Invega Sustenna 78 MG per 0.5 ML Extended Release Injectable Suspension in a Prefilled Syringe

Generic Name: PALIPERIDONE PALMITATE
Brand Name: INVEGA SUSTENNA
  • Substance Name(s):
  • PALIPERIDONE PALMITATE

DRUG INTERACTIONS

7 Drugs that may cause orthostatic hypotension: An additive effect may occur when co-administered with INVEGA SUSTENNA®.

(7.1) Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John’s Wort) during a dosing interval for INVEGA SUSTENNA®.

If administering a strong inducer is necessary, consider managing the patient using paliperidone extended release tablets.

(2.5, 7.1, 12.3) 7.1 Drugs Having Clinically Important Interactions with INVEGA SUSTENNA® Because paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3)], results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential.

Table 13: Clinically Important Drug Interactions with INVEGA SUSTENNA® Drugs with Potential for Inducing Orthostatic Hypotension Clinical Impact Because INVEGA SUSTENNA® has the potential for inducing orthostatic hypotension, an additive effect may occur when INVEGA SUSTENNA® is administered with other therapeutic agents that have this potential [see Warning and Precautions (5.7)] Intervention Monitor orthostatic vital signs in patients who are vulnerable to hypotension [see Warnings and Precautions (5.7)] Examples Nitrates Antihypertensive medicines: thiazide diuretics (e.g.

hydrochlorothiazide); beta blockers (e.g.

acebutolol); angiotensin-converting enzyme (ACE) inhibitors (e.g.

lisinopril); angiotensin II receptor blockers (ARBs) (e.g.

candesartan); calcium channel blockers (e.g.

amlodipine); alpha-blockers (e.g.

prazosin), alpha-agonists (e.g.

clonidine), other diuretics (e.g.

loop, K-sparing), vasodilators (e.g.

hydralazine) Strong Inducers of CYP3A4 and P-gp Clinical Impact The concomitant use of paliperidone and strong inducers of CYP3A4 and P-gp may decrease the exposure of paliperidone [see Clinical Pharmacology (12.3)] Intervention Avoid using CYP3A4 and/or P-gp inducers with INVEGA SUSTENNA® during the 1-month dosing interval, if possible.

If administering a strong inducer is necessary, consider managing the patient using paliperidone extended release tablets [see Dosage and Administration (2.5)] Examples Carbamazepine, rifampin, St John’s Wort Dopamine Agonist Clinical Impact Paliperidone may antagonize the effect of levodopa and other dopamine agonist Intervention Monitor and manage patient as clinically appropriate Examples Levodopa, bromocriptine, ropinirole and pramipexole 7.2 Drugs Having No Clinically Important Interactions with INVEGA SUSTENNA® Clinically meaningful pharmacokinetic interaction between INVEGA SUSTENNA® and valproate (including valproic acid and divalproex sodium) is not expected.

Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of INVEGA SUSTENNA® is required when administered with valproate [see Clinical Pharmacology (12.3)].

Additionally, no dosage adjustment is necessary for valproate when co-administered with INVEGA SUSTENNA® [See Clinical Pharmacology (12.3)].

Pharmacokinetic interaction between lithium and INVEGA SUSTENNA® is also unlikely.

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes.

In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism; however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone.

Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or inducers of these isozymes is unlikely.

[see Clinical Pharmacology (12.3)]

OVERDOSAGE

10 10.1 Human Experience No cases of overdose were reported in premarketing studies with INVEGA SUSTENNA®.

Because INVEGA SUSTENNA® is to be administered by healthcare professionals, the potential for overdosage by patients is low.

While experience with paliperidone overdose is limited, among the few cases of overdose reported in premarketing trials with oral paliperidone, the highest estimated ingestion was 405 mg.

Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness.

Other potential signs and symptoms include those resulting from an exaggeration of paliperidone’s known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and QT prolongation.

Torsades de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose with oral paliperidone.

Paliperidone is the major active metabolite of risperidone.

Overdose experience reported with risperidone can be found in the section of the risperidone package insert.

10.2 Management of Overdosage Contact a Certified Poison Control Center for the most up to date information on the management of INVEGA SUSTENNA® overdosage (1-800-222-1222 or www.poison.org).

Provide supportive care, including close medical supervision and monitoring.

Treatment should consist of general measures employed in the management of overdosage with any drug.

Consider the possibility of multiple drug overdosage.

Ensure an adequate airway, oxygenation, and ventilation.

Monitor cardiac rhythm and vital signs.

Use supportive and symptomatic measures.

There is no specific antidote to paliperidone.

Consider the prolonged-release characteristics of INVEGA SUSTENNA® and the long apparent half-life of paliperidone when assessing treatment needs and recovery.

DESCRIPTION

11 INVEGA SUSTENNA® contains paliperidone palmitate.

The active ingredient, paliperidone, is an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives.

INVEGA SUSTENNA® contains a racemic mixture of (+)- and (-)- paliperidone palmitate.

The chemical name is (9RS)-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimadin-9-yl hexadecanoate.

Its molecular formula is C39H57FN4O4 and its molecular weight is 664.89.

The structural formula is: Paliperidone palmitate is very slightly soluble in ethanol and methanol, practically insoluble in polyethylene glycol 400 and propylene glycol, and slightly soluble in ethyl acetate.

INVEGA SUSTENNA® is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in the following dose strengths of paliperidone palmitate (and deliverable volumes of the prefilled syringes): 39 mg (0.25 mL), 78 mg (0.5 mL), 117 mg (0.75 mL), 156 mg (1.0 mL), and 234 mg (1.5 mL).

The drug product hydrolyzes to the active moiety, paliperidone, resulting in dose strengths of 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg of paliperidone, respectively.

The inactive ingredients are polysorbate 20 (12 mg/mL), polyethylene glycol 4000 (30 mg/mL), citric acid monohydrate (5 mg/mL), disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, and water for injection.

INVEGA SUSTENNA® is provided in a prefilled syringe (cyclic-olefin-copolymer) with a plunger stopper and tip cap (bromobutyl rubber).

The kit also contains 2 safety needles (a 1 ½-inch 22 gauge safety needle and a 1-inch 23 gauge safety needle).

