INVEGA TRINZA® (paliperidone palmitate) extended-release

INVEGATRINZA

(paliperidone palmitate)

extended-release injectable suspension, for intramuscular use

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

INVEGA TRINZA

safely and effectively. See full prescribing information for

INVEGATRINZA

(paliperidone palmitate) extended-release injectable suspension,

for intramuscular use

Initial U.S. Approval: 2006

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 TRINZA

is not approved for

use in patients with dementia-related psychosis. (5.1)

------------------------------ RECENT MAJOR CHANGES ---------------------------

Warnings and Precautions (5.3, 5.5) 2/2021

------------------------------ INDICATIONS AND USAGE ---------------------------

INVEGA TRINZA

, a 3-month injection, is an atypical antipsychotic indicated for the

treatment of schizophrenia in patients after they have been adequately treated with

INVEGA SUSTENNA

(1-month paliperidone palmitate extended-release injectable

suspension) for at least four months. (1)

--------------------------- DOSAGE AND ADMINISTRATION -------------------------

• Use INVEGA TRINZA

only after the patient has been adequately treated with the

1-month paliperidone palmitate extended-release injectable suspension for at least

four months. (2.2)

• INVEGATRINZA

should be administered once every 3 months. (2.1)

• For intramuscular injection only. (2.1)

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

• For deltoid injection: For patients weighing less than 90 kg, use the 1-inch 22 gauge

thin wall needle. For patients weighing 90 kg or more, use the 1½-inch 22 gauge

thin wall needle.

• For gluteal injection: Regardless of patient weight, use the1½-inch 22 gauge thin

wall needle.

• Prior to administration, shake the preﬁlled syringe vigorously for at least 15 seconds

within 5 minutes prior to administration to ensure a homogeneous suspension. (2.1)

• Initiate INVEGA TRINZA

when the next 1-month paliperidone palmitate dose is

scheduled with an INVEGA TRINZA

dose based on the previous 1-month injection

dose as shown below. (2.2)

INVEGA TRINZA

Doses for Adult Patients Adequately Treated with

INVEGASUSTENNA

If the Last Dose of

INVEGASUSTENNA

is:

Initiate

INVEGATRINZA

at the

Following Dose:

78 mg 273 mg

117 mg 410 mg

156 mg 546 mg

234 mg 819 mg

Conversion from the INVEGASUSTENNA

39 mg dose was not studied.

• Missed Doses: Missing doses of INVEGA TRINZA

should be avoided. To manage

missed doses on exceptional occasions, refer to the Full Prescribing Information.

(2.3)

• Moderate to severe renal impairment (creatinine clearance < 50 mL/min):

INVEGATRINZA

is not recommended. (2.5)

• Mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min): Adjust

dosage and stabilize the patient using INVEGA SUSTENNA

, then transition to

INVEGATRINZA

. See above table. (2.5)

-------------------------- DOSAGE FORMS AND STRENGTHS ------------------------

Extended-release injectable suspension: 273 mg/0.88 mL, 410 mg/1.32 mL,

546 mg/1.75 mL, or 819 mg/2.63 mL (3)

--------------------------------- CONTRAINDICATIONS -------------------------------

Known hypersensitivity to paliperidone, risperidone, or to any excipients in

INVEGATRINZA

. (4)

---------------------------- 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, including fatalities).

INVEGATRINZA

is not approved for use in patients with dementia-related psychosis

(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: Atypical antipsychotic drugs have been associated with

metabolic changes that may increase cardiovascular/cerebrovascular risk. These

metabolic changes include:

◦ Hyperglycemia and Diabetes Mellitus: Monitor for symptoms of hyperglycemia

including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose

regularly in patients with diabetes or at risk for diabetes. (5.6)

◦ Dyslipidemia: Undesirable alterations have been observed. (5.6)

◦ Weight Gain: Signiﬁcant weight gain has been reported. Monitor weight gain. (5.6)

• Orthostatic Hypotension and Syncope: Use with caution in patients with known

cardiovascular or cerebrovascular disease and patients predisposed to hypotension

(5.7)

• Leukopenia, Neutropenia, and Agranulocytosis: Monitor complete blood count in

patients with a history of a clinically signiﬁcant low white blood cell count (WBC) or

a drug-induced leukopenia/neutropenia. Consider discontinuation 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)

-------------------------------- ADVERSE REACTIONS -------------------------------

The most common adverse reactions (incidence ≥ 5% and occurring at least twice as

often as placebo) were injection site reaction, weight increased, headache, upper

respiratory tract infection, akathisia, and parkinsonism. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals,

Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or

www.fda.gov/medwatch

-------------------------------- DRUG INTERACTIONS -------------------------------

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 TRINZA

. If administering a strong inducer is necessary, consider managing

the patient using paliperidone extended release tablets. (7.2, 12.3)

--------------------------- USE IN SPECIFIC POPULATIONS --------------------------

Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with

third trimester exposure. (8.1)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient

labeling.

Revised: 8/2021

INVEGA TRINZA

(paliperidone palmitate)

FULL PRESCRIBING INFORMATION

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 TRINZA

is not approved

for use in patients with dementia-related psychosis. [see Warnings and

Precautions (5.1)].

