Invega (Paliperidone): Side Effects, Uses, Dosage, Interactions, Warnings (2024)

Description for Invega

Paliperidone, the active ingredient in INVEGA® Extended-Release Tablets, is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives. INVEGA® contains a racemic mixture of (+)-and (-)-paliperidone. The chemical name is (±)-3-[2-[4-(6-fluoro-1,2benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4Hpyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C₂₃H₂₇FN₄O₃ and its molecular weight is 426.49. The structural formula is:

Paliperidone is sparingly soluble in 0.1N HCl and methylene chloride; practically insoluble in water, 0.1N NaOH, and hexane; and slightly soluble in N,N-dimethylformamide.

INVEGA® (paliperidone) Extended-Release Tablets are available in 1.5 mg (orange-brown), 3 mg (white), 6 mg (beige), and 9 mg (pink) strengths. INVEGA® utilizes OROS® osmotic drug-release technology [see Delivery System Components and Performance].

Inactive ingredients are carnauba wax, cellulose acetate, hydroxyethyl cellulose, propylene glycol, polyethylene glycol, polyethylene oxides, povidone, sodium chloride, stearic acid, butylated hydroxytoluene, hypromellose, titanium dioxide, and iron oxides. The 3 mg tablets also contain lactose monohydrate and triacetin.

Delivery System Components And Performance

INVEGA® uses osmotic pressure to deliver paliperidone at a controlled rate. The delivery system, which resembles a capsule-shaped tablet in appearance, consists of an osmotically active trilayer core surrounded by a subcoat and semipermeable membrane. The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components. There are two precision laser-drilled orifices on the drug-layer dome of the tablet. Each tablet strength has a different colored water-dispersible overcoat and print markings. In an aqueous environment, such as the gastrointestinal tract, the water-dispersible color overcoat erodes quickly. Water then enters the tablet through the semipermeable membrane that controls the rate at which water enters the tablet core, which, in turn, determines the rate of drug delivery. The hydrophilic polymers of the core hydrate and swell, creating a gel containing paliperidone that is then pushed out through the tablet orifices. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool as a tablet shell, along with insoluble core components.

Uses for Invega

Schizophrenia

INVEGA® (paliperidone) Extended-Release Tablets areindicated for the treatment of schizophrenia [see Clinical Studies].

The efficacy of INVEGA® in schizophrenia was establishedin three 6-week trials in adults and one 6-week trial in adolescents, as wellas one maintenance trial in adults.

Schizoaffective Disorder

INVEGA® (paliperidone) Extended-Release Tablets areindicated for the treatment of schizoaffective disorder as monotherapy and anadjunct to mood stabilizers and/or antidepressant therapy [see ClinicalStudies].

The efficacy of INVEGA® in schizoaffective disorder wasestablished in two 6-week trials in adults.

Dosage for Invega

Schizophrenia

Adults

The recommended dose of INVEGA® (paliperidone)Extended-Release Tablets for the treatment of schizophrenia in adults is 6 mgadministered once daily. Initial dose titration is not required. Although ithas not been systematically established that doses above 6 mg have additionalbenefit, there was a general trend for greater effects with higher doses. Thismust be weighed against the dose-related increase in adverse reactions. Thus,some patients may benefit from higher doses, up to 12 mg/day, and for somepatients, a lower dose of 3 mg/day may be sufficient. Dose increases above 6mg/day should be made only after clinical reassessment and generally shouldoccur at intervals of more than 5 days. When dose increases are indicated,increments of 3 mg/day are recommended. The maximum recommended dose is 12mg/day.

In a longer-term study, INVEGA® has been shown to beeffective in delaying time to relapse in patients with schizophrenia who werestabilized on INVEGA® for 6 weeks [see Clinical Studies]. INVEGA® shouldbe prescribed at the lowest effective dose for maintaining clinical stabilityand the physician should periodically reevaluate the long-term usefulness ofthe drug in individual patients.

Adolescents (12-17 Years Of Age)

The recommended starting dose of INVEGA® (paliperidone)Extended-Release Tablets for the treatment of schizophrenia in adolescents12-17 years of age is 3 mg administered once daily. Initial dose titration isnot required. Dose increases, if considered necessary, should be made onlyafter clinical reassessment and should occur at increments of 3 mg/day atintervals of more than 5 days. Prescribers should be mindful that, in theadolescent schizophrenia study, there was no clear enhancement to efficacy atthe higher doses, i.e., 6 mg for subjects weighing less than 51 kg and 12 mgfor subjects weighing 51 kg or greater, while adverse events were dose-related.

Schizoaffective Disorder

The recommended dose of INVEGA® (paliperidone)Extended-Release Tablets for the treatment of schizoaffective disorder inadults is 6 mg administered once daily. Initial dose titration is not required.Some patients may benefit from lower or higher doses within the recommendeddose range of 3 to 12 mg once daily. A general trend for greater effects wasseen with higher doses. This trend must be weighed against dose-relatedincrease in adverse reactions. Dosage adjustment, if indicated, should occuronly after clinical reassessment. Dose increases, if indicated, generallyshould occur at intervals of more than 4 days. When dose increases areindicated, increments of 3 mg/day are recommended. The maximum recommended doseis 12 mg/day.

Administration Instructions

INVEGA® can be taken with or without food.

INVEGA® must be swallowed whole with the aid of liquids.Tablets should not be chewed, divided, or crushed. The medication is containedwithin a nonabsorbable shell designed to release the drug at a controlled rate.The tablet shell, along with insoluble core components, is eliminated from thebody; patients should not be concerned if they occasionally notice in their stoolsomething that looks like a tablet.

Use With Risperidone

Concomitant use of INVEGA® with risperidone has not beenstudied. Since paliperidone is the major active metabolite of risperidone,consideration should be given to the additive paliperidone exposure ifrisperidone is coadministered with INVEGA® .

Dosage In Special Populations

Renal Impairment

Dosing must be individualized according to the patient'srenal function status. For patients with mild renal impairment (creatinineclearance ≥ 50 mL/min to < 80 mL/min), the recommended initial dose ofINVEGA® is 3 mg once daily. The dose may then be increased to a maximum of 6 mgonce daily based on clinical response and tolerability. For patients withmoderate to severe renal impairment (creatinine clearance ≥ 10 mL/min to< 50 mL/min), the recommended initial dose of INVEGA® is 1.5 mg once daily,which may be increased to a maximum of 3 mg once daily after clinicalreassessment. As INVEGA® has not been studied in patients with creatinineclearance below 10 mL/min, use is not recommended in such patients. [See CLINICALPHARMACOLOGY]

Hepatic Impairment

For patients with mild to moderate hepatic impairment,(Child-Pugh Classification A and B), no dose adjustment is recommended [seeCLINICAL PHARMACOLOGY]. INVEGA® has not been studied in patients withsevere hepatic impairment.

Elderly

Because elderly patients may have diminished renalfunction, dose adjustments may be required according to their renal functionstatus. In general, recommended dosing for elderly patients with normal renalfunction is the same as for younger adult patients with normal renal function.For patients with moderate to severe renal impairment (creatinine clearance 10mL/min to < 50 mL/min), the maximum recommended dose of INVEGA® is 3 mg oncedaily [see Renal Impairment above].

HOW SUPPLIED

Dosage Forms And Strengths

INVEGA® Extended-Release Tablets are available in thefollowing strengths and colors: 1.5 mg (orange-brown), 3 mg (white), 6 mg (beige),and 9 mg (pink). All tablets are capsule shaped and are imprinted with either“PAL 1.5”, “PAL 3”, “PAL 6”, or “PAL 9”.

INVEGA® (paliperidone) Extended-Release Tablets are availablein the following strengths and packages. All tablets are capsule-shaped.

1.5 mg tablets are orange-brown and imprinted with “PAL1.5”, and are available in bottles of 30 (NDC 50458-554-01).

3 mg tablets are white and imprinted with “PAL 3”, and areavailable in bottles of 30 (NDC 50458-550-01) and hospital unit dose packs of100 (NDC 50458-550-10).

6 mg tablets are beige and imprinted with “PAL 6”, andare available in bottles of 30 (NDC 50458-551-01) and hospital unit dose packsof 100 (NDC 50458-551-10).

9 mg tablets are pink and imprinted with “PAL 9”, and areavailable in bottles of 30 (NDC 50458-552-01) and hospital unit dose packs of100 (NDC 50458-552-10).

Storage And Handling

Store up to 25°C (77°F); excursions permitted to 15 -30°C(59 -86°F) [see USP Controlled Room Temperature]. Protect from moisture.

Keep out of reach of children.