Chemical Structure

CLINICAL STUDIES

14 14.1 Schizophrenia 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 14.

Table 14: Schizophrenia Short-term Studies Study Number Treatment Group Primary Efficacy Measure: PANSS Total Score Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted DifferenceDifference (drug minus placebo) in least-squares mean change from baseline.

(95% CI) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

Study 1 INVEGA SUSTENNA® (39 mg/4 weeks)p<0.05 (Doses statistically significantly superior to placebo).

86.9 (11.99) -11.2 (1.69) -5.1 (-9.01, -1.10) INVEGA SUSTENNA® (156 mg/4 weeks) 86.2 (10.77) -14.8 (1.68) -8.7 (-12.62, -4.78) INVEGA SUSTENNA® (234 mg/4 weeks) 88.4 (11.70) -15.9 (1.70) -9.8 (-13.71, -5.85) Placebo 86.8 (10.31) -6.1 (1.69) — Study 2 Because an insufficient number of subjects received the 234 mg/4 weeks dose, results from this group are not included.

INVEGA SUSTENNA® (78 mg/4 weeks) 89.9 (10.78) -6.9 (2.50) -3.5 (-8.73, 1.77) INVEGA SUSTENNA® (156 mg/4 weeks) 90.1 (11.66) -10.4 (2.47) -6.9 (-12.12, -1.68) Placebo 92.4 (12.55) -3.5 (2.15) — Study 3 INVEGA SUSTENNA® (39 mg/4 weeks) 90.7 (12.25) -19.8 (2.19) -6.6 (-11.40, -1.73) INVEGA SUSTENNA® (78 mg/4 weeks) 91.2 (12.02) -19.2 (2.19) -5.9 (-10.76, -1.07) INVEGA SUSTENNA® (156 mg/4 weeks) 90.8 (11.70) -22.5 (2.18) -9.2 (-14.07, -4.43) Placebo 90.7 (12.22) -13.3 (2.21) — Study 4 INVEGA SUSTENNA® (78 mg/4 weeks) 88.0 (12.39) -4.6 (2.43) -11.2 (-16.85, -5.57) INVEGA SUSTENNA® (156 mg/4 weeks) 85.2 (11.09) -7.4 (2.45) -14.0 (-19.51, -8.58) Placebo 87.8 (13.90) 6.6 (2.45) — 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 3.

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 3: Kaplan-Meier Plot of Cumulative Proportion of Subjects with Relapse Over Time (Schizophrenia Study 5) Figure 3 Long-Term Comparative Monotherapy Treatment versus Oral Antipsychotic Therapy (Study 6: SCH-3006) The efficacy of INVEGA SUSTENNA® in delaying time to treatment failure compared with selected oral antipsychotic medications was established in a long-term, randomized, flexible-dose study in subjects with schizophrenia and a history of incarceration.

Subjects were screened for up to 14 days followed by a 15-month treatment phase during which they were observed for treatment failure.

The primary endpoint was time to first treatment failure.

Treatment failure was defined as one of the following: arrest and/or incarceration; psychiatric hospitalization; discontinuation of antipsychotic treatment because of safety or tolerability; treatment supplementation with another antipsychotic because of inadequate efficacy; need for increase in level of psychiatric services to prevent an imminent psychiatric hospitalization; discontinuation of antipsychotic treatment because of inadequate efficacy; or suicide.

Treatment failure was determined by an Event Monitoring Board (EMB) that was blinded to treatment assignment.

A total of 444 subjects were randomly assigned to either INVEGA SUSTENNA® (N = 226; median dose 156 mg) or one of up to seven pre-specified, flexibly-dosed, commonly prescribed oral antipsychotic medications (N = 218; aripiprazole, haloperidol, olanzapine, paliperidone, perphenazine, quetiapine, or risperidone).

The selection of the oral antipsychotic medication was determined to be appropriate for the patient by the investigator.

A statistically significantly longer time to first treatment failure was seen for INVEGA SUSTENNA® compared with oral antipsychotic medications.

The median time to treatment failure was 416 days and 226 days for INVEGA SUSTENNA® and antipsychotic medications, respectively.

A Kaplan-Meier plot of time to first treatment failure is shown in Figure 4.

The frequencies of first treatment failure events by type are shown in Table 15.

The time to first arrest and/or incarceration or psychiatric hospitalization was also statistically significantly longer for the INVEGA SUSTENNA® group compared to the oral antipsychotic group.

Figure 4: Kaplan-Meier Plot of Time to First Treatment Failure in a Long-Term, Randomized, Flexible-Dose Study in Subjects with Schizophrenia and a History of Incarceration (Schizophrenia Study 6) * Median time to first treatment failure: 416 days with INVEGA SUSTENNA®; 226 days with oral antipsychotics Table 15: Components of Composite Endpoint in a Long-Term, Randomized, Flexible-Dose Study in Subjects with Schizophrenia and a History of Incarceration (Schizophrenia Study 6) Event Type INVEGA SUSTENNA® N=226 frequency (%) Oral Antipsychotics N=218 frequency (%) Hazard RatioHazard ratio of INVEGA SUSTENNA® to Oral Antipsychotics based on Cox regression model for time-to-event analysis.

Note that the hazard ratio did not appear constant throughout the trial.

[95% CI] First Treatment Failures 90 (39.8%) 117 (53.7%) 0.70 [0.53, 0.92] First Treatment Failure Component Events Arrest and/or incarceration 48 (21.2%) 64 (29.4%) Psychiatric hospitalization 18 (8.0%) 26 (11.9%) Discontinuation of antipsychotic treatment because of safety or tolerability 15 (6.6%) 8 (3.7%) Treatment supplementation with another antipsychotic because of inadequate efficacy 5 (2.2%) 6 (2.8%) Need for increase in level of psychiatric services to prevent an imminent psychiatric hospitalization 3 (1.3%) 4 (1.8%) Discontinuation of antipsychotic treatment because of inadequate efficacy 1 (0.4%) 9 (4.1%) Suicide 0 0 Arrest and/or Incarceration or Psychiatric Hospitalization Events, regardless of whether they were first events Analysis results, which incorporated relevant events collected after discontinuation for those who discontinued, were consistent with the results from the pre-specified analysis of this secondary endpoint.