1 INDICATIONS AND USAGE

INVEGA TRINZA

(paliperidone palmitate), a 3-month injection, is indicated for the

treatment of schizophrenia in patients after they have been adequately treated with

INVEGA SUSTENNA

(1-month paliperidone palmitate extended-release injectable

suspension) for at least four months [see Dosage and Administration (2.2) and Clinical

Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 Administration Instructions

INVEGATRINZA

should be administered once every 3 months.

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. It is important to shake the syringe vigorously

for at least 15 seconds to ensure a homogeneous suspension. Inject

INVEGA TRINZA

within 5 minutes of shaking vigorously [see Dosage and

Administration (2.8)].

INVEGATRINZA

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 TRINZA

must be administered using only the thin wall needles that are

provided in the INVEGA TRINZA

pack. Do not use needles from the 1-month

paliperidone palmitate extended-release injectable suspension pack or other

commercially-available needles to reduce the risk of blockage.

Deltoid Injection

The recommended needle size for administration of INVEGA TRINZA

into the deltoid

muscle is determined by the patient’s weight:

• For patients weighing less than 90 kg, the 1-inch, 22 gauge thin wall needle is

recommended.

• For patients weighing 90 kg or more, the 1½-inch, 22 gauge thin wall needle is

recommended.

Administer into the center of the deltoid muscle. Deltoid injections should be alternated

between the two deltoid muscles.

Gluteal Injection

Regardless of patient weight, the recommended needle size for administration of

INVEGA TRINZA

into the gluteal muscle is the 1½-inch, 22 gauge thin wall needle.

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

should be alternated between the two gluteal muscles.

Incomplete Administration

To avoid an incomplete administration of INVEGA TRINZA

, ensure that the preﬁlled

syringe is shaken vigorously for at least 15 seconds within 5 minutes prior to

administration to ensure a homogeneous suspension and ensure the needle does

not get clogged during injection [see Dosage and Administration (2.8)].

However, in the event of an incompletely administered dose, do not re-inject the dose

remaining in the syringe and do not administer another dose of INVEGA TRINZA

Closely monitor and treat the patient with oral supplementation as clinically appropriate

until the next scheduled 3-month injection of INVEGATRINZA

2.2 Schizophrenia

Adults

INVEGA TRINZA

is to be used only after INVEGA SUSTENNA

(1-month paliperidone

palmitate extended-release injectable suspension) has been established as adequate

treatment for at least fourmonths. In order to establish a consistent maintenance dose,

it is recommended that the last two doses of INVEGASUSTENNA

be the same dosage

strength before starting INVEGATRINZA

Initiate INVEGA TRINZA

when the next 1-month paliperidone palmitate dose is

scheduled with an INVEGA TRINZA

dose based on the previous 1-month injection

dose, using the equivalent 3.5-fold higher dose as shown in Table 1. INVEGATRINZA

may be administered up to 7 days before or after the monthly time point of the next

scheduled paliperidone palmitate 1-month dose.

INVEGA TRINZA

(paliperidone palmitate) INVEGA TRINZA

(paliperidone palmitate)

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-

RELATED PSYCHOSIS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Administration Instructions

2.2 Schizophrenia

2.3 Missed Doses

2.4 Use with Risperidone or with Oral Paliperidone

2.5 Dosage Adjustment in Renal Impairment

2.6 Switching from INVEGA TRINZA

to the 1-Month Paliperidone Palmitate

Extended-Release Injectable Suspension

2.7 Switching from INVEGA TRINZA

to Oral Paliperidone Extended-Release

Tablets

2.8 Instructions for Use

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with

Dementia-Related Psychosis

5.3 Neuroleptic Malignant Syndrome

5.4 QT Prolongation

5.5 Tardive Dyskinesia

5.6 Metabolic Changes

5.7 Orthostatic Hypotension and Syncope

5.8 Falls

5.9 Leukopenia, Neutropenia, and Agranulocytosis

5.10 Hyperprolactinemia

5.11 Potential for Cognitive and Motor Impairment

5.12 Seizures

5.13 Dysphagia

5.14 Priapism

5.15 Disruption of Body Temperature Regulation

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Drugs Having Clinically Important Interactions with INVEGA TRINZA

7.2 Drugs Having No Clinically Important Interactions with INVEGA TRINZA

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

8.8 Patients with Parkinson’s Disease or Lewy Body Dementia

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

9.3 Dependence

10 OVERDOSAGE

10.1 Human Experience

10.2 Management of Overdosage

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

Table 1. INVEGA TRINZA

Doses for Adult Patients Adequately Treated with

INVEGASUSTENNA

If the Last Dose of

INVEGASUSTENNA

is:

Initiate INVEGATRINZA

at the

Following Dose:

78 mg 273 mg

117 mg 410 mg

156 mg 546 mg

234 mg 819 mg

Conversion from the INVEGASUSTENNA

39 mg dose was not studied.

Following the initial INVEGA TRINZA

dose, INVEGA TRINZA

should be administered

every 3 months. If needed, dose adjustment can be made every 3 months in

increments within the range of 273 mg to 819 mg based on individual patient

tolerability and/or efﬁcacy. Due to the long-acting nature of INVEGA TRINZA

, the

patient’s response to an adjusted dose may not be apparent for several months [see

Clinical Pharmacology (12.3)].

