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Mechanism Of Action
Paliperidone palmitate is hydrolyzed to paliperidone [see Pharmacokinetics]. Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.
Paliperidone is a centrally active dopamine Type 2 (D2) receptor antagonist and a serotonin Type 2 (5HT2A) receptor antagonist. Paliperidone is also active as an antagonist at α1 and α2 adrenergic receptors and H1 histaminergic receptors, which may explain some of the other effects of the drug. 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 in vitro.
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 1 and lasts for as long as 126 days.
Following intramuscular injection of single doses (39 mg - 234 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 234 mg on day 1 and 156 mg on day 8 help attain therapeutic concentrations rapidly. The release profile and dosing regimen of INVEGA® SUSTENNA® results in sustained therapeutic concentrations. The AUC of paliperidone following INVEGA® SUSTENNA® administration was dose-proportional over a 39 mg-234 mg dose range, and less than dose-proportional for Cmax for doses exceeding 78 mg. The mean steady-state peak:trough ratio for an INVEGA® SUSTENNA® dose of 156 mg was 1.8 following gluteal administration and 2.2 following deltoid administration.
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
In a study with oral immediate-release 14C-paliperidone, 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 10% 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 discernible difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates.
The median apparent half-life of paliperidone following INVEGA® SUSTENNA® single-dose administration over the dose range of 39 mg - 234 mg ranged from 25 days - 49 days.
Long-Acting 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. The initiation regimen for INVEGA® SUSTENNA® (234 mg/156 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.
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.
Drug Interaction Studies
Potential for INVEGA® SUSTENNA® to Affect Other Drugs
In vitro studies in human liver microsomes demonstrated that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.
Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivo data are available, and the clinical relevance is unknown.
In a drug interaction study, co-administration of oral paliperidone extended-release tablets (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC24h and Cmax,ss) of valproate in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when oral paliperidone extended-release tablets 3-15 mg/day was added to their existing valproate treatment [see DRUG INTERACTIONS].
Potential for Other Drugs to Affect INVEGA® SUSTENNA®
While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies did not demonstrate decreased elimination by these isozymes; they contribute to only a small fraction of total body clearance. In vitro studies demonstrated that paliperidone is a P-gp substrate [see DRUG INTERACTIONS].
Co-administration of oral paliperidone extended-release 6 mg once daily with carbamazepine, a strong inducer of both CYP3A4 and P-gp, at 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. A minor decrease in the amount of drug excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration [see DRUG INTERACTIONS].
Co-administration of a single dose of oral paliperidone extended-release 12 mg tablet with divalproex sodium extended-release tablets (two 500 mg tablets once daily at steady-state) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Although this interaction has not been studied with INVEGA® SUSTENNA®, a clinically significant interaction would not be expected between divalproex sodium and INVEGA® SUSTENNA® intramuscular injection [see DRUG INTERACTIONS].
Paliperidone is metabolized to a limited extent by CYP2D6. In an interaction study in healthy subjects in which a single 3 mg dose of oral paliperidone extended-release was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers. Higher doses of paroxetine have not been studied. The clinical relevance is unknown.
INVEGA® SUSTENNA® has not been systematically studied in patients with renal impairment. Based on a limited number of observations with INVEGA® SUSTENNA® in subjects with mild renal impairment and pharmacokinetic simulations, the dose of INVEGA® SUSTENNA® should be reduced in patients with mild renal impairment; INVEGA® SUSTENNA® is not recommended in patients with moderate or severe renal impairment. Although INVEGA® SUSTENNA® was not studied in patients with moderate or severe renal impairment, 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 mL/min to < 80 mL/min), 64% in moderate (CrCl = 30 mL/min to < 50 mL/min), and 71% in severe (CrCl = 10 mL/min to < 30 mL/min) renal impairment, corresponding to an average increase in exposure (AUCinf) of 1.5 fold, 2.6 fold, and 4.8 fold, respectively, compared to healthy subjects [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].
INVEGA® SUSTENNA® has not been studied in patients with hepatic impairment. Based on a study with oral paliperidone in subjects with moderate hepatic impairment (Child-Pugh class B), no dose adjustment is required in patients with mild or moderate hepatic impairment. In the 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, although total paliperidone exposure decreased because of a decrease in protein binding. Paliperidone has not been studied in patients with severe hepatic impairment [see Use In Specific Populations].
No dosage adjustment is recommended based on age alone. However, dose adjustment may be required because of age-related decreases in creatinine clearance [see Renal Impairment above and DOSAGE AND ADMINISTRATION].
No dosage adjustment is recommended based on race. No differences in pharmacokinetics were observed between Japanese and Caucasians.
No dosage adjustment is recommended based on gender, although slower absorption was observed in females in a population pharmacokinetic analysis.
