superior to placebo in improving the PANSS total score. In this study, both the 50 mg/4 weeks and the 100 mg/4 weeks doses were superior to placebo in improving the PSP score. Although a 150 mg dose was included in this study, there were insufficient numbers of subjects receiving this dose to allow definitive conclusions concerning the efficacy of this dose.
In a third 13-week study (n=513) comparing three fixed doses of INVEGA SUSTENNA (25 mg/4 weeks, 50 mg/4 weeks, and 100 mg/4 weeks) to placebo, all three doses of INVEGA SUSTENNA were superior to placebo in improving the PANSS total score. In this study, none of the paliperidone dose groups achieved statistical significance when compared with placebo for the PSP score.
In the 9-week study (n=197) comparing two fixed doses of INVEGA SUSTENNA 50 mg/4 weeks and 100 mg/4 weeks) to placebo, both doses of INVEGA SUSTENNA were superior to placebo in improving PANSS total score.
The efficacy of INVEGA SUSTENNA in maintaining symptomatic control and delaying relapse of schizophrenia was established in a longer-term double-blind, placebo-controlled, flexible-dose study involving 849 non-elderly adult subjects who met DSM-IV criteria for schizophrenia. This study included a 33-week open-label acute treatment and stabilization phase, and a randomized, placebo-controlled phase to observe for relapse and a 52-week open-label extension period. In this study, doses of INVEGA SUSTENNA included 25, 50, 75 and 100 mg administered monthly; the 75 mg dose was allowed only in the 52-week open-label extension. Subjects initially received flexible doses (25-100 mg) of INVEGA SUSTENNA during a 9-week transition period. In order to enter the 24-week maintenance period, subjects were required to have a PANSS score of ≤75. Dosing adjustments were only allowed in the first 12 weeks of the maintenance period. During the variable length double-blind phase, patients were randomized to either the same dose of INVEGA SUSTENNA (median duration 171 days [range 1 day - 407 days]) they received during the stabilization phase administered every 4 weeks, or to placebo (median duration 105 days [range 8 days - 441 days]). A total of 410 stabilized patients were randomized to either INVEGA SUSTENNA or to placebo until they experienced a relapse of schizophrenia symptoms. Relapse was pre-defined as time to first emergence of one or more of the following: psychiatric hospitalization, ≥25% increase (if the baseline score was >40) or a 10-point increase (if the baseline score was ≤40) in total PANSS score on two consecutive assessments, deliberate self-injury, violent behavior, suicidal/homicidal ideation, or a score of ≥5 (if the maximum baseline score was ≤3) or ≥6 (if the maximum baseline score was 4) on two consecutive assessments of the individual PANSS items P1 (Delusions), P2 (Conceptual disorganization), P3 (Hallucinatory behavior), P6 (Suspiciousness/persecution), P7 (Hostility), or G8 (Uncooperativeness). The primary efficacy variable was time to relapse. A pre-planned interim analysis (after 68 recurrence events occurred), showed a significantly longer time to relapse in patients treated with INVEGA SUSTENNA compared to placebo (Figure 1), and the study was stopped early because maintenance of efficacy was demonstrated. (See Figure 1.)
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The result of the analysis based on the final data, including all data up to the date of study termination, was consistent with that of the primary efficacy analysis based on the interim data.
An examination of population subgroups did not reveal any clinically significant differences in responsiveness on the basis of gender, age, or race.
Pharmacokinetics: Absorption and Distribution:
Due to its extremely low water solubility, paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. Following a single intramuscular dose, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at a median tmax
of 13 days. The release of the drug starts as early as day I and lasts for as long as 126 days.
Following intramuscular injection of single doses (25-150 mg) in the deltoid muscle, on average, a 28% higher Cmax was observed compared with injection in the gluteal muscle. The two initial deltoid intramuscular injections of 150 mg on day 1 and 100 mg on day 8 help attain therapeutic concentrations rapidly. The release profile and dosing regimen of INVEGA SUSTENNA results in sustained therapeutic concentrations. The total exposure of paliperidone following INVEGA SUSTENNA administration was dose-proportional over a 25-150 mg dose range, and less than doseproportional for Cmax for doses exceeding 50 mg. The mean steady-state peak:trough ratio for a INVEGA SUSTENNA dose of 100 mg was 1.8 following gluteal administration and 2.2 following deltoid administration. The median apparent half-life of paliperidone following INVEGA SUSTENNA administration over the dose range of 25-150 mg ranged from 25-49 days.
Following administration of paliperidone palmitate the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6-1.8.
Based on a population analysis, the apparent volume of distribution of paliperidone is 391 L. The plasma protein binding of racemic paliperidone is 74%.
Metabolism and Elimination:
One week following administration of a single oral dose of 1 mg immediate-release 14C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolized in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four metabolic pathways have been identified in vivo,
none of which accounted for more than 6.5% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro
studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo
that these isozymes play a significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernable difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates. In vitro
studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of medicines metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5.
studies have shown that paliperidone is a P-gp substrate and a weak inhibitor of P-gp at high concentrations. No in vivo
data are available and the clinical relevance is unknown.
Paliperidone Palmitate Injection versus Oral Extended-Release Paliperidone: INVEGA SUSTENNA is designed to deliver paliperidone over a monthly period while extended-release oral paliperidone is administered on a daily basis. Figure 1 presents the median pharmacokinetic profiles for paliperidone for 5 weeks following INVEGA SUSTENNA administration using the recommended initiation regimen compared to the administration of an oral extended-release tablet (6 mg or 12 mg). The initiation regimen for INVEGA SUSTENNA (150 mg/100 mg in the deltoid muscle on Day 1/Day 8 was designed to rapidly attain steady-state paliperidone concentrations when initiating therapy without the use of oral supplementation. (See Figure 2.)