2.3 Missed Doses

Dosing Window

Missing doses of INVEGA TRINZA

should be avoided. If necessary, patients may be

given the injection up to 2 weeks before or after the 3-month time point.

Missed Dose 3½ Months to 4 Months Since Last Injection

If more than 3½ months (up to but less than 4 months) have elapsed since the last

injection of INVEGATRINZA

, the previously administered INVEGATRINZA

dose should

be administered as soon as possible, then continue with the 3-month injections

following this dose.

Missed Dose 4 Months to 9 Months Since Last Injection

If 4 months up to and including 9 months have elapsed since the last injection of

INVEGA TRINZA

, do NOT administer the next dose of INVEGA TRINZA

. Instead, use

the re-initiation regimen shown in Table2.

Table 2. Re-initiation Regimen After Missing 4 Months to 9 Months of

INVEGATRINZA

If the Last Dose of

INVEGATRINZA

was:

Administer INVEGASUSTENNA

two doses one week apart

(into deltoid muscle)

Then administer

INVEGATRINZA

(into deltoid

gluteal muscle)

Day 1 Day 8 1 month after

Day 8

273 mg 78 mg 78 mg 273 mg

410 mg 117 mg 117 mg 410 mg

546 mg 156 mg 156 mg 546 mg

819 mg 156 mg 156 mg 819 mg

See Instructions for Use for deltoid injection needle selection based on body weight.

Missed Dose Longer than 9 Months Since Last Injection

If more than 9 months have elapsed since the last injection of INVEGA TRINZA

re-initiate treatment with the 1-month paliperidone palmitate extended-release

injectable suspension as described in the prescribing information for that product.

INVEGA TRINZA

can then be resumed after the patient has been adequately treated

with the 1-month paliperidone palmitate extended-release injectable suspension for at

least 4 months.

2.4 Use with Risperidone or with Oral Paliperidone

Since paliperidone is the major active metabolite of risperidone, caution should be

exercised when INVEGA TRINZA

is coadministered with risperidone or oral

paliperidone for extended periods of time. Safety data involving concomitant use of

INVEGATRINZA

with other antipsychotics is limited.

2.5 Dosage Adjustment in Renal Impairment

INVEGATRINZA

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], adjust dosage and

stabilize the patient using the 1-month paliperidone palmitate extended-release

injectable suspension, then transition to INVEGA TRINZA

[see Table 1, Dosage and

Administration (2.2)]. [See also Use in Speciﬁc Populations (8.6) and Clinical

Pharmacology (12.3)]

INVEGA TRINZA

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)].

2.6 Switching from INVEGA TRINZA

to the 1-Month Paliperidone Palmitate

Extended-Release Injectable Suspension

For switching from INVEGA TRINZA

to INVEGA SUSTENNA

(1-month paliperidone

palmitate extended-release injectable suspension), the 1-month paliperidone palmitate

extended-release injectable suspension should be started 3 months after the last

INVEGATRINZA

dose, using the equivalent 3.5-fold lower dose as shown in Table 3.

The 1-month paliperidone palmitate extended-release injectable suspension should

then continue, dosed at monthly intervals.

Table 3. Conversion From INVEGATRINZA

to INVEGASUSTENNA

If the Last Dose of

INVEGATRINZA

is:

Initiate

INVEGASUSTENNA

3 Months Later at the Following Dose:

273 mg 78 mg

410 mg 117 mg

546 mg 156 mg

819 mg 234 mg

The initiation dosing as described in the prescribing information for INVEGASUSTENNA

is not required.

2.7 Switching from INVEGA TRINZA

to Oral Paliperidone Extended-Release

Tablets

For switching from INVEGATRINZA

to oral paliperidone extended-release tablets, the

daily dosing of the paliperidone extended-release tablets should be started 3 months

after the last INVEGA TRINZA

dose and transitioned over the next several months

following the last INVEGATRINZA

dose as described in Table 4. Table 4 provides dose

conversion regimens to allow patients previously stabilized on different doses of

INVEGA TRINZA

to attain similar paliperidone exposure with once daily paliperidone

extended-release tablets.

Table 4. INVEGA TRINZA

Doses and Once-Daily Paliperidone Extended-Release

Conversion Regimens Needed to Attain Similar Paliperidone Exposures

Weeks Since Last INVEGATRINZA

Dose

3 months to

18 weeks

Longer than

18weeks to

24weeks

Longer than

24weeks

Last

INVEGATRINZA

Dose

Doses of oral paliperidone extended-release tablets

273 mg 3 mg 3 mg 3 mg

410 mg 3 mg 3 mg 6 mg

546 mg 3 mg 6 mg 9 mg

819 mg 6 mg 9 mg 12 mg

2.8 Instructions for Use

MONTHS

Administer every 3 months

Shake syringe vigorously for at least 15 seconds

For intramuscular injection only. Do not administer by any other route.

Important

INVEGA TRINZA

should be administered by a healthcare professional as a single

injection. DONOT divide dose into multiple injections.

INVEGA TRINZA

is intended for intramuscular use only. Inject slowly, deep into the

muscle taking care to avoid injection into a blood vessel.