No dosage adjustment is recommended based on 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.
The efficacy of INVEGA® SUSTENNA® was established in the following adequate and well-controlled trials:
- Four short-term, fixed-dose trials and one maintenance trial in adults with schizophrenia as monotherapy [see Schizophrenia below]
- One long-term, flexible-dose maintenance trial in adults with schizoaffective disorder as monotherapy or as adjunctive therapy to a mood stabilizer or antidepressant [see Schizoaffective Disorder below]
Short-Term Monotherapy (Studies 1, 2, 3, 4)
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 total score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210.
In Study 1 (PSY-3007), a 13-week study (n=636) comparing three fixed doses of INVEGA® SUSTENNA® (initial deltoid injection of 234 mg followed by 3 gluteal or deltoid doses of either 39 mg/4 weeks, 156 mg/4 weeks or 234 mg/4 weeks) to placebo, all three doses of INVEGA® SUSTENNA® were superior to placebo in improving the PANSS total score.
In Study 2 (PSY-3003), another 13-week study (n=349) comparing three fixed doses of INVEGA® SUSTENNA® (78 mg/4 weeks, 156 mg/4 weeks, and 234 mg/4 weeks) to placebo, only 156 mg/4 weeks of INVEGA® SUSTENNA® was superior to placebo in improving the PANSS total score.
In Study 3 (PSY-3004), a third 13-week study (n=513) comparing three fixed doses of INVEGA® SUSTENNA® (39 mg/4 weeks, 78 mg/4 weeks, and 156 mg/4 weeks) to placebo, all three doses of INVEGA® SUSTENNA® were superior to placebo in improving the PANSS total score.
In Study 4 (SCH-201), the 9-week study (n=197) comparing two fixed doses of INVEGA® SUSTENNA® (78 mg/4 weeks and 156 mg/4 weeks) to placebo, both doses of INVEGA® SUSTENNA® were superior to placebo in improving PANSS total score.
A summary of the mean baseline PANSS scores along with the mean changes from baseline in the four short-term acute schizophrenia studies are provided in Table 13.
Table 13: Schizophrenia
|Study Number||Treatment Group||Primary Effi||cacy Measure: PAN||SS Total Score|
|Mean Baseline Score
|LS Mean Change from Baseline
|Study 1||INVEGA® SUSTENNA®
(39 mg/4 weeks)*
(156 mg/4 weeks)*
(234 mg/4 weeks)*
|Study 2b||INVEGA® SUSTENNA®
(78 mg/4 weeks)
(156 mg/4 weeks)*
|Study 3||INVEGA® SUSTENNA®
(39 mg/4 weeks)*
(78 mg/4 weeks)*
(156 mg/4 weeks)*
|Study 4||INVEGA® SUSTENNA®
(78 mg/4 weeks)*
(156 mg/4 weeks)*
|SD: standard deviation; SE:
standard error; LS Mean: least-squares mean; CI: unadjusted confidence
aDifference (drug minus placebo) in least-squares mean change from baseline.
bBecause an insufficient number of subjects received the 234 mg/4 weeks dose, results from this group are not included.
* p < 0.05 (Doses statistically significantly superior to placebo).
Maintenance Monotherapy Treatment (Study 5: PSY-3001)
The efficacy of INVEGA® SUSTENNA® in maintaining symptomatic control in schizophrenia was established in a longer-term double-blind, placebo-controlled, flexible-dose study involving adult subjects who met DSM-IV criteria for schizophrenia. This study included a minimum 12-week, fixed-dose stabilization phase, and a randomized, placebo-controlled phase to observe for relapse. During the double-blind phase, patients were randomized to either the same dose of INVEGA® SUSTENNA® they received during the stabilization phase, i.e., 39 mg, 78 mg, or 156 mg administered every 4 weeks, or to placebo. 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 specific PANSS items. The primary efficacy variable was time to relapse. A pre-planned interim analysis showed a statistically significantly longer time to relapse in patients treated with INVEGA® SUSTENNA® compared to placebo, and the study was stopped early because maintenance of efficacy was demonstrated. Thirty-four percent (34%) of subjects in the placebo group and 10% of subjects in the INVEGA® SUSTENNA® group experienced a relapse event. There was a statistically significant difference between the treatment groups in favor of INVEGA® SUSTENNA®. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 1. The time to relapse for subjects in the placebo group was statistically significantly shorter than for the INVEGA® SUSTENNA® group. An examination of population subgroups did not reveal any clinically significant differences in responsiveness on the basis of gender, age, or race.