Manufactured by: ALZA Corporation Vacaville, CA 95688 ORJanssen Cilag Manufacturing, LLC Gurabo, Puerto Rico 00778. Manufactured for:Janssen Pharmaceuticals, Inc. Titusville, NJ 08560. Revised: Feb 2017

Side Effects for Invega

Overall Adverse Reaction Profile

The following adverse reactions are discussed in moredetail in other sections of the labeling:

• Increased mortality in elderly patients with dementia-related psychosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
• Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS]
• Neuroleptic malignant syndrome [see WARNINGS AND PRECAUTIONS]
• QT prolongation [see WARNINGS AND PRECAUTIONS]
• Tardive dyskinesia [see WARNINGS AND PRECAUTIONS]
• Metabolic changes [see WARNINGS AND PRECAUTIONS]
• Hyperprolactinemia [see WARNINGS AND PRECAUTIONS]
• Potential for gastrointestinal obstruction [see WARNINGS AND PRECAUTIONS]
• Orthostatic hypotension and syncope [see WARNINGS AND PRECAUTIONS]
• Falls [see WARNINGS AND PRECAUTIONS]
• Leukopenia, neutropenia, and agranulocytosis [see WARNINGS AND PRECAUTIONS]
• Potential for cognitive and motor impairment [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]
• Dysphagia [see WARNINGS AND PRECAUTIONS]
• Suicide [see WARNINGS AND PRECAUTIONS]
• Priapism [see WARNINGS AND PRECAUTIONS]
• Thrombotic thrombocytopenic purpura (TTP) [see WARNINGS AND PRECAUTIONS]
• Disruption of body temperature regulation [see WARNINGS AND PRECAUTIONS]
• Antiemetic effect [see WARNINGS AND PRECAUTIONS]
• Increased sensitivity in patients with Parkinson's disease or those with dementia with Lewy bodies [see WARNINGS AND PRECAUTIONS]
• Diseases or conditions that could affect metabolism or hemodynamic responses [see WARNINGS AND PRECAUTIONS]

The most common adverse reactions in clinical trials inadult subjects with schizophrenia (reported in 5% or more of subjects treatedwith INVEGA® and at least twice the placebo rate in any of the dose groups)were extrapyramidal symptoms, tachycardia, and akathisia. The most commonadverse reactions in clinical trials in adult patients with schizoaffectivedisorder (reported in 5% or more of subjects treated with INVEGA® and at leasttwice the placebo rate) were extrapyramidal symptoms, somnolence, dyspepsia,constipation, weight increased, and nasopharyngitis.

The most common adverse reactions that were associatedwith discontinuation from clinical trials in adult subjects with schizophrenia(causing discontinuation in 2% of INVEGA®-treated subjects) were nervous systemdisorders. The most common adverse reactions that were associated withdiscontinuation from clinical trials in adult subjects with schizoaffectivedisorder were gastrointestinal disorders, which resulted in discontinuation in1% of INVEGA®-treated subjects. [See Discontinuations Due to Adverse Reactions].

The safety of INVEGA® was evaluated in 1205 adultsubjects with schizophrenia who participated in three placebo-controlled,6-week, double-blind trials, of whom 850 subjects received INVEGA® at fixeddoses ranging from 3 mg to 12 mg once daily. The information presented in thissection was derived from pooled data from these three trials. Additional safetyinformation from the placebo-controlled phase of the long-term maintenancestudy, in which subjects received INVEGA® at daily doses within the range of 3mg to 15 mg (n=104), is also included.

The safety of INVEGA® was evaluated in 150 adolescentsubjects 12-17 years of age with schizophrenia who received INVEGA® in the doserange of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlledtrial.

The safety of INVEGA® was also evaluated in 622 adultsubjects with schizoaffective disorder who participated in twoplacebo-controlled, 6-week, double-blind trials. In one of these trials, 206subjects were assigned to one of two dose levels of INVEGA®: 6 mg with theoption to reduce to 3 mg (n=108) or 12 mg with the option to reduce to 9 mg(n=98) once daily. In the other study, 214 subjects received flexible doses ofINVEGA® (3-12 mg once daily). Both studies included subjects who receivedINVEGA® either as monotherapy or as an adjunct to mood stabilizers and/orantidepressants. Adverse events during exposure to study treatment wereobtained by general inquiry and recorded by clinical investigators using theirown terminology. Consequently, to provide a meaningful estimate of theproportion of individuals experiencing adverse events, events were grouped instandardized categories using MedDRA terminology.

Throughout this section, adverse reactions are reported.Adverse reactions are adverse events that were considered to be reasonablyassociated with the use of INVEGA® (adverse drug reactions) based on thecomprehensive assessment of the available adverse event information. A causalassociation for INVEGA® often cannot be reliably established in individualcases. Further, because clinical trials are conducted under widely varyingconditions, adverse reaction rates observed in the clinical trials of a drugcannot be directly compared to rates in the clinical trials of another drug andmay not reflect the rates observed in clinical practice.

Commonly-Observed Adverse Reactions In Double-Blind, Placebo-Controlled Clinical Trials – Schizophrenia In Adults And Adolescents

Adult Patients With Schizophrenia

Table 4 enumerates the pooled incidences of adversereactions reported in the three placebo-controlled, 6-week, fixed-dose studiesin adults, listing those that occurred in 2% or more of subjects treated withINVEGA® in any of the dose groups, and for which the incidence in INVEGA®-treatedsubjects in any of the dose groups was greater than the incidence in subjectstreated with placebo.

Table 4: Adverse Reactions Reported by ≥ 2% ofINVEGA®-Treated Adult Subjects with Schizophrenia in ThreeShort-Term, Fixed-Dose, Placebo-Controlled Clinical Trials*

Adolescent Patients With Schizophrenia

Table 5 lists the adverse reactions reported in afixed-dose, placebo-controlled study in adolescent subjects 12-17 years of agewith schizophrenia, listing those that occurred in 2% or more of subjectstreated with INVEGA® in any of the dose groups, and for which the incidence inINVEGA®-treated subjects in any of the dose groups was greater than theincidence in subjects treated with placebo.

Table 5: Adverse Reactions Reported by ≥ 2% ofINVEGA®-Treated Adolescent Subjects with Schizophrenia in aFixed-Dose, Placebo-Controlled Clinical Trial*

Commonly-Observed Adverse Reactions In Double-Blind, Placebo-Controlled Clinical Trials – Schizoaffective Disorder In Adults

Table 6 enumerates the pooled incidences of adversereactions reported in the two placebo-controlled 6-week studies in adultsubjects, listing those that occurred in 2% or more of subjects treated withINVEGA® and for which the incidence in INVEGA®-treated subjects was greaterthan the incidence in subjects treated with placebo.

Table 6: Adverse Drug Reactions Reported by ≥ 2%of INVEGA®-Treated Adult Subjects with Schizoaffective Disorderin Two Double-Blind, Placebo-Controlled Clinical Trials *

Monotherapy Versus Adjunctive Therapy

The designs of the two placebo-controlled, 6-week,double-blind trials in adult subjects with schizoaffective disorder includedthe option for subjects to receive antidepressants (except monoamine oxidaseinhibitors) and/or mood stabilizers (lithium, valproate, or lamotrigine). Inthe subject population evaluated for safety, 230 (55%) subjects received INVEGA®as monotherapy and 190 (45%) subjects received INVEGA® as an adjunct to moodstabilizers and/or antidepressants. When comparing these 2 subpopulations, onlynausea occurred at a greater frequency (≥ 3% difference) in subjectsreceiving INVEGA® as monotherapy.

Discontinuations Due To Adverse Reactions

Schizophrenia Trials

The percentages of subjects who discontinued due toadverse reactions in the three schizophrenia placebo-controlled, 6-week,fixed-dose studies in adults were 3% and 1% in INVEGA®-and placebo-treatedsubjects, respectively. The most common reasons for discontinuation werenervous system disorders (2% and 0% in INVEGA®-and placebo-treated subjects,respectively).

Among the adverse reactions in the 6-week, fixed-dose,placebo-controlled study in adolescents with schizophrenia, only dystonia ledto discontinuation (<1% of INVEGA®-treated subjects).

Schizoaffective Disorder Trials

The percentages of subjects who discontinued due toadverse reactions in the two schizoaffective disorder placebo-controlled 6-weekstudies in adults were 1% and <1% in INVEGA®-and placebo-treated subjects,respectively. The most common reasons for discontinuation were gastrointestinaldisorders (1% and 0% in INVEGA®-and placebo-treated subjects, respectively).

Dose-Related Adverse Reactions

Schizophrenia Trials

Based on the pooled data from the threeplacebo-controlled, 6-week, fixed-dose studies in adult subjects withschizophrenia, among the adverse reactions that occurred with a greater than 2%incidence in the subjects treated with INVEGA®, the incidences of the followingadverse reactions increased with dose: somnolence, orthostatic hypotension,akathisia, dystonia, extrapyramidal disorder, hypertonia, parkinsonism, andsalivary hypersecretion. For most of these, the increased incidence was seenprimarily at the 12 mg dose, and, in some cases, the 9 mg dose.

In the 6-week, fixed-dose, placebo-controlled study inadolescents with schizophrenia, among the adverse reactions that occurred with>2% incidence in the subjects treated with INVEGA® , the incidences of thefollowing adverse reactions increased with dose: tachycardia, akathisia,extrapyramidal symptoms, somnolence, and headache.