Read complete instructions prior to use.

Dosing

This medication should be administered once every 3 months.

Preparation

Peel off tab label from the syringe and place in patient record.

INVEGATRINZA

requires longer and more vigorous shaking than INVEGASUSTENNA

(1-month paliperidone palmitate extended-release injectable suspension). Shake the

syringe vigorously, with the syringe tip pointing up, for at least 15 seconds within

5 minutes priortoadministration (see Step 2).

Thin Wall Safety Needle Selection

Thin wall safety needles are designed to be used with INVEGATRINZA

. Therefore, it is

important to only use the needles provided in the INVEGATRINZA

kit.

INVEGA TRINZA

(paliperidone palmitate) INVEGA TRINZA

(paliperidone palmitate)

Dose pack contents

Preﬁlled Thin Wall

Syringe Safety Needles

Rubber

Cap

Syringe Tip

Luer

Connection

22G×1½”

22G×1”

Needle

Pouch

Needle

Sheath

Select needle1

Needle selection is determined by injection area and patient weight.

If administering a If administering a

Deltoid injection Gluteal injection

If patient weighs: If patient weighs:

Less than 90 kg Less than 90 kg

pink hub yellow hub

22G×1”

22G×1½”

90 kg or more 90 kg or more

yellow hub yellow hub

22G×1½”

Immediately discard the unused needle in an approved

sharps container. Do not save for future use.

Prepare for injection

SHAKE VIGOROUSLY

for at least 15 seconds

With the syringe tip pointing up, SHAKE VIGOROUSLY

with a loose wrist for at least 15 seconds to ensure a

homogeneous suspension.

NOTE: This medication requires longer and more

vigorous shaking than the 1-month paliperidone

palmitate extended-release injectable suspension.

Proceed to the next step immediately after

shaking. If more than 5 minutes pass before

injection, shake vigorously, with the syringe

tip pointing up, again for at least 15 seconds

to re-suspend the medication.

SEC

Check suspension

After shaking the syringe for at least 15 seconds, check the liquid in the viewing

window.

The suspension should appear uniform and milky white in color.

It is also normal to see small air bubbles.

INVEGA TRINZA

(paliperidone palmitate) INVEGA TRINZA

(paliperidone palmitate)

Open needle pouch and remove cap

First, open needle pouch by peeling the cover back half way. Place on a clean surface.

Then, holding the syringe upright, twist and pull the rubber cap to remove.

Grasp needle pouch

Fold back needle cover and plastic tray. Then, ﬁrmly grasp the needle sheath through

the pouch, as shown.

Attach needle

With your other hand, hold the syringe by the luer connection and attach it to the safety

needle with a gentle clockwise twisting motion.

Do not remove the pouch until the syringe and needle are securely attached.

Remove needle sheath

Pull the needle sheath away from the needle in a straight motion.

Do not twist the sheath, as this may loosen the needle from the syringe.

Remove air bubbles

Hold the syringe upright and tap gently to make any air bubbles rise to the top.

Remove air by pressing the plunger rod upward carefully until a drop of liquid comes

out of the needle tip.

Inject

Inject dose

Deltoid

Gluteal

Slowly inject the entire contents of the syringe intramuscularly, deep into the

selected deltoid or gluteal muscle.

Do not administer by any other route.

After injection4

Secure needle

After the injection is complete, use your thumb or a ﬂat surface to secure the needle in

the safety device. The needle is secure when a “click” sound is heard.

INVEGA TRINZA

(paliperidone palmitate) INVEGA TRINZA

(paliperidone palmitate)

Dispose properly

Dispose of the syringe and unused needle in an approved sharps container.

Thin wall safety needles are designed speciﬁcally for

use with INVEGA TRINZA

. Unused needle should be

discarded and not saved for future use.

3 DOSAGE FORMS AND STRENGTHS

INVEGA TRINZA

is available as a white to off-white aqueous extended-release

injectable suspension for intramuscular injection in dose strengths of 273 mg/0.88 mL,

410 mg/1.32 mL, 546 mg/1.75 mL, and 819 mg/2.63 mL paliperidone palmitate in

single-dose preﬁlled syringes.

4 CONTRAINDICATIONS

INVEGATRINZA

is contraindicated in patients with a known hypersensitivity to either

paliperidone or risperidone, or to any of the excipients in the INVEGA TRINZA

formulation. Hypersensitivity reactions, including anaphylactic reactions and

angioedema, have been reported in patients treated with risperidone and in patients

treated with paliperidone. Paliperidone palmitate is converted to paliperidone, which is

a metabolite of risperidone.

5 WARNINGS AND PRECAUTIONS

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 TRINZA

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, the 1-month paliperidone palmitate extended-release injectable

suspension, or INVEGA TRINZA

in elderly patients with dementia. These medications

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

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been

reported in association with antipsychotic drugs, including paliperidone.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status

including delirium, and 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.

If NMS is suspected, immediately discontinue INVEGA TRINZA and provide symptomatic

treatment and monitoring.

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 paliperidone on the QT interval were evaluated in a double-blind, active-

controlled (moxiﬂoxacin 400 mg single dose), multicenter Thorough QT study with oral

paliperidone in adult patients, and in four ﬁxed-dose efﬁcacy studies and one

maintenance study of the 1-month paliperidone palmitate injectable product.