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Median plasma concentration-time profiles following median pharmacokinetic profiles for paliperidone for 5 weeks following INVEGA SUSTENNA administration using the recommended initiation regimen (initiating with paliperidone palmitate equivalent to paliperidone 150 mg/ 100 mg in the deltoid muscle on Day 1/Day 8) compared to the daily administration of an oral extended-release tablet (6 mg or 12 mg).
In general, overall initiation plasma levels with INVEGA SUSTENNA were within the exposure range observed with 6-12 mg extended-release oral paliperidone. The use of the INVEGA SUSTENNA initiation regimen allowed patients to stay in this exposure window of 6-12 mg extended-release oral paliperidone even on trough pre-dose days (Day 8 and Day 36). The intersubject variability for paliperidone pharmacokinetics following delivery from INVEGA SUSTENNA was lower relative to the variability determined from extended-release oral paliperidone tablets. Because of the difference in median pharmacokinetic profiles between the two products, caution should be exercised when making a direct comparison of their pharmacokinetic properties.
Elderly (65 years of age and older): No dosage adjustment is recommended based on age alone. However, dose adjustment may be required because of agerelated decreases in creatinine clearance (see Renal Impairment as follows and Dosage & Administration).
Renal Impairment: The dose of INVEGA SUSTENNA should be reduced in patients with mild renal impairment; INVEGA SUSTENNA is not recommended for use in patients with moderate or severe renal impairment (see Dosage & Administration). The disposition of a single oral dose paliperidone 3 mg extended-release tablet was studied in subjects with varying degrees of renal function. Elimination of paliperidone decreased with decreasing estimated creatinine clearance. Total clearance of paliperidone was reduced in subjects with impaired renal function by 32% on average in mild (CrCl = 50 to <80 mL/min), 64% in moderate (CrCl = 30 to <50 mL/min), and 71% in severe (CrCl = 10 to <30 mL/min) renal impairment, corresponding to an average increase in exposure (AUCinf) of 1.5, 2.6, and 4.8 fold, respectively, compared to healthy subjects. Based on a limited number of observations with INVEGA SUSTENNA in subjects with mild renal impairment and pharmacokinetic simulations, the recommended initiation of INVEGA SUSTENNA for patients with mild renal impairment is with a dose of 100 mg on treatment day I and 75 mg one week later, both administered in the deltoid muscle; thereafter, follow with monthly (every 4 weeks) injections of 50 mg in either the deltoid or gluteal muscle, adjusted within the range of 25 to 100 mg based on patient tolerability and/or efficacy (see Dosage & Administration).
Hepatic Impairment: Paliperidone is not extensively metabolized in the liver. Although INVEGA SUSTENNA was not studied on patients with hepatic impairment, no dose adjustment is required in patients with mild or moderate hepatic impairment. In a study with oral paliperidone in subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of free paliperidone were similar to those of healthy subjects. Paliperidone has not been studied in patients with severe hepatic impairment.
Race: Population pharmacokinetics analysis of data from studies with oral paliperidone revealed no evidence of race-related differences in the pharmacokinetics of paliperidone following INVEGA SUTENNA administration.
Gender: No clinically significant differences were observed between men and women.
Smoking Status: Based on in vitro
studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone. Consistent with these in vitro
results, population pharmacokinetic evaluation has not revealed any differences between smokers and non-smokers.
As with other drugs that antagonize dopamine D2 receptors, intramuscularly-injected paliperidone palmitate, as well as orally-dosed paliperidone, elevated serum prolactin levels in repeat-dose toxicity studies.
In a 7-week juvenile toxicity study in rats with oral doses of paliperidone of 0.16, 0.63, and 2.5 mg/kg/day, which are 0.12, 0.5, and 1.8 times the maximum recommended human oral dose of 12 mg/day for adolescents on a mg/m2
basis, no effects on growth, sexual maturation, and reproductive performance were observed. Oral doses up to 2.5 mg/kg/day did not impair neurobehavioral development in males and females, except for an effect on learning and memory in female rats treated at 2.5 mg/kg/day. This effect was not observed after discontinuation of treatment.
In a 40-week study in juvenile dogs treated with oral risperidone (which is extensively converted to paliperidone) at doses of 0.31, 1.25, and 5 mg/kg/day, sexual maturation was not adversely affected at 0.31 and 1.25 mg/kg/day. Long bone growth was not affected at 0.31 mg/kg/day; effects were observed at 1.25 and 5 mg/kg/day.
The carcinogenic potential of intramuscularly injected paliperidone palmitate was assessed in rats. There was a statistically significant increase in mammary gland adenocarcinomas in female rats at 10, 30 and 60 mg/kg/month. Male rats showed a statistically significant increase in mammary gland adenomas and carcinomas at 30 and 60 mg/kg/month which is 1.2 and 2.2 times the exposure level at the maximum recommended human 150 mg dose of INVEGA SUSTENNA.
The carcinogenic potential of oral paliperidone, an active metabolite of risperidone, was assessed based on studies with risperidone conducted in mice and rats. Risperidone was administered at doses up to 10 mg/kg/day for 18 months to mice and for 25 months to rats. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. An increase in mammary, pituitary, and endocrine pancreas tumors has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2 antagonism. The relevance of these tumor findings in rodents in terms of human risk is unknown.
No evidence of mutagenic potential for paliperidone was found in the Ames reverse mutation test, the mouse lymphoma assay, or the rat micronucleus test. Paliperidone palmitate showed no genotoxic properties in the Ames reverse mutation test or the mouse lymphoma assay.
Although oral paliperidone treatment resulted in prolactin- and CNS-mediated effects, the fertility of male and female rats was not affected. At a maternally toxic dose, female rats showed a slightly lower number of live embryos.