Schizoaffective Disorder Trials

In a placebo-controlled, 6-week, high-and low-dose studyin adult subjects with schizoaffective disorder, akathisia, dystonia,dysarthria, myalgia, nasopharyngitis, rhinitis, cough, and pharyngolaryngealpain occurred more frequently (i.e., a difference of at least 2%) in subjectswho received higher doses of INVEGA® compared with subjects who received lowerdoses.

Demographic Differences

An examination of population subgroups in the threeplacebo-controlled, 6-week, fixed-dose studies in adult subjects withschizophrenia and in the two placebo-controlled, 6-week studies in adultsubjects with schizoaffective disorder did not reveal any evidence ofclinically relevant differences in safety on the basis of gender or race alone;there was also no difference on the basis of age [see Use In SpecificPopulations].

Extrapyramidal Symptoms (EPS)

Pooled data from the three placebo-controlled, 6-week,fixed-dose studies in adult subjects with schizophrenia provided informationregarding treatment-emergent EPS. Several methods were used to measure EPS: (1)the Simpson-Angus global score (mean change from baseline) which broadlyevaluates Parkinsonism, (2) the Barnes Akathisia Rating Scale global clinicalrating score (mean change from baseline) which evaluates akathisia, (3) use ofanticholinergic medications to treat emergent EPS (Table 7), and (4) incidenceof spontaneous reports of EPS (Table 8). For the Simpson-Angus Scale,spontaneous EPS reports and use of anticholinergic medications, there was adose-related increase observed for the 9 mg and 12 mg doses. There was nodifference observed between placebo and INVEGA® 3 mg and 6 mg doses for any ofthese EPS measures.

Table 7: Treatment-Emergent Extrapyramidal Symptoms(EPS) Assessed by Incidence of Ratings Scales and Use of AnticholinergicMedication – Schizophrenia Studies in Adults

Table 8: Treatment-Emergent Extrapyramidal Symptoms(EPS)-Related Adverse Events by MedDRA Preferred Term – Schizophrenia Studiesin Adults

Compared to data from the studies in adults subjects withschizophrenia, pooled data from the two placebo-controlled 6-week studies inadult subjects with schizoaffective disorder showed similar types andfrequencies of EPS as measured by rating scales, anticholinergic medicationuse, and spontaneous reports of EPS-related adverse events. For subjects withschizoaffective disorder, there was no dose-related increase in EPS observedfor parkinsonism with the Simpson-Angus scale or akathisia with the BarnesAkathisia Rating Scale. There was a dose-related increase observed withspontaneous EPS reports of hyperkinesia and dystonia and in the use ofanticholinergic medications.

Table 9 shows the EPS data from the pooledschizoaffective disorder trials.

Table 9: Treatment-Emergent Extrapyramidal Symptoms(EPS)-Related Adverse Events by MedDRA Preferred Term – SchizoaffectiveDisorder Studies in Adults

The incidences of EPS-related adverse events in theadolescent schizophrenia studies showed a similar dose-related pattern to thosein the adult studies. There were notably higher incidences of dystonia,hyperkinesia, tremor, and parkinsonism in the adolescent population as comparedto the adult studies (Table 10).

Table 10: Treatment-Emergent Extrapyramidal Symptoms(EPS)-Related Adverse Events by MedDRA Preferred Term – Schizophrenia Studiesin Adolescent Subjects

Dystonia

Class Effect

Symptoms of dystonia, prolonged abnormal contractions ofmuscle groups, may occur in susceptible individuals during the first few daysof treatment. Dystonic symptoms include: spasm of the neck muscles, sometimesprogressing to tightness of the throat, swallowing difficulty, difficultybreathing, and/or protrusion of the tongue. While these symptoms can occur atlow doses, they occur more frequently and with greater severity with highpotency and at higher doses of first generation antipsychotic drugs. Anelevated risk of acute dystonia is observed in males and younger age groups.

Laboratory Test Abnormalities

In the pooled data from the three placebo-controlled,6-week, fixed-dose studies in adult subjects with schizophrenia and from thetwo placebo-controlled, 6-week studies in adult subjects with schizoaffectivedisorder, between-group comparisons revealed no medically important differencesbetween INVEGA® and placebo in the proportions of subjects experiencingpotentially clinically significant changes in routine serum chemistry,hematology, or urinalysis parameters. Similarly, there were no differencesbetween INVEGA® and placebo in the incidence of discontinuations due to changesin hematology, urinalysis, or serum chemistry, including mean changes frombaseline in fasting glucose, insulin, c-peptide, triglyceride, HDL, LDL, andtotal cholesterol measurements. However, INVEGA® was associated with increasesin serum prolactin [see WARNINGS AND PRECAUTIONS].

Other Adverse Reactions Observed During Premarketing Evaluation Of INVEGA®

The following additional adverse reactions occurred in< 2% of INVEGA®-treated subjects in the above schizophrenia andschizoaffective disorder clinical trial datasets. The following also includesadditional adverse reactions reported at any frequency by INVEGA®-treatedsubjects who participated in other clinical studies.

Cardiac disorders: bradycardia, palpitations

Eye disorders: eye movement disorder

Gastrointestinal disorders: flatulence

General disorders: edema

Immune system disorders: anaphylactic reaction

Infections and infestations: urinary tract infection

Investigations: alanine aminotransferaseincreased, aspartate aminotransferase increased

Musculoskeletal and connective tissue disorders: arthralgia,pain in extremity

Nervous system disorders: opisthotonus

Psychiatric disorders: agitation, insomnia,nightmare

Reproductive system and breast disorders: breastdiscomfort, menstruation irregular, retrograde ejacul*tion

Respiratory, thoracic and mediastinal disorders: nasalcongestion

Skin and subcutaneous tissue disorders: pruritus, rash

Vascular disorders: hypertension

The safety of INVEGA® was also evaluated in a long-termtrial designed to assess the maintenance of effect with INVEGA® in adults withschizophrenia [see Clinical Studies]. In general, adverse reactiontypes, frequencies, and severities during the initial 14-week open-label phaseof this study were comparable to those observed in the 6-week,placebo-controlled, fixed-dose studies. Adverse reactions reported during thelong-term double-blind phase of this study were similar in type and severity tothose observed in the initial 14-week open-label phase.

Postmarketing Experience

The following adverse reactions have been identifiedduring postapproval use of INVEGA®; because these reactions were reportedvoluntarily from a population of uncertain size, it is not possible to reliablyestimate their frequency: angioedema, ileus, priapism, swollen tongue, tardivedyskinesia, urinary incontinence, urinary retention.

Adverse Reactions Reported With Risperidone

Paliperidone is the major active metabolite ofrisperidone. Adverse reactions reported with risperidone can be found in theADVERSE REACTIONS section of the risperidone package insert.

Drug Interactions for Invega

Potential For INVEGA® To Affect Other Drugs

Given the primary CNS effects of paliperidone [see ADVERSEREACTIONS], INVEGA® should be used with caution in combination with othercentrally acting drugs and alcohol. Paliperidone may antagonize the effect oflevodopa and other dopamine agonists.

Because of its potential for inducing orthostatichypotension, an additive effect may be observed when INVEGA® is administeredwith other therapeutic agents that have this potential [see WARNINGS ANDPRECAUTIONS].

Paliperidone is not expected to cause clinicallyimportant pharmaco*kinetic interactions with drugs that are metabolized bycytochrome P450 isozymes. In vitro studies in human liver microsomes showedthat paliperidone does not substantially inhibit the metabolism of drugsmetabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10,CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected toinhibit clearance of drugs that are metabolized by these metabolic pathways ina clinically relevant manner. Paliperidone is also not expected to have enzymeinducing properties.

Paliperidone is a weak inhibitor of P-glycoprotein (P-gp)at high concentrations. No in vivo data are available and the clinicalrelevance is unknown.

Pharmaco*kinetic interaction between lithium and INVEGA® isunlikely.

In a drug interaction study, co-administration of INVEGA®(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 pharmaco*kinetics(AUC24h and Cmax,ss) of valproate in 13 patients stabilized on valproate. In aclinical study, subjects on stable doses of valproate had comparable valproateaverage plasma concentrations when INVEGA® 3-15 mg/day was added to theirexisting valproate treatment.

Potential For Other Drugs To Affect INVEGA®

Paliperidone is not a substrate of CYP1A2, CYP2A6,CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers ofthese isozymes is unlikely. While in vitro studies indicate that CYP2D6 andCYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies donot show decreased elimination by these isozymes and they contribute to only asmall fraction of total body clearance. In vitro studies have shown thatpaliperidone is a P-gp substrate.

Co-administration of INVEGA® 6 mg once daily with carbamazepine,a strong inducer of both CYP3A4 and P-glycoprotein (P-gp), at 200 mg twicedaily caused a decrease of approximately 37% in the mean steady-state Cmax andAUC 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 ofdrug excreted unchanged in the urine suggests that there was little effect onthe CYP metabolism or bioavailability of paliperidone during carbamazepineco-administration. On initiation of carbamazepine, the dose of INVEGA® shouldbe re-evaluated and increased if necessary. Conversely, on discontinuation ofcarbamazepine, the dose of INVEGA® should be re-evaluated and decreased ifnecessary.