In the Thorough 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 (QT interval corrected for heart rate using the population speciﬁed linear derived

method) 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 (C

max ss

=113 ng/mL) was approximately 2-fold the exposure with the maximum

recommended 819 mg dose of INVEGA TRINZA

administered in the deltoid muscle

(predicted median C

max ss

=56 ng/mL). In this same study, a 4 mg dose of the

immediate-release oral formulation of paliperidone, for which C

max 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 four ﬁxed-dose efﬁcacy studies of the 1-month paliperidone palmitate injectable

product, no subject had 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, 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.

In the long-term maintenance trial of INVEGATRINZA

in subjects with schizophrenia,

an increase in QTcLD exceeding 60 msec was observed in 1 subject (< 1%) in the

open-label phase, no subject had an increase in QTcLD exceeding 60 msec after

treatment with INVEGA TRINZA

in the double-blind phase, and no subject had a

QTcLD value of > 480 msec at any point in the study.

5.5 Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting 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 with the duration of treatment and the cumulative dose.

The syndrome can develop after relatively brief treatment periods, even at low doses. It

may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is

discontinued. Antipsychotic treatment, itself, however, may suppress (or partially

suppress) the signs and symptoms of the syndrome possibly masking the underlying

process. The effect that symptomatic suppression has upon the long-term course of

the syndrome is unknown.

Given these considerations, INVEGA TRINZA

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: (1) who suffer from a chronic

illness that is known to respond to antipsychotic drugs, and (2) for whom alternative,

equally effective, but potentially less harmful treatments are not available or

appropriate. In patients who do require chronic treatment, use the lowest dose and the

shortest duration of treatment producing a satisfactory clinical response. Periodically

reassess the need for continued treatment.

If signs and symptoms of tardive dyskinesia appear in a patient treated with

INVEGA TRINZA

, drug discontinuation should be considered. Consideration should be

given to the long-acting nature of INVEGA TRINZA

. However, some patients may

require treatment with INVEGA TRINZA

despite the presence of the syndrome.

INVEGA TRINZA

(paliperidone palmitate) INVEGA TRINZA

(paliperidone palmitate)

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 TRINZA

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.

Data from the long-term maintenance trial with INVEGA TRINZA

in subjects with

schizophrenia are presented in Table 5.

Table 5. Change in Fasting Glucose from the Long-Term Maintenance Trial with

INVEGATRINZA

in Subjects with Schizophrenia

Open-Label

Phase

(relative to

open-label

baseline)

Double-Blind Phase

(relative to

double-blind baseline)

Paliperidone

Palmitate

Placebo INVEGATRINZA

Mean change from baseline (mg/dL)

n=397 n=120 n=138

Serum Glucose

Change from baseline

1.2 -1.6 -1.2

Proportion of Patients with Shifts

n=397 n=128 n=148

Serum Glucose

Normal to High

2.3% 2.3% 4.1%

(<100 mg/dL to

≥126 mg/dL)

(9/397) (3/128) (6/148)

During the open-label phase, subjects received several doses of the 1-month

paliperidone palmitate extended-release injectable suspension followed by a single

dose of INVEGATRINZA

[see Clinical Studies (14)].

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical

antipsychotics.

Data from the long-term maintenance trial with INVEGA TRINZA

in subjects with

schizophrenia are presented in Table 6.

Table 6. Change in Fasting Lipids from the Long-Term Maintenance Trial with

INVEGATRINZA

in Subjects with Schizophrenia

Open-Label Phase

(relative to

open-label baseline)

Double-Blind Phase

(relative to

double-blind baseline)

Paliperidone

Palmitate

Placebo INVEGATRINZA

Mean change from baseline (mg/dL)

Cholesterol n=400 n=120 n=138

Change from baseline 0.5 -0.4 0.9

LDL n=396 n=119 n=138

Change from baseline 1.1 -0.4 1.1

HDL n=397 n=119 n=138

Change from baseline -0.2 -0.5 -1.3

Triglycerides n=400 n=120 n=138

Change from baseline 0.1 -2.0 5.1

Proportion of Patients with Shifts

Cholesterol Normal

to High

2.0% 3.9% 1.4%

(<200 mg/dL to

≥240 mg/dL)

(8/400) (5/128) (2/148)

LDL Normal to High 0.3% 0.8% 0%

(<100 mg/dL to

≥160 mg/dL)

(1/396) (1/127) (0/148)

HDL Normal to Low 8.6% 9.4% 13.5%

(≥40 mg/dL to

<40 mg/dL)

(34/397) (12/127) (20/148)

Triglycerides Normal

to High

4.5% 1.6% 8.1%

(<150 mg/dL to

≥200 mg/dL)

(18/400) (2/128) (12/148)

During the open-label phase, subjects received several doses of the 1-month

paliperidone palmitate extended-release injectable suspension followed by a single

dose of INVEGATRINZA

[see Clinical Studies (14)].

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 long-term maintenance trial with

INVEGATRINZA

in subjects with schizophrenia are presented in Table 7.