76 (33.6%) 98 (45.0%) 0.70 [0.52, 0.94] Figure 4 14.2 Schizoaffective Disorder 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 DSM-IV 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-S-SCA 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 5.

Figure 5: Kaplan-Meier Plot of Cumulative Proportion of Subjects with Relapse Over Time (SAff Study 1) Table 16 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 16: Summary of Relapse Rates (SAff Study 1).

Number (Percent) of Subjects Who Relapsed Placebo N=170 INVEGA SUSTENNA® N=164 All Subjects 57 (33.5%) 25 (15.2%) Monotherapy subset N=73 24 (32.9%) N=78 9 (11.5%) Adjunct to Antidepressants or Mood Stabilizer subset N=97 33 (34.0%) N=86 16 (18.6%) Psychotic Symptoms 8 subjects experienced a relapse without psychotic symptoms.

53 (31.2%) 21 (12.8%) Mood Symptoms 16 subjects experienced a relapse without any mood symptoms.

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%) Figure 4

HOW SUPPLIED

16 /STORAGE AND HANDLING INVEGA SUSTENNA® is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in dose strengths of 39 mg, 78 mg, 117 mg, 156 mg, and 234 mg paliperidone palmitate.

The kit contains a prefilled syringe and 2 safety needles (a 1 ½-inch 22 gauge safety needle and a 1-inch 23 gauge safety needle).

39 mg paliperidone palmitate kit (NDC 50458-560-01) 78 mg paliperidone palmitate kit (NDC 50458-561-01) 117 mg paliperidone palmitate kit (NDC 50458-562-01) 156 mg paliperidone palmitate kit (NDC 50458-563-01) 234 mg paliperidone palmitate kit (NDC 50458-564-01) Storage and Handling Store at room temperature (25°C, 77°F); excursions between 15°C and 30°C (between 59°F and 86°F) are permitted.

Do not mix with any other product or diluent.

RECENT MAJOR CHANGES

Warnings and Precautions (5.5) 12/2017

GERIATRIC USE

8.5 Geriatric Use Clinical studies of INVEGA SUSTENNA® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with renal impairment [see Clinical Pharmacology (12.3)], who should be given reduced doses.

Because elderly patients are more likely to have decreased renal function, adjust dose based on renal function [see Dosage and Administration (2.5)].

DOSAGE FORMS AND STRENGTHS

3 INVEGA SUSTENNA® is available as a white to off-white aqueous extended-release injectable suspension for intramuscular injection in dose strengths of 39 mg, 78 mg, 117 mg, 156 mg, and 234 mg paliperidone palmitate.

Extended-release injectable suspension: 39 mg, 78 mg, 117 mg, 156 mg, or 234 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3)].

Paliperidone is the major active metabolite of risperidone.

The mechanism of action of paliperidone is unclear.

However, the drug’s therapeutic effect in schizophrenia could be mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.

INDICATIONS AND USAGE

1 INVEGA SUSTENNA® (paliperidone palmitate) is indicated for the treatment of: Schizophrenia in adults [see Clinical Studies (14.1)].

Schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants [see Clinical Studies (14.2)].

INVEGA SUSTENNA® is an atypical antipsychotic indicated for Treatment of schizophrenia in adults.

(1) Treatment of schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants.

(1)

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of INVEGA SUSTENNA® in patients < 18 years of age have not been established.

Juvenile Animal Studies In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents dosed at 12 mg/day.

No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which produced plasma levels of paliperidone 2–3 times those in adolescents.

Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day.

Decreased bone length and density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone which were similar to those in children and adolescents receiving the MRHD of risperidone.

In addition, a delay in sexual maturation was seen at all doses in both males and females.

The above effects showed little or no reversibility in females after a 12-week drug-free recovery period.

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

PREGNANCY

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including INVEGA SUSTENNA®, during pregnancy.

Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations).

Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not established a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).

There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including INVEGA SUSTENNA®, during pregnancy (see Clinical Considerations).

Paliperidone has been detected in plasma in adult subjects up to 126 days after a single-dose administration of INVEGA SUSTENNA® [see Clinical Pharmacology (12.3)], and the clinical significance of INVEGA SUSTENNA® administered before pregnancy or anytime during pregnancy is not known.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

In animal reproduction studies, there were no treatment related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate during the period of organogenesis at doses up to 10 times the maximum recommended human dose (MRHD) of 234 mg paliperidone based on mg/m2 body surface area.

There were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg of paliperidone based on mg/m2 body surface area.

Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone (see Animal data).

Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide.

Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth.

It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including INVEGA SUSTENNA®, during the third trimester of pregnancy.

These symptoms have varied in severity.

Monitor neonates exhibiting extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.

Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects.

A prospective observational study including 6 women treated with risperidone, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone.

A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.

There was a small increase in the risk of major birth defects (RR= 1.26, 95% CI 1.02–1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88–1.81) in a subgroup of 1566 women exposed to the parent compound of paliperidone, risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.

Animal Data There were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate extended-release injectable suspension during the period of organogenesis at doses up to 250 mg/kg, which is 10 times MRHD of 234 mg paliperidone based on mg/m2 body surface area.

In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg based on mg/m2 body surface area.

Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone.

Cleft palate was observed in the offspring of pregnant mice treated with risperidone at 3 to 4 times the MRHD of 16 mg based on mg/m2 body surface area; maternal toxicity occurred at 4 times the MHRD.

There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to 6 times the MRHD of 16 mg/day risperidone based on mg/m2 body surface area.

When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/m2 body surface area, reached adulthood, learning was impaired.

Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development and growth of the offspring was delayed.

In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on mg/m2 body surface area; it is not known whether these deaths were due to a direct effect on the fetuses or pups or, to effects on the dams (see RISPERDAL® package insert).

BOXED WARNING

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

INVEGA SUSTENNA® is not approved for use in patients with dementia-related psychosis.

[see Warnings and Precautions (5.1)] .

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

INVEGA SUSTENNA® is not approved for use in patients with dementia-related psychosis.

(5.1)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g.

stroke, transient ischemic attack).

(5.2) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of drug and close monitoring.

(5.3) QT Prolongation: Avoid use with drugs that also increase QT interval and in patients with risk factors for prolonged QT interval.

(5.4) Tardive Dyskinesia: Discontinue drug if clinically appropriate.