Paliperidone is metabolized to a limited extent by CYP2D6[see CLINICAL PHARMACOLOGY]. In an interaction study in healthy subjectsin which a single 3 mg dose of INVEGA® was administered concomitantly with 20mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposureswere on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers.Higher doses of paroxetine have not been studied. The clinical relevance isunknown.

Co-administration of a single dose of INVEGA® 12 mg withdivalproex sodium extended-release tablets (two 500 mg tablets once daily)resulted in an increase of approximately 50% in the Cmax and AUC ofpaliperidone. Dosage reduction for INVEGA® should be considered when INVEGA® isco-administered with valproate after clinical assessment.

Pharmaco*kinetic interaction between lithium and INVEGA® isunlikely.

Drug Abuse And Dependence

Controlled Substance

INVEGA® (paliperidone) is not a controlled substance.

Abuse

Paliperidone has not been systematically studied inanimals or humans for its potential for abuse. It is not possible to predictthe extent to which a CNS-active drug will be misused, diverted, and/or abusedonce marketed. Consequently, patients should be evaluated carefully for ahistory of drug abuse, and such patients should be observed closely for signsof INVEGA® misuse or abuse (e.g., development of tolerance, increases in dose,drug-seeking behavior).

Dependence

Paliperidone has not been systematically studied inanimals or humans for its potential for tolerance or physical dependence.

Warnings for Invega

Included as part of the PRECAUTIONS section.

Precautions for Invega

Increased Mortality In Elderly Patients With Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treatedwith antipsychotic drugs are at an increased risk of death. INVEGA® (paliperidone)is not approved for the treatment of dementia-related psychosis [see BOXEDWARNING].

Cerebrovascular Adverse Reactions, Including Stroke, In Elderly Patients With Dementia-Related Psychosis

In placebo-controlled trials with risperidone,aripiprazole, and olanzapine in elderly subjects with dementia, there was ahigher incidence of cerebrovascular adverse reactions (cerebrovascularaccidents and transient ischemic attacks) including fatalities compared toplacebo-treated subjects. INVEGA® was not marketed at the time these studieswere performed. INVEGA® is not approved for the treatment of patients withdementia-related psychosis [see also BOXED WARNING and Increased Mortality in Elderly Patients with Dementia-Related Psychosis].

Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred toas Neuroleptic Malignant Syndrome (NMS) has been reported in association withantipsychotic drugs, including paliperidone. Clinical manifestations of NMS arehyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomicinstability (irregular pulse or blood pressure, tachycardia, diaphoresis, andcardiac dysrhythmia). Additional signs may include elevated creatinephosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndromeis complicated. In arriving at a diagnosis, it is important to identify casesin which the clinical presentation includes both serious medical illness (e.g.,pneumonia, systemic infection, etc.) and untreated or inadequately treatedextrapyramidal signs and symptoms (EPS). Other important considerations in thedifferential diagnosis include central anticholinergic toxicity, heat stroke,drug fever, and primary central nervous system pathology.

The management of NMS should include: (1) immediatediscontinuation of antipsychotic drugs and other drugs not essential toconcurrent therapy; (2) intensive symptomatic treatment and medical monitoring;and (3) treatment of any concomitant serious medical problems for whichspecific treatments are available. There is no general agreement about specificpharmacological treatment regimens for uncomplicated NMS.

If a patient appears to require antipsychotic drugtreatment after recovery from NMS, reintroduction of drug therapy should beclosely monitored, since recurrences of NMS have been reported.

QT Prolongation

Paliperidone causes a modest increase in the corrected QT(QTc) interval. The use of paliperidone should be avoided in combination withother drugs that are known to prolong QTc including Class 1A (e.g., quinidine,procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmicmedications, antipsychotic medications (e.g., chlorpromazine, thioridazine),antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class ofmedications known to prolong the QTc interval. Paliperidone should also beavoided in patients with congenital long QT syndrome and in patients with ahistory of cardiac arrhythmias.

Certain circ*mstances may increase the risk of theoccurrence of torsade de pointes and/or sudden death in association with theuse of drugs that prolong the QTc interval, including (1) bradycardia; (2)hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolongthe QTc interval; and (4) presence of congenital prolongation of the QTinterval.

The effects of paliperidone on the QT interval wereevaluated in a double-blind, active-controlled (moxifloxacin 400 mg singledose), multicenter QT study in adults with schizophrenia and schizoaffectivedisorder, and in three placebo-and active-controlled 6-week, fixed-doseefficacy trials in adults with schizophrenia.

In the QT study (n=141), the 8 mg dose ofimmediate-release oral paliperidone (n=50) showed a mean placebo-subtractedincrease from baseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on day 8 at1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8mg dose of paliperidone immediate-release was more than twice the exposureobserved with the maximum recommended 12 mg dose of INVEGA® (Cmax ss = 113ng/mL and 45 ng/mL, respectively, when administered with a standard breakfast).In this same study, a 4 mg dose of the immediate-release oral formulation ofpaliperidone, for which Cmax ss = 35 ng/mL, showed an increasedplacebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hourspost-dose. None of the subjects had a change exceeding 60 msec or a QTcLD exceeding500 msec at any time during this study.

For the three fixed-dose efficacy studies in subjectswith schizophrenia, electrocardiogram (ECG) measurements taken at various timepoints showed only one subject in the INVEGA® 12 mg group had a change exceeding60 msec at one time-point on Day 6 (increase of 62 msec). No subject receivingINVEGA® had a QTcLD exceeding 500 msec at any time in any of these threestudies.

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary,dyskinetic movements may develop in patients treated with antipsychotic drugs.Although the prevalence of the syndrome appears to be highest among theelderly, especially elderly women, it is impossible to predict which patientswill develop the syndrome. Whether antipsychotic drug products differ in theirpotential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and thelikelihood that it will become irreversible appear to increase as the durationof treatment and the total cumulative dose of antipsychotic drugs administeredto the patient increase, but the syndrome can develop after relatively brieftreatment periods at low doses, although this is uncommon.

There is no known treatment for established tardive dyskinesia,although the syndrome may remit, partially or completely, if antipsychotictreatment is withdrawn. Antipsychotic treatment itself may suppress (orpartially suppress) the signs and symptoms of the syndrome and may thus maskthe underlying process. The effect of symptomatic suppression on the long-termcourse of the syndrome is unknown.

Given these considerations, INVEGA® should be prescribedin a manner that is most likely to minimize the occurrence of tardivedyskinesia. Chronic antipsychotic treatment should generally be reserved forpatients who suffer from a chronic illness that is known to respond toantipsychotic drugs. In patients who do require chronic treatment, the smallestdose and the shortest duration of treatment producing a satisfactory clinicalresponse should be sought. The need for continued treatment should bereassessed periodically.

If signs and symptoms of tardive dyskinesia appear in apatient treated with INVEGA®, drug discontinuation should be considered.However, some patients may require treatment with INVEGA® despite the presenceof the syndrome.

Metabolic Changes

Atypical antipsychotic drugs have been associated withmetabolic changes that may increase cardiovascular/cerebrovascular risk. Thesemetabolic changes include hyperglycemia, dyslipidemia, and body weight gain.While all of the drugs in the class have been shown to produce some metabolicchanges, each drug has its own specific risk profile.

Hyperglycemia And Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some casesextreme and associated with ketoacidosis or hyperosmolar coma or death, havebeen reported in patients treated with all atypical antipsychotics. These caseswere, for the most part, seen in post-marketing clinical use and epidemiologicstudies, not in clinical trials, and there have been few reports ofhyperglycemia or diabetes in trial subjects treated with INVEGA®. Assessment ofthe relationship between atypical antipsychotic use and glucose abnormalitiesis complicated by the possibility of an increased background risk of diabetesmellitus in patients with schizophrenia and the increasing incidence ofdiabetes mellitus in the general population. Given these confounders, the relationshipbetween atypical antipsychotic use and hyperglycemia-related adverse events isnot completely understood. However, epidemiological studies suggest anincreased risk of treatment-emergent hyperglycemia-related adverse events inpatients treated with the atypical antipsychotics. Because INVEGA® was notmarketed at the time these studies were performed, it is not known if INVEGA® isassociated with this increased risk.

Patients with an established diagnosis of diabetesmellitus who are started on atypical antipsychotics should be monitoredregularly for worsening of glucose control. Patients with risk factors fordiabetes mellitus (e.g., obesity, family history of diabetes) who are startingtreatment with atypical antipsychotics should undergo fasting blood glucosetesting at the beginning of treatment and periodically during treatment. Anypatient treated with atypical antipsychotics should be monitored for symptomsof hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.Patients who develop symptoms of hyperglycemia during treatment with atypicalantipsychotics should undergo fasting blood glucose testing. In some cases,hyperglycemia has resolved when the atypical antipsychotic was discontinued;however, some patients required continuation of anti-diabetic treatment despitediscontinuation of the suspect drug.