Table 7. Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7%

Gain in Body Weight from the Long-Term Maintenance Trial with

INVEGATRINZA

in Subjects with Schizophrenia

Open-Label Phase

(relative to

open-label baseline)

Double-Blind Phase

(relative to

double-blind baseline)

Paliperidone

Palmitate

Placebo INVEGATRINZA

n=466 n=142 n=157

Weight (kg)

Change from baseline

1.42 -1.28 0.94

Weight Gain ≥ 7%

increase from

baseline

15.2% 0.7% 9.6%

During the open-label phase, subjects received several doses of the 1-month

paliperidone palmitate extended-release injectable suspension followed by a single

dose of INVEGATRINZA

[see Clinical Studies (14)].

5.7 Orthostatic Hypotension and Syncope

Paliperidone can induce orthostatic hypotension and syncope in some patients because

of its alpha-adrenergic blocking activity. In the long-term maintenance trial, syncope

was reported in < 1% (1/506) of subjects treated with the 1-month paliperidone

palmitate extended-release injectable suspension during the open-label phase; there

were no cases reported during the double-blind phase in either treatment group. In the

long-term maintenance trial, orthostatic hypotension was reported as an adverse

event by < 1% (1/506) of subjects treated with the 1-month paliperidone palmitate

extended-release injectable suspension and < 1% (1/379) of subjects after receiving a

single-dose of INVEGA TRINZA

during the open-label phase; there were no cases

reported during the double-blind phase in either treatment group.

INVEGA TRINZA

(paliperidone palmitate) INVEGA TRINZA

(paliperidone palmitate)

INVEGA TRINZA

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TRINZA

, 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TRINZA

. 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TRINZA

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 treated promptly if such symptoms or signs occur. Discontinue

INVEGA TRINZA

in patients with severe neutropenia (absolute neutrophil count

<1000/mm

) and follow their WBC until recovery.

5.10 Hyperprolactinemia

Like other drugs that antagonize dopamine D

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.

In a long-term maintenance trial of INVEGA TRINZA

, 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 double-blind phase were noted in a higher

percentage of males in the INVEGATRINZA

group than in the placebo group (46% vs.

25%) and in a higher percentage of females in the INVEGATRINZA

group than in the

placebo group (32% vs. 15%). During the double-blind phase, 1 female (2.4%) in the

INVEGA TRINZA

group experienced an adverse reaction of amenorrhea, while no

potentially prolactin-related adverse reactions were noted among females in the

placebo group. There were no potentially prolactin-related adverse reactions among

males in either group.

Prior to the double-blind phase (during the 29-week open-label phase of the long-term

maintenance trial), the mean (SD) serum prolactin values at baseline in males (N=368)

were 17.1 (13.55) ng/mL and 51.6 (40.85) ng/mL in females (N=122). Twelve weeks

after a single injection of INVEGA TRINZA

at the end of the open-label phase, mean

(SD) prolactin values were 25.8 (13.49) ng/mL in males (N=322) and 70.6 (40.23) ng/mL

in females (N=107). During the open-label phases 27% of females and 42% 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 (7.9% vs. 3.7%). Amenorrhea (4.7%) and galactorrhea

(3.1%) were the most commonly observed (≥3%) potentially prolactin-related adverse

reactions in females. Among males in the open-label phase, no potentially prolactin-

related adverse reaction was observed with a rate greater than 3%.

5.11 Potential for Cognitive and Motor Impairment

Somnolence, sedation, and dizziness were reported as adverse reactions in subjects

treated with INVEGA TRINZA

[see Adverse Reactions (6.1)]. Antipsychotics, including

INVEGA TRINZA

, 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 long-term maintenance trial there were no reports of seizures or convulsions. In

the pivotal clinical studies with the 1-month paliperidone palmitate extended-release

injectable suspension which included four ﬁxed-dose, double-blind, placebo-controlled

studies in subjects with schizophrenia, <1% (1/1293) of subjects treated with the

1-month injection 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TRINZA

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 TRINZA

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 TRINZA

, 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TRINZA

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.

6 ADVERSE REACTIONS

The following are discussed in more detail in other sections of the labeling:

• Increased mortality in elderly patients with dementia-related psychosis [see Boxed

Warning and Warnings and Precautions (5.1)]

• Cerebrovascular adverse reactions, including stroke, in elderly patients with

dementia-related psychosis [see Warnings and Precautions (5.2)]

• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]

• QT prolongation [see Warnings and Precautions (5.4)]

• Tardive dyskinesia [see Warnings and Precautions (5.5)]

• Metabolic changes [see Warnings and Precautions (5.6)]

• Orthostatic hypotension and syncope [see Warnings and Precautions (5.7)]

• Falls [see Warnings and Precautions (5.8)]

• Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.9)]

• Hyperprolactinemia [see Warnings and Precautions (5.10)]

• Potential for cognitive and motor impairment [see Warnings and Precautions (5.11)]

• Seizures [see Warnings and Precautions (5.12)]

• Dysphagia [see Warnings and Precautions (5.13)]

• Priapism [see Warnings and Precautions (5.14)]

• Disruption of body temperature regulation [see Warnings and Precautions (5.15)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction

rates observed in the clinical trials of a drug cannot be directly compared to rates

in the clinical trials of another drug and may not reﬂect the rates observed in

clinical practice.