(5.5) Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain.

(5.6) Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope.

(5.7) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia.

Consider discontinuing INVEGA SUSTENNA® if clinically significant decline in WBC in the absence of other causative factors.

(5.9) Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration.

(5.10) Potential for Cognitive and Motor Impairment: Use caution when operating machinery.

(5.11) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold.

(5.12) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.

Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality.

The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

INVEGA SUSTENNA® is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)].

5.2 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 a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects.

No studies have been conducted with oral paliperidone, INVEGA SUSTENNA®, or the 3-month paliperidone palmitate extended-release injectable suspension in elderly patients with dementia.

These medicines are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)].

5.3 Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including paliperidone.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).

Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated.

In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).

Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available.

There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

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

5.4 QT Prolongation Paliperidone causes a modest increase in the corrected QT (QTc) interval.

The use of paliperidone should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval.

Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.

Certain circumstances may increase the risk of the occurrence of Torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

The effects of oral paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter QT study in adults with schizophrenia and schizoaffective disorder, and in three placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia.

In the QT study (n=141), the 8 mg dose of immediate-release oral paliperidone (n=50) showed a mean placebo-subtracted increase from baseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on day 8 at 1.5 hours post-dose.

The mean steady-state peak plasma concentration for this 8 mg dose of paliperidone immediate release (Cmax ss = 113 ng/mL) was more than 2-fold the exposure observed with the maximum recommended 234 mg dose of INVEGA SUSTENNA® administered in the deltoid muscle (predicted median Cmax ss = 50 ng/mL).

In this same study, a 4 mg dose of the immediate-release oral formulation of paliperidone, for which Cmax ss = 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose.

In the three fixed-dose efficacy studies of oral paliperidone extended release in subjects with schizophrenia, electrocardiogram (ECG) measurements taken at various time points showed only one subject in the oral paliperidone 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec).

In the four fixed-dose efficacy studies of INVEGA SUSTENNA® in subjects with schizophrenia and in the long-term study in subjects with schizoaffective disorder, no subject experienced a change in QTcLD exceeding 60 msec and no subject had a QTcLD value of > 500 msec at any time point.

In the maintenance study in subjects with schizophrenia, no subject had a QTcLD change > 60 msec, and one subject had a QTcLD value of 507 msec (Bazett’s QT corrected interval [QTcB] value of 483 msec); this latter subject also had a heart rate of 45 beats per minute.

5.5 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 the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome.

Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

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

The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process.

The effect of symptomatic suppression on the long-term course of the syndrome is unknown.

Given these considerations, INVEGA SUSTENNA® should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.

Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs.

In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.

The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient treated with INVEGA SUSTENNA®, drug discontinuation should be considered.

However, some patients may require treatment with INVEGA SUSTENNA® despite the presence of the syndrome.

5.6 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk.

These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain.

While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics.

These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials.

Hyperglycemia and diabetes have been reported in trial subjects treated with INVEGA SUSTENNA®.

Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population.

Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood.

However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.

Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment.

Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics 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 despite discontinuation of the suspect drug.

Pooled data from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 5.

Table 5: Change in Fasting Glucose from Four Placebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with Schizophrenia INVEGA SUSTENNA® Placebo 39 mg 78 mg 156 mg 234/39 mgInitial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection.

Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection.

[see Clinical Studies (14.1)].

234/156 mg 234/234 mg Mean change from baseline (mg/dL) n=367 n=86 n=244 n=238 n=110 n=126 n=115 Serum Glucose Change from baseline -1.3 1.3 3.5 0.1 3.4 1.8 -0.2 Proportion of Patients with Shifts Serum Glucose Normal to High 4.6% 6.3% 6.4% 3.9% 2.5% 7.0% 6.6% (<100 mg/dL to ≥126 mg/dL) (11/241) (4/64) (11/173) (6/154) (2/79) (6/86) (5/76) In a long-term open-label pharmacokinetic and safety study in subjects with schizophrenia in which the highest dose available (234 mg) was evaluated, INVEGA SUSTENNA® was associated with a mean change in glucose of -0.4 mg/dL at Week 29 (n=109) and +6.8 mg/dL at Week 53 (n=100).

During the initial 25-week open-label period of a long-term study in subjects with schizoaffective disorder, INVEGA SUSTENNA® was associated with mean change in glucose of +5.3 mg/dL (n=518).

At the endpoint of the subsequent 15-month double-blind period of the study, INVEGA SUSTENNA® was associated with a mean change in glucose of +0.3 mg/dL (n=131) compared with a mean change of +4.0 mg/dL in the placebo group (n=120).

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

Pooled data from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 6.

Table 6: Change in Fasting Lipids from Four Placebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with Schizophrenia INVEGA SUSTENNA® Placebo 39 mg 78 mg 156 mg 234/39 mgInitial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection.

Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection.

[see Clinical Studies (14.1)].

234/156 mg 234/234 mg Mean change from baseline (mg/dL) Cholesterol n=366 n=89 n=244 n=232 n=105 n=119 n=120 Change from baseline -6.6 -6.4 -5.8 -7.1 -0.9 -4.2 9.4 LDL n=275 n=80 n=164 n=141 n=104 n=117 n=108 Change from baseline -6.0 -4.8 -5.6 -4.8 0.9 -2.4 5.2 HDL n=286 n=89 n=165 n=150 n=105 n=118 n=115 Change from baseline 0.7 2.1 0.6 0.3 1.5 1.1 0.0 Triglycerides n=366 n=89 n=244 n=232 n=105 n=119 n=120 Change from baseline -16.7 7.6 -9.0 -11.5 -14.1 -20.0 11.9 Proportion of Patients with Shifts Cholesterol Normal to High 3.2% 2.0% 2.0% 2.1% 0% 3.1% 7.1% (<200 mg/dL to ≥240 mg/dL) (7/222) (1/51) (3/147) (3/141) (0/69) (2/65) (6/84) LDL Normal to High 1.1% 0% 0% 0% 0% 0% 0% (<100 mg/dL to ≥160 mg/dL) (1/95) (0/29) (0/67) (0/46) (0/41) (0/37) (0/44) HDL Normal to Low 13.8% 14.8% 9.6% 14.2% 12.7% 10.5% 16.0% (≥40 mg/dL to <40 mg/dL) (28/203) (9/61) (11/115) (15/106) (9/71) (8/76) (13/81) Triglycerides Normal to High 3.6% 6.1% 9.2% 7.2% 1.3% 3.7% 10.7% (<150 mg/dL to ≥200 mg/dL) (8/221) (3/49) (14/153) (10/139) (1/79) (3/82) (9/84) In a long-term open-label pharmacokinetic and safety study in subjects with schizophrenia in which the highest dose available (234 mg) was evaluated, the mean changes from baseline in lipid values are presented in Table 7.