Pooled data from the three placebo-controlled, 6-week,fixed-dose studies in adult subjects with schizophrenia are presented in Table1a.

Table 1a: Change in Fasting Glucose from ThreePlacebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects withSchizophrenia

In the uncontrolled, longer-term open-label extensionstudies, INVEGA® was associated with a mean change in glucose of +3.3 mg/dL atWeek 24 (n=570) and +4.6 mg/dL at Week 52 (n=314).

Data from the placebo-controlled 6-week study inadolescent subjects (12-17 years of age) with schizophrenia are presented inTable 1b.

Table 1b: Change in Fasting Glucose from aPlacebo-Controlled 6-Week Study in Adolescent Subjects (12-17 years of age)with Schizophrenia

Dyslipidemia

Undesirable alterations in lipids have been observed inpatients treated with atypical antipsychotics.

Pooled data from the three placebo-controlled, 6-week,fixed-dose studies in adult subjects with schizophrenia are presented in Table2a.

Table 2a: Change in Fasting Lipids from ThreePlacebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects withSchizophrenia

In the uncontrolled, longer-term open-label extensionstudies, INVEGA® was associated with a mean change in (a) total cholesterol of-1.5 mg/dL at Week 24 (n=573) and -1.5 mg/dL at Week 52 (n=317), (b)triglycerides of -6.4 mg/dL at Week 24 (n=573) and -10.5 mg/dL at Week 52(n=317); (c) LDL of -1.9 mg/dL at Week 24 (n=557) and -2.7 mg/dL at Week 52(n=297); and (d) HDL of +2.2 mg/dL at Week 24 (n=568) and +3.6 mg/dL at Week 52(n=302).

Data from the placebo-controlled 6-week study inadolescent subjects (12-17 years of age) with schizophrenia are presented inTable 2b.

Table 2b: Change in Fasting Lipids from aPlacebo-Controlled 6-Week Study in Adolescent Subjects (12-17 years of age)with Schizophrenia

Weight Gain

Weight gain has been observed with atypical antipsychoticuse. Clinical monitoring of weight is recommended.

Schizophrenia Trials

Data on mean changes in body weight and the proportion ofsubjects meeting a weight gain criterion of ≥ 7% of body weight from thethree placebo-controlled, 6-week, fixed-dose studies in adult subjects arepresented in Table 3a.

Table 3a: Mean Change in Body Weight (kg) and theProportion of Subjects with ≥ 7% Gain in Body Weight from ThreePlacebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia

In the uncontrolled, longer-term open-label extensionstudies, INVEGA® was associated with a mean change in weight of +1.4 kg at Week24 (n=63) and +2.6 kg at Week 52 (n=302).

Weight gain in adolescent subjects with schizophrenia wasassessed in a 6-week, double-blind, placebo-controlled study and an open-labelextension with a median duration of exposure to INVEGA® of 182 days. Data onmean changes in body weight and the proportion of subjects meeting a weightgain criterion of ≥ 7% of body weight [see Clinical Studies] fromthe placebo-controlled 6-week study in adolescent subjects (12-17 years of age)are presented in Table 3b.

Table 3b: Mean Change in Body Weight (kg) and theProportion of Subjects with ≥ 7% Gain in Body Weight from aPlacebo-Controlled 6-Week Study in Adolescent Subjects (12-17 years of age) withSchizophrenia

In the open-label long-term study the proportion of totalsubjects treated with INVEGA® with an increase in body weight of ≥ 7%from baseline was 33%. When treating adolescent patients with INVEGA®, weightgain should be assessed against that expected with normal growth. When takinginto consideration the median duration of exposure to INVEGA® in the open-labelstudy (182 days) along with expected normal growth in this population based onage and gender, an assessment of standardized scores relative to normative dataprovides a more clinically relevant measure of changes in weight. The meanchange from open-label baseline to endpoint in standardized score for weightwas 0.1 (4% above the median for normative data). Based on comparison to thenormative data, these changes are not considered to be clinically significant.

Schizoaffective Disorder Trials

In the pooled data from the two placebo-controlled,6-week studies in adult subjects with schizoaffective disorder, a higherpercentage of INVEGA®-treated subjects (5%) had an increase in body weight of≥ 7% compared with placebo-treated subjects (1%). In the study thatexamined high-and low-dose groups, the increase in body weight of ≥ 7%was 3% in the low-dose group, 7% in the high-dose group, and 1% in the placebogroup.

Hyperprolactinemia

Like other drugs that antagonize dopamine D2 receptors,paliperidone elevates prolactin levels and the elevation persists duringchronic administration. Paliperidone has a prolactin-elevating effect similarto that seen with risperidone, a drug that is associated with higher levels ofprolactin than other antipsychotic drugs.

Hyperprolactinemia, regardless of etiology, may suppresshypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion.This, in turn, may inhibit reproductive function by impairing gonadalsteroidogenesis in both female and male patients. Galactorrhea, amenorrhea,gynecomastia, and impotence have been reported in patients receivingprolactin-elevating compounds. Long-standing hyperprolactinemia when associatedwith hypogonadism may lead to decreased bone density in both female and malesubjects.

Tissue culture experiments indicate that approximatelyone-third of human breast cancers are prolactin dependent in vitro, a factor ofpotential importance if the prescription of these drugs is considered in apatient with previously detected breast cancer. An increase in the incidence ofpituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammaryadenocarcinomas, pituitary and pancreatic adenomas) was observed in therisperidone carcinogenicity studies conducted in mice and rats [see NonclinicalToxicology]. Neither clinical studies nor epidemiologic studies conductedto date have shown an association between chronic administration of this classof drugs and tumorigenesis in humans, but the available evidence is too limitedto be conclusive.

Potential For Gastrointestinal Obstruction

Because the INVEGA® tablet is non-deformable and does notappreciably change in shape in the gastrointestinal tract, INVEGA® shouldordinarily not be administered to patients with preexisting severegastrointestinal narrowing (pathologic or iatrogenic, for example: esophagealmotility disorders, small bowel inflammatory disease, “short gut” syndrome dueto adhesions or decreased transit time, past history of peritonitis, cysticfibrosis, chronic intestinal pseudo obstruction, or Meckel's diverticulum).There have been rare reports of obstructive symptoms in patients with knownstrictures in association with the ingestion of drugs in non-deformablecontrolled-release formulations. Because of the controlled-release design ofthe tablet, INVEGA® should only be used in patients who are able to swallow thetablet whole [see DOSAGE AND ADMINISTRATION and PATIENT INFORMATION].

A decrease in transit time, e.g., as seen with diarrhea,would be expected to decrease bioavailability and an increase in transit time,e.g., as seen with gastrointestinal neuropathy, diabetic gastroparesis, orother causes, would be expected to increase bioavailability. These changes inbioavailability are more likely when the changes in transit time occur in theupper GI tract.

Orthostatic Hypotension And Syncope

Paliperidone can induce orthostatic hypotension andsyncope in some patients because of its alpha-blocking activity. In pooledresults of the three placebo-controlled, 6-week, fixed-dose trials in subjectswith schizophrenia, syncope was reported in 0.8% (7/850) of subjects treatedwith INVEGA® (3 mg, 6 mg, 9 mg, 12 mg) compared to 0.3% (1/355) of subjectstreated with placebo. INVEGA® should be used with caution in patients withknown cardiovascular disease (e.g., heart failure, history of myocardialinfarction or ischemia, conduction abnormalities), cerebrovascular disease, orconditions that predispose the patient to hypotension (e.g., dehydration,hypovolemia, and treatment with antihypertensive medications). Monitoring oforthostatic vital signs should be considered in patients who are vulnerable tohypotension.

Falls

Somnolence, postural hypotension, motor and sensoryinstability have been reported with the use of antipsychotics, including INVEGA®,which may lead to falls and, consequently, fractures or other fall-relatedinjuries. For patients, particularly the elderly, with diseases, conditions, ormedications that could exacerbate these effects, assess the risk of falls wheninitiating antipsychotic treatment and recurrently for patients on long-termantipsychotic therapy.

Leukopenia, Neutropenia, And Agranulocytosis

Class Effect

In clinical trial and/or postmarketing experience, eventsof leukopenia/neutropenia have been reported temporally related toantipsychotic agents, including INVEGA® . Agranulocytosis has also beenreported.

Possible risk factors for leukopenia/neutropenia includepre-existing low white blood cell count (WBC) and history of drug-inducedleukopenia/neutropenia. Patients with a history of a clinically significant lowWBC or a drug-induced leukopenia/neutropenia should have their complete bloodcount (CBC) monitored frequently during the first few months of therapy anddiscontinuation of INVEGA® should be considered at the first sign of aclinically significant decline in WBC in the absence of other causativefactors.

Patients with clinically significant neutropenia shouldbe carefully monitored for fever or other symptoms or signs of infection andtreated promptly if such symptoms or signs occur. Patients with severeneutropenia (absolute neutrophil count <1000/mm³) should discontinue INVEGA®and have their WBC followed until recovery.