Patient Exposure

The data described in this section include data from two clinical trials. One is a long-

term maintenance trial, in which 506 subjects with schizophrenia received several

doses of the 1-month paliperidone palmitate extended-release injectable suspension

during the open-label phase, of which 379 subjects continued to receive a single

injection of INVEGA TRINZA

during the open-label phase, and 160 subjects were

subsequently randomized to receive at least one dose of INVEGA TRINZA

and

145 subjects received placebo during the double-blind placebo-controlled phase. The

mean (SD) duration of exposure during the double-blind phase was 150 (79) days in

the placebo group and 175 (90) days in the INVEGA TRINZA

group. The other is a

Phase 1 study (N=308), which included patients with schizophrenia who received a

single injection of INVEGATRINZA

concomitantly with other oral antipsychotics.

INVEGA TRINZA

(paliperidone palmitate) INVEGA TRINZA

(paliperidone palmitate)

Adverse Reactions in a Double-Blind, Placebo-Controlled (Long-Term Maintenance)

Clinical Trial

Commonly Observed Adverse Reactions: The most common adverse reactions

(incidence at least 5% in the open-label phase, or in the INVEGATRINZA

group and at

least twice the incidence in the placebo group during the double-blind phase) were

injection site reaction, weight increased, headache, upper respiratory tract infection,

akathisia, and parkinsonism.

Discontinuation of Treatment Due to Adverse Events: The percentages of subjects

who discontinued due to adverse events in the long-term maintenance trial were 5.1%

during the open-label phase. During the double-blind phase, no INVEGA TRINZA

treated subject and one placebo-treated subject discontinued due to adverse events.

Adverse Reactions Occurring at an Incidence of 2% or More in INVEGATRINZA

Treated Patients: The safety proﬁle of INVEGATRINZA

was similar to that seen with

the 1-month paliperidone extended-release injectable suspension. Table 8 lists the

adverse reactions reported in a long-term maintenance trial in subjects with

schizophrenia.

Table 8. Incidences of Adverse Reactions 2% or More of INVEGA TRINZA

-Treated

Patients (and Greater than Placebo) for the Open-Label and Double-Blind

Phases of a Long-Term Maintenance Trial in Patients with Schizophrenia

---- Open Label---- ------------ Double Blind ------------

Paliperidone

Palmitate

Placebo INVEGA TRINZA

System Organ Class (N=506) (N=145) (N=160)

Adverse Reaction

General disorders and administration site conditions

Injection site

reaction

12 0 3

Infections and infestations

Upper respiratory

tract infection

5 4 10

Urinary tract infection <1 1 3

Metabolism and nutrition disorders

Weight increased 10 3 9

Nervous system disorders

Akathisia 5 2 5

Headache 7 4 9

Parkinsonism 5 0 4

Table includes adverse reactions that were reported in 2% or more of subjects in the

INVEGA TRINZA

group during the double-blind phase and which occurred at greater

incidence than in the placebo group.

During the open-label phase, subjects received several doses of the 1-month

paliperidone palmitate extended-release injectable suspension followed by a single

dose of INVEGATRINZA

prior to randomization to either placebo or INVEGATRINZA

in the subsequent double-blind phase [see Clinical Studies (14)].

The following terms were combined:

Injection site reaction includes Injection site reaction, Injection site erythema, Injection

site extravasation, Injection site induration, Injection site inﬂammation, Injection site mass,

Injection site nodule, Injection site pain, Injection site swelling.

Weight increased includes Weight increased, Waist circumference increased.

Upper respiratory tract infection includes Upper respiratory tract infection,

Nasopharyngitis, Pharyngitis, Rhinitis.

Akathisia includes Akathisia, Restlessness.

Parkinsonism includes Parkinsonism, Cogwheel rigidity, Drooling, Extrapyramidal

disorder, Hypokinesia, Muscle rigidity, Muscle tightness, Musculoskeletal stiffness,

Salivary hypersecretion.

Incidence is based on the number of subjects experiencing at least one adverse

event, not the number of events.

Demographic Differences

An examination of population subgroups in the long-term maintenance trial did not

reveal any evidence of differences in safety on the basis of age, gender, or race alone;

however, there were few subjects 65 years of age and older.

Extrapyramidal Symptoms (EPS)

Data from the long-term maintenance trial provided information regarding EPS. Several

methods were used to measure EPS: (1) the Simpson-Angus global score which

broadly evaluates parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical

rating score which evaluates akathisia, (3) the Abnormal Involuntary Movement Scale

scores which evaluates dyskinesia, and (4) use of anticholinergic medications to treat

EPS (Table 9), and (5) incidence of spontaneous reports of EPS (Table 10).

Table 9. Extrapyramidal Symptoms (EPS) Assessed by Incidence of Rating Scales

and Use of Anticholinergic Medication

Percentage of Subjects

Open-label

Phase

Double-blind

Phase

Paliperidone

Palmitate

Placebo INVEGATRINZA

Scale

(N=506)

(N=145)

(N=160)

Parkinsonism

6 3 6

Akathisia

3 1 4

Dyskinesia

1 3 3

Use of Anticholinergic

Medications

11 9 11

During the open-label phase, subjects received several doses of the 1-month

paliperidone palmitate extended-release injectable suspension followed by a single

dose of INVEGATRINZA

[see Clinical Studies (14)].