Table 7: Change in Fasting Lipids from Long-term Open-label Pharmacokinetic and Safety Study in Subjects with Schizophrenia INVEGA SUSTENNA® 234 mg Week 29 Week 53 Mean change from baseline (mg/dL) Cholesterol n=112 n=100 Change from baseline -1.2 0.1 LDL n=107 n=89 Change from baseline -2.7 -2.3 HDL n=112 n=98 Change from baseline -0.8 -2.6 Triglycerides n=112 n=100 Change from baseline 16.2 37.4 The mean changes from baseline in lipid values during the initial 25-week open-label period and at the endpoint of the subsequent 15-month double-blind period in a long-term study in subjects with schizoaffective disorder are presented in Table 8.

Table 8: Change in Fasting Lipids from an Open-Label and Double-Blind Periods of a Long-Term Study in Subjects with Schizoaffective Disorder Open-Label Period Double-Blind Period INVEGA SUSTENNA® Placebo INVEGA SUSTENNA® Mean change from baseline (mg/dL) Cholesterol n=198 n=119 n=132 Change from baseline -3.9 -4.2 2.3 LDL n=198 n=117 n=130 Change from baseline -2.7 -2.8 5.9 HDL n=198 n=119 n=131 Change from baseline -2.7 -0.9 -0.7 Triglycerides n=198 n=119 n=132 Change from baseline 7.0 2.5 -12.3 Weight Gain Weight gain has been observed with atypical antipsychotic use.

Clinical monitoring of weight is recommended.

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 9.

Table 9: Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight from Four Placebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with Schizophrenia INVEGA SUSTENNA® Placebo 39 mg 78 mg 156 mg 234/39 mgInitial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection.

Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection.

[see Clinical Studies (14.1)].

234/156 mg 234/234 mg n=451 n=116 n=280 n=267 n=137 n=144 n=145 Weight (kg) Change from baseline -0.4 0.4 0.8 1.4 0.4 0.7 1.4 Weight Gain ≥ 7% increase from baseline 3.3% 6.0% 8.9% 9.0% 5.8% 8.3% 13.1% In a long-term open-label pharmacokinetic and safety study in which the highest dose available (234 mg) was evaluated, INVEGA SUSTENNA® was associated with a mean change in weight of +2.4 kg at Week 29 (n=134) and +4.3 kg at Week 53 (n=113).

During the initial 25-week open-label period of a long-term study in subjects with schizoaffective disorder, INVEGA SUSTENNA® was associated with a mean change in weight of +2.2 kg and 18.4% of subjects had an increase in body weight of ≥ 7% (n=653).

At the endpoint of the subsequent 15-month double-blind period of the study, INVEGA SUSTENNA® was associated with a mean change in weight of -0.2 kg and 13.0% of subjects had an increase in body weight of ≥ 7% (n=161); the placebo group had a mean change in weight of -0.8 kg and 6.0% of subjects had an increase in body weight of ≥ 7% (n=168).

5.7 Orthostatic Hypotension and Syncope Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-adrenergic blocking activity.

Syncope was reported in < 1% (4/1293) of subjects treated with INVEGA SUSTENNA® in the recommended dose range of 39 mg to 234 mg in the four fixed-dose, double-blind, placebo-controlled trials compared with 0% (0/510) of subjects treated with placebo.

In the four fixed-dose efficacy studies in subjects with schizophrenia, orthostatic hypotension was reported as an adverse event by < 1% (2/1293) of INVEGA SUSTENNA®-treated subjects compared to 0% (0/510) with placebo.

Incidences of orthostatic hypotension and syncope in the long-term studies in subjects with schizophrenia and schizoaffective disorder were similar to those observed in the short-term studies.

INVEGA SUSTENNA® should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications).

Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

5.8 Falls Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA SUSTENNA®, which may lead to falls and, consequently, fractures or other fall-related injuries.

For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.9 Leukopenia, Neutropenia, and Agranulocytosis In clinical trial and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including INVEGA SUSTENNA®.

Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia.

In patients with a history of a clinically significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy.

In such patients, consider discontinuation of INVEGA SUSTENNA® at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur.

Discontinue INVEGA SUSTENNA® in patients with severe neutropenia (absolute neutrophil count < 1000/mm3) and follow their WBC until recovery.

5.10 Hyperprolactinemia Like other drugs that antagonize dopamine D2 receptors, paliperidone elevates prolactin levels and the elevation persists during chronic administration.

Paliperidone has a prolactin-elevating effect similar to that seen with risperidone, a drug that is associated with higher levels of prolactin than other antipsychotic drugs.

Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion.

This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients.

Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer.

An increase in the incidence of pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)].

Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.

Prolactin data from two long-term, double-blind, placebo-controlled studies with INVEGA SUSTENNA® are presented below; one study was in a population of patients with schizophrenia; the second study was in patients with schizoaffective disorder.

Schizophrenia In a long-term maintenance trial of INVEGA SUSTENNA® in schizophrenia patients (Study PSY-3001), see Clinical Studies (14.1) , elevations of prolactin to above the reference range (> 18 ng/mL in males and > 30 ng/mL in females) relative to open-label baseline at any time during the double-blind phase were noted in a higher percentage of the patients in the INVEGA SUSTENNA® group than those in the placebo group in males (51.9% vs.

29.0%) and in females (50.5% vs.

42.9%).

During the double-blind phase, 4 females (4.2%) in the INVEGA SUSTENNA® group experienced potentially prolactin-related adverse reactions (amenorrhea N=2; galactorrhea N=1; menstruation irregular N=1), while 2 females (2.2%) in the placebo group experienced potentially prolactin-related adverse reactions (amenorrhea N=1; breast pain N=1).