Potential For Cognitive And Motor Impairment

Somnolence was reported in subjects treated with INVEGA® [seeADVERSE REACTIONS]. Antipsychotics, including INVEGA®, have thepotential to impair judgment, thinking, or motor skills. Patients should becautioned about performing activities requiring mental alertness, such asoperating hazardous machinery or operating a motor vehicle, until they arereasonably certain that paliperidone therapy does not adversely affect them.

Seizures

During premarketing clinical trials in subjects withschizophrenia (the three placebo-controlled, 6-week, fixed-dose studies and astudy conducted in elderly schizophrenic subjects), seizures occurred in 0.22%of subjects treated with INVEGA® (3 mg, 6 mg, 9 mg, 12 mg) and 0.25% ofsubjects treated with placebo. Like other antipsychotic drugs, INVEGA® shouldbe used cautiously in patients with a history of seizures or other conditionsthat potentially lower the seizure threshold. Conditions that lower the seizurethreshold may be more prevalent in patients 65 years or older.

Dysphagia

Esophageal dysmotility and aspiration have beenassociated with antipsychotic drug use. Aspiration pneumonia is a common causeof morbidity and mortality in patients with advanced Alzheimer's dementia.INVEGA® and other antipsychotic drugs should be used cautiously in patients atrisk for aspiration pneumonia.

Suicide

The possibility of suicide attempt is inherent inpsychotic illnesses, and close supervision of high-risk patients shouldaccompany drug therapy. Prescriptions for INVEGA® should be written for thesmallest quantity of tablets consistent with good patient management in orderto reduce the risk of overdose.

Priapism

Drugs with alpha-adrenergic blocking effects have beenreported to induce priapism. Priapism has been reported with INVEGA® duringpostmarketing surveillance. Severe priapism may require surgical intervention.

Thrombotic Thrombocytopenic Purpura (TTP)

No cases of TTP were observed during clinical studieswith paliperidone. Although cases of TTP have been reported in association withrisperidone administration, the relationship to risperidone therapy is unknown.

Body Temperature Regulation

Disruption of the body's ability to reduce core bodytemperature has been attributed to antipsychotic agents. Appropriate care isadvised when prescribing INVEGA® to patients who will be experiencingconditions which may contribute to an elevation in core body temperature, e.g.,exercising strenuously, exposure to extreme heat, receiving concomitantmedication with anticholinergic activity, or being subject to dehydration.

Antiemetic Effect

An antiemetic effect was observed in preclinical studieswith paliperidone. This effect, if it occurs in humans, may mask the signs andsymptoms of overdosage with certain drugs or of conditions such as intestinalobstruction, Reye's syndrome, and brain tumor.

Use In Patients With Concomitant Illness

Clinical experience with INVEGA® in patients with certainconcomitant illnesses is limited [see CLINICAL PHARMACOLOGY].

Patients with Parkinson's Disease or Dementia with LewyBodies are reported to have an increased sensitivity to antipsychoticmedication. Manifestations of this increased sensitivity include confusion,obtundation, postural instability with frequent falls, extrapyramidal symptoms,and clinical features consistent with the neuroleptic malignant syndrome.

INVEGA® has not been evaluated or used to any appreciableextent in patients with a recent history of myocardial infarction or unstableheart disease. Patients with these diagnoses were excluded from premarketingclinical trials. Because of the risk of orthostatic hypotension with INVEGA®,caution should be observed in patients with known cardiovascular disease [see Orthostatic Hypotension and Syncope].

Monitoring: Laboratory Tests

No specific laboratory tests are recommended.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Carcinogenicity studies of paliperidone have not beenperformed.

Carcinogenicity studies of risperidone, which isextensively converted to paliperidone in rats, mice, and humans, were conductedin Swiss albino mice and Wistar rats. Risperidone was administered in the dietat daily doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice andfor 25 months to rats. A maximum tolerated dose was not achieved in male mice.There were statistically significant increases in pituitary gland adenomas,endocrine pancreas adenomas, and mammary gland adenocarcinomas. The no-effectdose for these tumors was less than or equal to the maximum recommended humandose of risperidone on a mg/m² basis (see risperidone package insert).An increase in mammary, pituitary, and endocrine pancreas neoplasms has beenfound in rodents after chronic administration of other antipsychotic drugs andis considered to be mediated by prolonged dopamine D2 antagonism andhyperprolactinemia. The relevance of these tumor findings in rodents in termsof human risk is unknown [see WARNINGS AND PRECAUTIONS].

Mutagenesis

No evidence of genotoxic potential for paliperidone wasfound in the Ames reverse mutation test, the mouse lymphoma assay, or the invivo rat micronucleus test.

Impairment Of Fertility

In a study of fertility, the percentage of treated femalerats that became pregnant was not affected at oral doses of paliperidone of upto 2.5 mg/kg/day. However, pre-and post-implantation loss was increased, andthe number of live embryos was slightly decreased, at 2.5 mg/kg, a dose thatalso caused slight maternal toxicity. These parameters were not affected at adose of 0.63 mg/kg, which is half of the maximum recommended human dose on amg/m² basis.

The fertility of male rats was not affected at oral dosesof paliperidone of up to 2.5 mg/kg/day, although sperm count and spermviability studies were not conducted with paliperidone. In a subchronic studyin Beagle dogs with risperidone, which is extensively converted to paliperidonein dogs and humans, all doses tested (0.31 mg/kg -5.0 mg/kg) resulted indecreases in serum testosterone and in sperm motility and concentration. Serumtestosterone and sperm parameters partially recovered, but remained decreasedafter the last observation (two months after treatment was discontinued).

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well controlled studies ofINVEGA® in pregnant women.

Use of first generation antipsychotic drugs during thelast trimester of pregnancy has been associated with extrapyramidal symptoms inthe neonate. These symptoms are usually self- limited. It is not known whetherpaliperidone, when taken near the end of pregnancy, will lead to similarneonatal signs and symptoms.

In animal reproduction studies, there were no increasesin fetal abnormalities when pregnant rats and rabbits were treated during theperiod of organogenesis with up to 8 times the maximum recommended human doseof paliperidone (on a mg/m² basis).

In rat reproduction studies with risperidone, which isextensively converted to paliperidone in rats and humans, there were increasesin pup deaths seen at oral doses which are less than the maximum recommendedhuman dose of risperidone on a mg/m² basis (see risperidone package insert).

Non-teratogenic Effects

Neonates exposed to antipsychotic drugs during the thirdtrimester of pregnancy are at risk for extrapyramidal and/or withdrawalsymptoms following delivery. There have been reports of agitation, hypertonia,hypotonia, tremor, somnolence, respiratory distress, and feeding disorder inthese neonates. These complications have varied in severity; while in somecases symptoms have been self-limited, in other cases neonates have requiredintensive care unit support and prolonged hospitalization.

INVEGA® should be used during pregnancy only if thepotential benefit justifies the potential risk to the fetus.

Nursing Mothers

Paliperidone is excreted in human breast milk. The knownbenefits of breastfeeding should be weighed against the unknown risks of infantexposure to paliperidone.

Pediatric Use

Safety and effectiveness of INVEGA® in the treatment ofschizophrenia were evaluated in 150 adolescent subjects 12-17 years of age withschizophrenia who received INVEGA® in the dose range of 1.5 mg to 12 mg/day ina 6-week, double-blind, placebo-controlled trial.

Safety and effectiveness of INVEGA® for the treatment ofschizophrenia in patients < 12 years of age have not been established.Safety and effectiveness of INVEGA® for the treatment of schizoaffectivedisorder in patients < 18 years of age have not been studied.

In a study in which juvenile rats were treated with oralpaliperidone from days 24 to 73 of age, a reversible impairment of performancein a test of learning and memory was seen, in females only, with a no-effectdose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidonesimilar to those in adolescents. No other consistent effects on neurobehavioralor reproductive development were seen up to the highest dose tested (2.5mg/kg/day), which produced plasma levels of paliperidone 2-3 times those inadolescents.

Juvenile dogs were treated for 40 weeks with oralrisperidone, which is extensively metabolized to paliperidone in animals andhumans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length anddensity were seen with a no-effect dose of 0.31 mg/kg/day, which producedplasma levels (AUC) of risperidone plus paliperidone which were similar tothose in children and adolescents receiving the maximum recommended human doseof risperidone. In addition, a delay in sexual maturation was seen at all dosesin both males and females. The above effects showed little or no reversibilityin females after a 12-week drug-free recovery period.

The long-term effects of INVEGA® on growth and sexualmaturation have not been fully evaluated in children and adolescents.

Geriatric Use

The safety, tolerability, and efficacy of INVEGA® wereevaluated in a 6-week placebo-controlled study of 114 elderly subjects withschizophrenia (65 years of age and older, of whom 21 were 75 years of age andolder). In this study, subjects received flexible doses of INVEGA® (3 mg to 12mg once daily). In addition, a small number of subjects 65 years of age andolder were included in the 6-week placebo-controlled studies in which adultschizophrenic subjects received fixed doses of INVEGA® (3 mg to 15 mg oncedaily) [see Clinical Studies]. There were no subjects ≥ 65 yearsof age in the schizoaffective disorder studies.