Figure 1: Kaplan-Meier Plot of Cumulative Proportion of Subjects
with Relapse Over Time (Schizophrenia Study 5)
Maintenance Treatment – Monotherapy and as Adjunct to Mood Stabilizer or Antidepressant (SAff Study 1: SCA-3004)
The efficacy of INVEGA® SUSTENNA® in maintaining symptom control in schizoaffective disorder was established in a long-term double-blind, placebo-controlled, flexible-dose randomized-withdrawal study designed to delay relapse in adult subjects who met DSM-IV criteria for schizoaffective disorder, as confirmed by the Structured Clinical Interview for DSMIV Disorders. The population included subjects with schizoaffective bipolar and depressive types. Subjects received INVEGA® SUSTENNA® either as monotherapy or as an adjunct to stable doses of antidepressant or mood stabilizers.
This study included a 13-week, open-label, flexible-dose (INVEGA® SUSTENNA® 78 mg, 117 mg, 156 mg, or 234 mg) lead-in period which enrolled a total of 667 subjects who had 1) acute exacerbation of psychotic symptoms; 2) score ≥ 4 on ≥ 3 PANSS items of delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, tension, and poor impulse control; and 3) prominent mood symptoms ≥ 16 on the Young Mania Rating Scale (YMRS) and/or the Hamilton Rating Scale for Depression, 21-item version (HAM-D-21). Subjects were 19 to 66 years old (mean 39.5 years) and 53.5% were male. The mean scores at open-label enrollment of PANSS total was 85.8 (range 42 to 128), HAM-D-21 was 20.4 (range 3 to 43), YMRS was 18.6 (range 0 to 50), and CGI-SSCA was 4.4 (range 2 to 6).
After the 13-week open-label flexible-dose INVEGA® SUSTENNA® treatment, 432 subjects met stabilization criteria (PANSS total score ≤ 70, YMRS ≤ 12, and HAM-D-21 ≤ 12) and continued into the 12-week open-label fixed-dose stabilization period.
A total of 334 subjects who met stabilization criteria for 12 consecutive weeks were randomized (1:1) to continue the same dose of INVEGA® SUSTENNA® or to placebo in the 15-month, double-blind, maintenance period. For the 164 subjects who were randomized to INVEGA® SUSTENNA®, dose distribution was 78 mg (4.9%), 117 mg (9.8%), 156 mg (47.0%), and 234 mg (38.4%). The primary efficacy variable was time to relapse. Relapse was defined as the first occurrence of one or more of the following: 1) psychiatric hospitalization; 2) intervention employed to avert hospitalization; 3) clinically significant self-injury, suicidal or homicidal ideation or violent behavior; 4) a score of ≥ 6 (if the score was > 4 at randomization) of any of the individual PANSS items: delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, or poor impulse control; 5) on two consecutive assessments within 7 days: ≥ 25% increase (if the score at randomization was > 45) or ≥ 10-point increase (if the score at randomization was > 45) in total PANSS score; a score of ≥ 5 (if the score was > 3 at randomization) of any of the individual PANSS items: delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, or poor impulse control; an increase of ≥ 2 points (if the score was 1 [not ill] to 3 [mildly ill] at randomization) or increase of ≥ 1 point (if the score was ≥ 4 [moderately ill or worse] at randomization) in CGI-S-SCA overall score.
There was a statistically significant difference in time to relapse between the treatment groups in favor of INVEGA® SUSTENNA®. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 2.
Figure 2: Kaplan-Meier Plot of Cumulative
Proportion of Subjects with Relapse Over Time (SAff Study 1)
Table 14 summarizes the number of subjects with relapse in the overall population, by subgroup (monotherapy vs. adjunctive therapy), and by symptom type at the first occurrence of relapse.
Table 14: Summary of Relapse Rates (SAff Study 1).
|Number (Percent) of Subjects Who Relapsed|
|All Subjects||57 (33.5%)||25 (15.2%)|
|24 (32.9%)||9 (11.5%)|
|Adjunct to Antidepressants or Mood Stabilizer subset||N=97||N=86|
|33 (34.0%)||16 (18.6%)|
|Psychotic Symptomsa||53 (31.2%)||21 (12.8%)|
|Any Mood Symptoms||48 (28.2%)||18 (11.0%)|
|Manic||16 (9.4%)||5 (3.0%)|
|Depressive||23 (13.5%)||8 (4.9%)|
|Mixed||9 (5.3%)||5 (3.0%)|
|a8 subjects experienced a relapse without psychotic
b16 subjects experienced a relapse without any mood symptoms.
Last reviewed on RxList: 7/1/2015
This monograph has been modified to include the generic and brand name in many instances.
Additional Invega Sustenna Information
- Invega Sustenna Drug Interactions Center: paliperidone palmitate im
- Invega Sustenna Side Effects Center
- Invega Sustenna Overview including Precautions
- Invega Sustenna FDA Approved Prescribing Information including Dosage
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