One male (0.9%) in the INVEGA SUSTENNA® group experienced erectile dysfunction and 1 male (0.9%) in placebo group experienced gynecomastia.

Prior to the double-blind phase (during the 33-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline were 14.9 (22.3) ng/mL in males (N=490) and 35.2 (39.6) ng/mL in females (N=358).

At the end of the open-label phase, mean (SD) prolactin values were 24.7 (22.5) ng/mL in males (N=470) and 59.5 (38.1) ng/mL in females (N=333).

During the open-label phases 49.2% of females and 47.7% of males experienced elevations of prolactin above the reference range relative to baseline, and a higher proportion of females experienced potentially prolactin-related adverse reactions compared to males (5.3% vs.

1.8%).

Amenorrhea (2.5%) in females and no single potentially prolactin-related adverse reaction in males were observed with a rate greater than 2%.

Schizoaffective Disorder In a long-term maintenance trial of INVEGA SUSTENNA® in patients with schizoaffective disorder (Study SCA-3004) see Clinical Studies (14.2) , elevations of prolactin to above the reference range (> 13.13 ng/mL in males and > 26.72 ng/mL in females) relative to open-label baseline at any time during the 15-month double-blind phase were noted in a higher percentage of patients in the INVEGA SUSTENNA® group than those in the placebo group in males (55.6% vs.

23.2%) and in females (44.3% vs.

25.0%).

During the 15-month double-blind phase, 11 females (13.9%) in the INVEGA SUSTENNA® group had 14 potentially prolactin-related adverse reactions (hyperprolactinemia N=3; blood prolactin increased N=4; libido decreased N=1; amenorrhea N=3; galactorrhea N=3), while 5 females (5.8%) in the placebo group had 6 potentially prolactin-related adverse reactions (hyperprolactinemia N=2; blood prolactin increased N=1; amenorrhea N=2; galactorrhea N=1).

Six males (7.1%) in the INVEGA SUSTENNA® group experienced 6 potentially prolactin-related adverse reactions (hyperprolactinemia N=4; libido decreased N=1; erectile dysfunction N=1), while 1 male (1.2%) in the placebo group experienced adverse reaction of blood prolactin increased.

Prior to the 15-month double-blind phase (during the 25-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline were 14.6 (14.0) ng/mL in males (N=352) and 39.1 (44.6) ng/mL in females (N=302).

At the end of the open-label phase, mean (SD) prolactin values were 32.8 (17.2) ng/mL in males (N=275) and 72.4 (46.5) ng/mL in females (N=239).

During the open-label phase, 48.9% of females and 53.3% of males experienced elevations of prolactin above the reference range relative to baseline, and a higher proportion of females experienced potentially prolactin-related adverse reactions compared to males (10.0% vs.

9.0%).

Amenorrhea (5.8%) and galactorrhea (2.9%) in females and libido decrease (2.8%) and erectile dysfunction (2.5%) in males were observed with a rate greater than 2%.

5.11 Potential for Cognitive and Motor Impairment Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA SUSTENNA® [see Adverse Reactions (6.1)].

Antipsychotics, including INVEGA SUSTENNA®, have the potential to impair judgment, thinking, or motor skills.

Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that paliperidone therapy does not adversely affect them.

5.12 Seizures In the four fixed-dose double-blind placebo-controlled studies in subjects with schizophrenia, <1% (1/1293) of subjects treated with INVEGA SUSTENNA® in the recommended dose range of 39 mg to 234 mg experienced an adverse event of convulsion compared with <1% (1/510) of placebo-treated subjects who experienced an adverse event of grand mal convulsion.

Like other antipsychotic drugs, INVEGA SUSTENNA® should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

5.13 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.

INVEGA SUSTENNA® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

5.14 Priapism Drugs with alpha-adrenergic blocking effects have been reported to induce priapism.

Although no cases of priapism have been reported in clinical trials with INVEGA SUSTENNA®, priapism has been reported with oral paliperidone during postmarketing surveillance.

Severe priapism may require surgical intervention.

5.15 Disruption of Body Temperature Regulation Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents.

Appropriate care is advised when prescribing INVEGA SUSTENNA® to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

Neuroleptic Malignant Syndrome (NMS) Counsel patients about a potentially fatal side effect referred to as Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs.

Patients should contact their healthcare provider or report to the emergency room if they experience the following signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia [see Warnings and Precautions (5.3)].

Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.5)].

Metabolic Changes Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia (high blood sugar) and diabetes mellitus (e.g., polydipsia, polyuria, polyphagia, and weakness), and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.6)].

Orthostatic Hypotension Educate patients about the risk of orthostatic hypotension, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.7)].

Leukopenia/Neutropenia Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia they should have their CBC monitored while taking INVEGA SUSTENNA® [see Warnings and Precautions (5.9)].

Hyperprolactinemia Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of INVEGA SUSTENNA®.

Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males [see Warnings and Precautions (5.10)].

Interference with Cognitive and Motor Performance As INVEGA SUSTENNA® has the potential to impair judgment, thinking, or motor skills, caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that INVEGA SUSTENNA® therapy does not affect them adversely [see Warnings and Precautions (5.11)].

Priapism Advise patients of the possibility of painful or prolonged penile erections (priapism).

Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.14)].

Heat Exposure and Dehydration Counsel patients on the importance of avoiding overheating and dehydration [see Warnings and Precautions (5.15)].

Concomitant Medication Advise patients to inform their healthcare providers if they are taking, or plan to take any prescription or over-the-counter drugs as there is a potential for interactions [see Drug Interactions (7)].

Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with INVEGA SUSTENNA®.

Advise patients that INVEGA SUSTENNA® may cause extrapyramidal and/or withdrawal symptoms in a neonate.

Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to INVEGA SUSTENNA® during pregnancy [see Use in Specific Populations (8.1)].

Lactation Advise breastfeeding women using INVEGA SUSTENNA® to monitor infants for somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)].

Infertility Advise females of reproductive potential that INVEGA SUSTENNA® may impair fertility due to an increase in serum prolactin levels.

The effects on fertility are reversible [see Use in Specific Populations (8.3)].

DOSAGE AND ADMINISTRATION

2 For intramuscular injection only.

(2.1) Each injection must be administered only by a healthcare professional.