Overall, of the total number of subjects in schizophreniaclinical studies of INVEGA® (n=1796), including those who received INVEGA® orplacebo, 125 (7.0%) were 65 years of age and older and 22 (1.2%) were 75 yearsof age and older. No overall differences in safety or effectiveness wereobserved between these subjects and younger subjects, and other reportedclinical experience has not identified differences in response between theelderly and younger patients, but greater sensitivity of some older individualscannot be ruled out.

This drug is known to be substantially excreted by thekidney and clearance is decreased in patients with moderate to severe renalimpairment [see CLINICAL PHARMACOLOGY], who should be given reduceddoses. Because elderly patients are more likely to have decreased renalfunction, care should be taken in dose selection, and it may be useful tomonitor renal function [see DOSAGE AND ADMINISTRATION].

Renal Impairment

Dosing must be individualized according to the patient'srenal function status [see DOSAGE AND ADMINISTRATION].

Hepatic Impairment

No dosage adjustment is required in patients with mild tomoderate hepatic impairment. INVEGA® has not been studied in patients withsevere hepatic impairment.

Overdose Information for Invega

Human Experience

While experience with paliperidone overdose is limited,among the few cases of overdose reported in pre-marketing trials, the highestestimated ingestion of INVEGA® was 405 mg. Observed signs and symptoms includedextrapyramidal symptoms and gait unsteadiness. Other potential signs and symptomsinclude those resulting from an exaggeration of paliperidone's knownpharmacological effects, i.e., drowsiness and somnolence, tachycardia andhypotension, and QT prolongation. Torsade de pointes and ventricularfibrillation have been reported in a patient in the setting of overdose.

Paliperidone is the major active metabolite ofrisperidone. Overdose experience reported with risperidone can be found in theOVERDOSAGE section of the risperidone package insert.

Management Of Overdosage

There is no specific antidote to paliperidone, therefore,appropriate supportive measures should be instituted and close medicalsupervision and monitoring should continue until the patient recovers.Consideration should be given to the extended-release nature of the productwhen assessing treatment needs and recovery. Multiple drug involvement shouldalso be considered.

In case of acute overdose, establish and maintain anairway and ensure adequate oxygenation and ventilation. Gastric lavage (afterintubation if patient is unconscious) and administration of activated charcoaltogether with a laxative should be considered.

The possibility of obtundation, seizures, or dystonicreaction of the head and neck following overdose may create a risk ofaspiration with induced emesis.

Cardiovascular monitoring should commence immediately,including continuous electrocardiographic monitoring for possible arrhythmias.If antiarrhythmic therapy is administered, disopyramide, procainamide, andquinidine carry a theoretical hazard of additive QT-prolonging effects whenadministered in patients with an acute overdose of paliperidone. Similarly thealpha-blocking properties of bretylium might be additive to those ofpaliperidone, resulting in problematic hypotension.

Hypotension and circulatory collapse should be treatedwith appropriate measures, such as intravenous fluids and/or sympathomimeticagents (epinephrine and dopamine should not be used, since beta stimulation mayworsen hypotension in the setting of paliperidone-induced alpha blockade). Incases of severe extrapyramidal symptoms, anticholinergic medication should beadministered.

Contraindications for Invega

INVEGA® is contraindicated in patients with a knownhypersensitivity to either paliperidone or risperidone, or to any of theexcipients in the INVEGA® formulation. Hypersensitivity reactions, includinganaphylactic reactions and angioedema, have been reported in patients treatedwith risperidone and in patients treated with paliperidone. Paliperidone is ametabolite of risperidone.

Clinical Pharmacology for Invega

Mechanism Of Action

Paliperidone is the major active metabolite ofrisperidone. The mechanism of action of paliperidone, as with other drugshaving efficacy in schizophrenia, is unknown, but it has been proposed that thedrug's therapeutic activity in schizophrenia is mediated through a combinationof central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptorantagonism.

Pharmacodynamics

Paliperidone is a centrally active dopamine Type 2 (D2)antagonist and with predominant serotonin Type 2 (5HT2A) activity. Paliperidoneis also active as an antagonist at α1 and α2 adrenergic receptors andH1 histaminergic receptors, which may explain some of the other effects of thedrug. Paliperidone has no affinity for cholinergic muscarinic or β1-andβ2-adrenergic receptors. The pharmacological activity of the (+)-and(-)-paliperidone enantiomers is qualitatively and quantitatively similar invitro.

Pharmaco*kinetics

Following a single dose, the plasma concentrations ofpaliperidone gradually rise to reach peak plasma concentration (Cmax)approximately 24 hours after dosing. The pharmaco*kinetics of paliperidonefollowing INVEGA® administration are dose-proportional within the availabledose range. The terminal elimination half-life of paliperidone is approximately23 hours.

Steady-state concentrations of paliperidone are attainedwithin 4-5 days of dosing with INVEGA® in most subjects. The mean steady-statepeak:trough ratio for an INVEGA® dose of 9 mg was 1.7 with a range of 1.2-3.1.

Following administration of INVEGA®, the (+) and (-)enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio ofapproximately 1.6 at steady state.

Absorption And Distribution

The absolute oral bioavailability of paliperidonefollowing INVEGA® administration is 28%.

Administration of a 12 mg paliperidone extended-releasetablet to healthy ambulatory subjects with a standard high-fat/high-caloricmeal gave mean Cmax and AUC values of paliperidone that were increased by 60%and 54%, respectively, compared with administration under fasting conditions.Clinical trials establishing the safety and efficacy of INVEGA® were carriedout in subjects without regard to the timing of meals. While INVEGA® can betaken without regard to food, the presence of food at the time of INVEGA® administrationmay increase exposure to paliperidone [see DOSAGE AND ADMINISTRATION].

Based on a population analysis, the apparent volume ofdistribution of paliperidone is 487 L. The plasma protein binding of racemicpaliperidone is 74%.

Metabolism And Elimination

Although in vitro studies suggested a role for CYP2D6 andCYP3A4 in the metabolism of paliperidone, in vivo results indicate that theseisozymes play a limited role in the overall elimination of paliperidone [seeDRUG INTERACTIONS].

One week following administration of a single oral doseof 1 mg immediate-release ¹⁴C-paliperidone to 5 healthy volunteers,59% (range 51% -67%) of the dose was excreted unchanged into urine, 32% (26%-41%) of the dose was recovered as metabolites, and 6% -12% of the dose was notrecovered. Approximately 80% of the administered radioactivity was recovered inurine and 11% in the feces. Four primary metabolic pathways have beenidentified in vivo, none of which could be shown to account for more than 10%of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazolescission.

Population pharmaco*kinetic analyses found no differencein exposure or clearance of paliperidone between extensive metabolizers andpoor metabolizers of CYP2D6 substrates.

Special Populations

Renal Impairment

The dose of INVEGA® should be reduced in patients withmoderate or severe renal impairment [see DOSAGE AND ADMINISTRATION]. Thedisposition of a single dose paliperidone 3 mg extended-release tablet wasstudied in adult subjects with varying degrees of renal function. Eliminationof paliperidone decreased with decreasing estimated creatinine clearance. Totalclearance of paliperidone was reduced in subjects with impaired renal functionby 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 inexposure (AUCinf) of 1.5 fold, 2.6 fold, and 4.8 fold, respectively, comparedto healthy subjects. The mean terminal elimination half-life of paliperidonewas 24 hours, 40 hours, and 51 hours in subjects with mild, moderate, andsevere renal impairment, respectively, compared with 23 hours in subjects withnormal renal function (CrCl ≥ 80 mL/min).

Hepatic Impairment

In a study in adult subjects with moderate hepaticimpairment (Child-Pugh class B), the plasma concentrations of free paliperidonewere similar to those of healthy subjects, although total paliperidone exposuredecreased because of a decrease in protein binding. Consequently, no doseadjustment is required in patients with mild or moderate hepatic impairment.INVEGA® has not been studied in patients with severe hepatic impairment.

Adolescents (12-17 Years Of Age)

Paliperidone systemic exposure in adolescents weighing≥ 51 kg (≥ 112 lbs) was similar to that in adults. In adolescentsweighing < 51 kg (< 112 lbs), a 23% higher exposure was observed; this isconsidered not to be clinically significant. Age did not influence thepaliperidone exposure.

Elderly

No dosage adjustment is recommended based on age alone.However, dose adjustment may be required because of age-related decreases increatinine clearance [see Renal Impairment above and DOSAGE AND ADMINISTRATION].

Race

No dosage adjustment is recommended based on race. Nodifferences in pharmaco*kinetics were observed in a pharmaco*kinetic studyconducted in Japanese and Caucasians.

Gender

No dosage adjustment is recommended based on gender. Nodifferences in pharmaco*kinetics were observed in a pharmaco*kinetic studyconducted in men and women.

Smoking

No dosage adjustment is recommended based on smokingstatus. Based on in vitro studies utilizing human liver enzymes, paliperidoneis not a substrate for CYP1A2; smoking should, therefore, not have an effect onthe pharmaco*kinetics of paliperidone.

Clinical Studies

Schizophrenia

Adults

The acute efficacy of INVEGA® (3 mg to 15 mg once daily)was established in three placebo-controlled and active-controlled (olanzapine),6-week, fixed-dose trials in non-elderly adult subjects (mean age of 37) whomet DSM-IV criteria for schizophrenia. Studies were carried out in NorthAmerica, Eastern Europe, Western Europe, and Asia. The doses studied amongthese three trials included 3 mg/day, 6 mg/day, 9 mg/day, 12 mg/day, and 15mg/day. Dosing was in the morning without regard to meals.

Efficacy was evaluated using the Positive and NegativeSyndrome Scale (PANSS), a validated multi-item inventory composed of fivefactors to evaluate positive symptoms, negative symptoms, disorganizedthoughts, uncontrolled hostility/excitement, and anxiety/depression. Efficacywas also evaluated using the Personal and Social Performance (PSP) scale. ThePSP is a validated clinician-rated scale that measures personal and socialfunctioning in the domains of socially useful activities (e.g., work andstudy), personal and social relationships, self-care, and disturbing andaggressive behaviors.

In all 3 studies (n=1665), INVEGA® was superior toplacebo on the PANSS at all doses. Mean effects at all doses were fairlysimilar, although the higher doses in all studies were numerically superior.INVEGA® was also superior to placebo on the PSP in these trials.

An examination of population subgroups did not reveal anyevidence of differential responsiveness on the basis of gender, age (there werefew patients over 65), or geographic region. There were insufficient data toexplore differential effects based on race.

In a longer-term trial, adult outpatients meeting DSM-IVcriteria for schizophrenia who had clinically responded (defined as PANSS score≤ 70 or ≤ 4 on pre-defined PANSS subscales, as well as having beenon a stable fixed dose of INVEGA® for the last two weeks of an 8-week run-inphase) were entered into a 6-week open-label stabilization phase where theyreceived INVEGA® (doses ranging from 3 mg to 15 mg once daily). After thestabilization phase, patients were randomized in a double-blind manner toeither continue on INVEGA® at their achieved stable dose, or to placebo, untilthey experienced a relapse of schizophrenia symptoms. Relapse was pre-definedas significant increase in PANSS (or pre-defined PANSS subscales),hospitalization, clinically significant suicidal or homicidal ideation, ordeliberate injury to self or others. An interim analysis of the data showed asignificantly longer time to relapse in patients treated with INVEGA® comparedto placebo, and the trial was stopped early because maintenance of efficacy wasdemonstrated.

Adolescents

The efficacy of INVEGA® in adolescent subjects withschizophrenia was established in a randomized, double-blind, parallel-group,placebo-controlled, 6-week study using a fixed-dose weight-based treatmentgroup design over the dose range of 1.5 to 12 mg/day. The study was carried outin the US, India, Romania, Russia, and Ukraine, and involved subjects 12-17years of age meeting DSM-IV criteria for schizophrenia, with diagnosisconfirmation using the Kiddie Schedule for Affective Disorders andSchizophrenia-Present and Lifetime Version (K-SADSPL).

Eligible subjects were randomly assigned to 1 of 4treatment groups: a placebo group or INVEGA® Low, Medium, or High dose groups.Doses were administered based on body weight to minimize the risk of exposinglower-weight adolescents to high doses of INVEGA®. Subjects weighing between 29kg and less than 51 kg at the baseline visit were randomly assigned to receiveplacebo or 1.5 mg (Low dose), 3 mg (Medium dose), or 6 mg (High dose) of INVEGA®daily, and subjects weighing at least 51 kg at the baseline visit were randomlyassigned to receive placebo or 1.5 mg (Low dose), 6 mg (Medium dose), or 12 mg(High dose) of INVEGA® daily. Dosing was in the morning without regard tomeals.

Efficacy was evaluated using PANSS. Overall, this studydemonstrated the efficacy of INVEGA® in adolescents with schizophrenia in thedose range of 3 to 12 mg/day. Doses within this broad range were shown to beeffective, however, there was no clear enhancement to efficacy at the higherdoses, i.e., 6 mg for subjects weighing less than 51 kg and 12 mg for subjectsweighing 51 kg or greater. Although paliperidone was adequately toleratedwithin the dose range of 3 to 12 mg/day, adverse events were dose related.

Schizoaffective Disorder

Adults

The acute efficacy of INVEGA® (3 mg to 12 mg once daily)in the treatment of schizoaffective disorder was established in twoplacebo-controlled, 6-week trials in non-elderly adult subjects. Enrolledsubjects 1) met DSM-IV criteria for schizoaffective disorder, as confirmed bythe Structured Clinical Interview for DSM-IV Disorders, 2) had a Positive andNegative Syndrome Scale (PANSS) total score of at least 60, and 3) hadprominent mood symptoms as confirmed by a score of at least 16 on the YoungMania Rating Scale and/or Hamilton Rating Scale for Depression. The populationincluded subjects with schizoaffective bipolar and depressive types. In one ofthese trials, efficacy was assessed in 211 subjects who received flexible dosesof INVEGA® (3-12 mg once daily). In the other study, efficacy was assessed in203 subjects who were assigned to one of two dose levels of INVEGA®: 6 mg withthe option to reduce to 3 mg (n=105) or 12 mg with the option to reduce to 9 mg(n=98) once daily. Both studies included subjects who received INVEGA® eitheras monotherapy [no mood stabilizers and/or antidepressants (55%)] or as anadjunct to mood stabilizers and/or antidepressants (45%). The most commonly usedmood stabilizers were valproate and lithium. The most commonly usedantidepressants were SSRIs and SNRIs. INVEGA® was dosed in the morning withoutregard to meals. Studies were carried out in the United States, Eastern Europe,Russia, and Asia.

Efficacy was evaluated using the PANSS, a validatedmulti-item inventory composed of five factors to evaluate positive symptoms,negative symptoms, disorganized thoughts, uncontrolled hostility/excitement,and anxiety/depression. As secondary outcomes, mood symptoms were evaluatedusing the Hamilton Depression Rating Scale (HAM-D-21) and the Young ManiaRating Scale (YMRS).

The INVEGA® group in the flexible-dose study (dosedbetween 3 and 12 mg/day, mean modal dose of 8.6 mg/day) and the higher dosegroup of INVEGA® in the 2 dose-level study (12 mg/day with option to reduce to9 mg/day) were each superior to placebo in the PANSS. Numerical improvements inmood symptoms were also observed, as measured by the HAM-D21 and YMRS. In thelower dose group of the 2 dose-level study (6 mg/day with option to reduce to 3mg/day), INVEGA® was not significantly different from placebo as measured bythe PANSS.

Taking the results of both studies together, INVEGA® improvedthe symptoms of schizoaffective disorder at endpoint relative to placebo whenadministered either as monotherapy or as an adjunct to mood stabilizers and/orantidepressants. An examination of population subgroups did not reveal anyevidence of differential responsiveness on the basis of gender, age, orgeographic region. There were insufficient data to explore differential effectsbased on race.

Patient Information for Invega

Physicians are advised to discuss the following issueswith patients for whom they prescribe INVEGA® .

Orthostatic Hypotension

Patients should be advised that there is risk oforthostatic hypotension, particularly at the time of initiating treatment,re-initiating treatment, or increasing the dose [see WARNINGS ANDPRECAUTIONS].

Interference With Cognitive And Motor Performance

As INVEGA® has the potential to impair judgment,thinking, or motor skills, patients should be cautioned about operatinghazardous machinery, including automobiles, until they are reasonably certain thatINVEGA® therapy does not affect them adversely [see WARNINGS AND PRECAUTIONS].

Pregnancy

Patients should be advised to notify their physician ifthey become pregnant or intend to become pregnant during treatment with INVEGA®[see Use In Specific Populations].

Nursing

Caution should be exercised when INVEGA® is administeredto a nursing woman. The known benefits of breastfeeding should be weighedagainst the unknown risks of infant exposure to paliperidone. [See Use In SpecificPopulations].

Concomitant Medication

Patients should be advised to inform their physicians ifthey are taking, or plan to take, any prescription or over-the-counter drugs,as there is a potential for interactions [see DRUG INTERACTIONS].

Alcohol

Patients should be advised to avoid alcohol while takingINVEGA® [see DRUG INTERACTIONS].

Heat Exposure And Dehydration

Patients should be advised regarding appropriate care inavoiding overheating and dehydration [see WARNINGS AND PRECAUTIONS].

Administration

Patients should be informed that INVEGA® should beswallowed whole with the aid of liquids. Tablets should not be chewed, divided,or crushed. The medication is contained within a nonabsorbable shell designedto release the drug at a controlled rate. The tablet shell, along withinsoluble core components, is eliminated from the body; patients should not beconcerned if they occasionally notice something that looks like a tablet in theirstool [see DOSAGE AND ADMINISTRATION].