(2.1) For deltoid injection, use 1-inch 23G needle for patients weighing less than 90 kg or 1½-inch 22G needle for patients weighing 90 kg or more.

For gluteal injection, use 1½-inch 22G needle regardless of patient weight.

(2.1) Indication Initiation Dosing (deltoid) Monthly Maintenance DoseAdministered 5 weeks after the first injection.

(deltoid or gluteal) Maximum Monthly Dose Day 1 Day 8 Schizophrenia (2.2) 234 mg 156 mg 39–234 mgThe recommended maintenance dose for treatment of schizophrenia is 117 mg.

Some patients may benefit from lower or higher maintenance doses within the additional available strengths (39 mg, 78 mg, 156 mg, and 234 mg).

234 mg Schizoaffective disorder (2.2) 234 mg 156 mg 78–234 mgAdjust dose based on tolerability and/or efficacy using available strengths.

The 39 mg strength was not studied in the long-term schizoaffective disorder study.

234 mg For patients naïve to oral paliperidone or oral or injectable risperidone, establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with INVEGA SUSTENNA®.

(2.2) Missed Doses: To manage either a missed second initiation dose or a missed monthly maintenance dose, refer to the Full Prescribing Information.

(2.3) Moderate to severe renal impairment (creatinine clearance < 50 mL/min): INVEGA SUSTENNA® is not recommended.

(2.5) Mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min): Administer 156 mg on treatment day 1 and 117 mg one week later, both administered in the deltoid muscle.

Follow with monthly injections of 78 mg in either the deltoid or gluteal muscle.

(2.5) 2.1 Administration Instructions Each injection must be administered only by a healthcare professional.

Parenteral drug products should be inspected visually for foreign matter and discoloration prior to administration, whenever product and container permit.

INVEGA SUSTENNA® is intended for intramuscular use only.

Do not administer by any other route.

Avoid inadvertent injection into a blood vessel.

Administer the dose in a single injection; do not administer the dose in divided injections.

Inject slowly, deep into the deltoid or gluteal muscle.

INVEGA SUSTENNA® must be administered using only the needles that are provided in the INVEGA SUSTENNA® kit.

The recommended needle size for administration of INVEGA SUSTENNA® into the deltoid muscle is determined by the patient’s weight: For patients weighing less than 90 kg, the 1-inch, 23 gauge needle is recommended.

For patients weighing 90 kg or more, the 1½-inch, 22 gauge needle is recommended.

Deltoid injections should be alternated between the two deltoid muscles.

The recommended needle size for administration of INVEGA SUSTENNA® into the gluteal muscle is the 1½-inch, 22 gauge needle regardless of patient weight.

Administer into the upper-outer quadrant of the gluteal muscle.

Gluteal injections should be alternated between the two gluteal muscles.

2.2 Schizophrenia and Schizoaffective Disorder For patients who have never taken oral paliperidone or oral or injectable risperidone, it is recommended to establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with INVEGA SUSTENNA®.

The recommended dosing of INVEGA SUSTENNA® for each approved indication is displayed in Table 1.

The recommended initiation of INVEGA SUSTENNA® is with a dose of 234 mg on treatment day 1 and 156 mg one week later, both administered in the deltoid muscle.

Following the second initiation dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle.

Table 1: Recommended Dosing of INVEGA SUSTENNA® for Adults with Schizophrenia or Schizoaffective Disorder Indication Initiation Dosing (deltoid) Monthly Maintenance DoseAdministered 5 weeks after the first injection.

(deltoid or gluteal) Maximum Monthly Dose Day 1 Day 8 Schizophrenia 234 mg 156 mg 39–234 mgThe recommended maintenance dose for treatment of schizophrenia is 117 mg.

Some patients may benefit from lower or higher maintenance doses within the additional available strengths (39 mg, 78 mg, 156 mg, and 234 mg).

234 mg Schizoaffective disorder 234 mg 156 mg 78–234 mgAdjust dose based on tolerability and/or efficacy using available strengths.

The 39 mg strength was not studied in the long-term schizoaffective disorder study.

234 mg Adjustment of the maintenance dose may be made monthly.

When making dose adjustments, the prolonged-release characteristics of INVEGA SUSTENNA® should be considered [see Clinical Pharmacology (12.3)], as the full effect of the dose adjustment may not be evident for several months.

2.3 Missed Doses Avoiding Missed Doses It is recommended that the second initiation dose of INVEGA SUSTENNA® be given one week after the first dose.

To avoid a missed dose, patients may be given the second dose 4 days before or after the one-week time point.

Similarly, the third and subsequent injections after the initiation regimen are recommended to be given monthly.

To avoid a missed monthly dose, patients may be given the injection up to 7 days before or after the monthly time point.

Management of a Missed Second Initiation Dose If the target date for the second INVEGA SUSTENNA® injection (one week ± 4 days) is missed, the recommended reinitiation depends on the length of time which has elapsed since the patient’s first injection.

In case of a missed second initiation dose follow the dosing instructions provided in Table 2.

Table 2: Management of a Missed Second Initiation Dose TIMING OF MISSED SECOND INITIATION DOSE DOSING Less than 4 weeks since first injection Administer the second initiation dose of 156 mg in the deltoid muscle as soon as possible.

It is recommended to administer a third injection of 117 mg in either the deltoid or gluteal muscle 5 weeks after the first injection (regardless of the timing of the second injection).

Thereafter, resume regular monthly dosing in either the deltoid or gluteal muscle.

4 to 7 weeks since first injection Resume dosing with two injections of 156 mg in the following manner: Administer a deltoid injection as soon as possible.

Administer a second deltoid injection 1 week later.

Thereafter, resume regular monthly dosing in either the deltoid or gluteal muscle.

More than 7 weeks since first injection Restart dosing with recommended initiation (see Section 2.2, Table 1): Administer a 234 mg deltoid injection on Day 1.

Administer a 156 mg deltoid injection 1 week later.

Thereafter, resume regular monthly dosing in either the deltoid or gluteal muscle.

Management of a Missed Maintenance Dose In case of a missed maintenance dose follow the dosing instructions provided in Table 3.

Table 3: Management of a Missed Maintenance Dose TIMING OF MISSED MAINTENANCE DOSE DOSING 4 to 6 weeks since last injection Resume regular monthly dosing as soon as possible at the patient’s previously stabilized dose, followed by injections at monthly intervals.

More than 6 weeks to 6 months since last injection Resume the same dose the patient was previously stabilized on (unless the patient was stabilized on a dose of 234 mg, then the first 2 injections should each be 156 mg) in the following manner: Administer a deltoid injection as soon as possible.

Administer a second deltoid injection 1 week later at the same dose.

Thereafter, resume administering the previously stabilized dose in the deltoid or gluteal muscle 1 month after the second injection.

More than 6 months since last injection Restart dosing with recommended initiation (see Section 2.2, Table 1 ): Administer a 234 mg deltoid injection on Day 1.

Administer a 156 mg deltoid injection 1 week later.

Thereafter, resume administering the previously stabilized dose in the deltoid or gluteal muscle 1 month after the second injection.

2.4 Use with Risperidone or with Oral Paliperidone Since paliperidone is the major active metabolite of risperidone, caution should be exercised when INVEGA SUSTENNA® is coadministered with risperidone or with oral paliperidone for extended periods of time.

Safety data involving concomitant use of INVEGA SUSTENNA® with other antipsychotics is limited.

2.5 Dosage Adjustments Renal Impairment INVEGA SUSTENNA® has not been systematically studied in patients with renal impairment [see Clinical Pharmacology (12.3)].

For patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min [Cockcroft-Gault Formula]), initiate INVEGA SUSTENNA® with a dose of 156 mg on treatment day 1 and 117 mg one week later.

Administer both doses in the deltoid muscle.

Thereafter, follow with monthly injections of 78 mg in either the deltoid or gluteal muscle [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

INVEGA SUSTENNA® is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Coadministration with Strong CYP3A4/P-glycoprotein (P-gp) Inducers Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John’s Wort) during the 1-month dosing interval for INVEGA SUSTENNA®, if possible.

If administering a strong inducer is necessary, consider managing the patient using paliperidone extended release tablets [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

2.6 Switching from Other Antipsychotics There are no systematically collected data to specifically address switching patients with schizophrenia or schizoaffective disorder from other antipsychotics to INVEGA SUSTENNA®, or concerning concomitant administration with other antipsychotics.

Switching from Oral Antipsychotics For patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability should be established with oral paliperidone or oral risperidone prior to initiating treatment with INVEGA SUSTENNA®.

Previous oral antipsychotics can be gradually discontinued at the time of initiation of treatment with INVEGA SUSTENNA®.

Recommended initiation of INVEGA SUSTENNA® is with a dose of 234 mg on treatment day 1 and 156 mg one week later, both administered in the deltoid muscle [see Dosage and Administration (2.2)].

Patients previously stabilized on different doses of INVEGA® Extended-Release tablets can attain similar paliperidone steady-state exposure during maintenance treatment with INVEGA SUSTENNA® monthly doses as depicted in Table 4.

Table 4: Doses of INVEGA® and INVEGA SUSTENNA® Needed to Attain Similar Steady-State Paliperidone Exposure During Maintenance Treatment Formulation INVEGA® Extended-Release Tablet INVEGA SUSTENNA® Injection Dosing Frequency Once Daily Once every 4 weeks Dose (mg) 12 234 9 156 6 117 3 39–78 Switching from Long-Acting Injectable Antipsychotics For patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability should be established with oral paliperidone or oral risperidone prior to initiating treatment with INVEGA SUSTENNA®.

When switching patients currently at steady-state on a long-acting injectable antipsychotic, initiate INVEGA SUSTENNA® therapy in place of the next scheduled injection.

INVEGA SUSTENNA® should then be continued at monthly intervals.

The one-week initiation dosing regimen as described in Section 2.2 is not required.

See Table 1 above for recommended monthly maintenance dosing.

Based on previous clinical history of tolerability and/or efficacy, some patients may benefit from lower or higher maintenance doses within the available strengths (39 mg, 78 mg, 117 mg, 156 mg, and 234 mg).

The 39 mg strength was not studied in the long-term schizoaffective disorder study.

Monthly maintenance doses can be administered in either the deltoid or gluteal muscle [see Dosage and Administration (2.2)].

If INVEGA SUSTENNA® is discontinued, its prolonged-release characteristics must be considered.

As recommended with other antipsychotic medications, the need for continuing existing extrapyramidal symptoms (EPS) medication should be re-evaluated periodically.

2.7 Instructions for Use Each injection must be administered only by a healthcare professional.

The kit contains a prefilled syringe and 2 safety needles (a 1 ½-inch 22 gauge needle and a 1-inch 23 gauge needle) for intramuscular injection.

INVEGA SUSTENNA® is for single use only.

a.Shake the syringe vigorously for a minimum of 10 seconds to ensure a homogeneous suspension.

b.Select the appropriate needle.

For DELTOID injection: If the patient weighs less than 90 kg, use the 1-inch 23 gauge needle (needle with blue colored hub).

If the patient weighs 90 kg or more, use the 1 ½-inch 22 gauge needle (needle with gray colored hub).

For GLUTEAL injection: Use the 1 ½-inch 22 gauge needle (needle with gray colored hub) regardless of patient’s weight.

c.While holding the syringe upright, remove the rubber tip cap with an easy clockwise twisting motion.

d.Peel the safety needle pouch half way open.

Grasp the needle sheath using the plastic peel pouch.

Attach the safety needle to the luer connection of the syringe with an easy clockwise twisting motion.

e.Pull the needle sheath away from the needle with a straight pull.

Do not twist the sheath as the needle may be loosened from the syringe.

f.Bring the syringe with the attached needle in upright position to de-aerate.

De-aerate the syringe by moving the plunger rod carefully forward.

g.Inject the entire contents intramuscularly slowly, deep into the selected deltoid or gluteal muscle of the patient.

Do not administer by any other route.

h.After the injection is complete, use either thumb or finger of one hand (h1, h2) or a flat surface (h3) to activate the needle protection system.

The needle protection system is fully activated when a ‘click’ is heard.

Discard the syringe with needle appropriately.

h1 h2 h3 Figure Figure Figure Figure Figure Figure h1 h2 h3