For Parkinsonism, percent of subjects with Simpson-Angus Total score > 0.3 at any

time (Global score deﬁned as total sum of items score divided by the number of

items)

For Akathisia, percent of subjects with Barnes Akathisia Rating Scale global score

≥ 2 at any time

For Dyskinesia, percent of subjects with a score ≥ 3 on any of the ﬁrst 7 items or a

score ≥ 2 on two or more of any of the ﬁrst 7 items of the Abnormal Involuntary

Movement Scale at any time

Percent of subjects who received anticholinergic medications to treat EPS

Table 10. Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred

Term

Percentage of Subjects

Open-label

Phase

Double-blind

Phase

Paliperidone

Palmitate

Placebo INVEGATRINZA

EPS Group

(N=506)

(N=145)

(N=160)

Overall percentage of

subjects with EPS-

related adverse events

10 3 8

Parkinsonism 4 0 4

Hyperkinesia 5 2 5

Tremor 2 0 1

Dyskinesia <1 1 1

Dystonia 1 0 1

During the open-label phase, subjects received several doses of the 1-month

paliperidone palmitate extended-release injectable suspension followed by a single

dose of INVEGATRINZA

[see Clinical Studies (14)].

Parkinsonism group includes: Cogwheel rigidity, drooling, extrapyramidal disorder,

hypokinesia, muscle rigidity, muscle tightness, musculoskeletal stiffness, parkinsonism

Hyperkinesia group includes: Akathisia, restlessness

Dystonia group includes: Blepharospasm, dystonia, muscle spasms

After injection of INVEGATRINZA

in the open-label phase, 12 (3.2%) subjects had EPS

that were new or worsened in severity, with events under the groupings of hyperkinesia

(1.6%) and parkinsonism (1.3%) being the most common. After injection of

INVEGA TRINZA

in the open-label or double-blind phases, one subject discontinued

from the open-label phase due to restlessness.

An examination of the time to EPS during the double-blind phase showed no clustering

of these events at visits that would be expected to correspond to median peak plasma

concentrations of paliperidone for subjects randomized to INVEGATRINZA

Dystonia

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur

in susceptible individuals during the ﬁrst few days of treatment. Dystonic symptoms

include: spasm of the neck muscles, sometimes progressing to tightness of the throat,

swallowing difﬁculty, difﬁculty breathing, and/or protrusion of the tongue. While these

symptoms can occur at low doses, they occur more frequently and with greater

severity with high potency and at higher doses of ﬁrst generation antipsychotic drugs.

An elevated risk of acute dystonia is observed in males and younger age groups.

Pain Assessment and Local Injection Site Reactions

Investigator ratings of injection site. Redness and swelling were observed in 2% or

less of subjects in the INVEGA TRINZA

and placebo groups during the double-blind

phase of the long-term maintenance study, and were rated mild based on investigator

ratings using a 4-point scale (0=absent; 1=mild; 2=moderate; 3=severe). There were

no reports of induration in either group during the double-blind phase, and no subjects

discontinued due to INVEGATRINZA

injection.

Subject ratings of injection site pain. Subject evaluations of injection pain during the

double-blind phase also were similar for placebo and INVEGATRINZA

INVEGA TRINZA

(paliperidone palmitate) INVEGA TRINZA

(paliperidone palmitate)

Subject ratings of injection site pain in the single-dose Phase 1 study allowed for

assessment of the temporal course of injection site pain. Residual injection pain

peaked 1 or 6 hours after injection, and trended downward 3 days after the injection.

Deltoid injections were numerically more painful than gluteal injections, although most

pain ratings were below 10 mm on a 100-mm scale.

Other Adverse Reactions Observed During the Clinical Trial Evaluation of

INVEGATRINZA

The following additional adverse reactions were identiﬁed in the long-term

maintenance trial. The following list does not include reactions: 1) already listed in

previous tables or elsewhere in labeling, 2) for which a drug cause was remote,

3) which were so general as to be uninformative, 4) which were not considered to have

signiﬁcant clinical implications, or 5) occurred at an incidence lower than that of

placebo-treated patients.

Cardiac disorders: tachycardia

Gastrointestinal disorders: nausea, vomiting

Metabolism and nutrition disorders: hyperinsulinemia

Psychiatric disorders: anxiety

Additional Adverse Reactions Reported in Clinical Trials with the 1-Month Paliperidone

Palmitate Extended-Release Injectable Suspension

The following is a list of additional adverse reactions that have been reported in clinical

trials with the 1-month paliperidone palmitate extended-release injectable suspension:

Cardiac disorders: atrioventricular block ﬁrst degree, bradycardia, bundle branch

block, palpitations, postural orthostatic tachycardia syndrome

Ear and labyrinth disorders: vertigo

Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurred

Gastrointestinal disorders: abdominal discomfort/abdominal pain upper, diarrhea, dry

mouth, toothache

General disorders and administration site conditions: asthenia, fatigue

Immune system disorders: hypersensitivity

Investigations: electrocardiogram abnormal

Metabolism and nutrition disorders: decreased appetite, increased appetite

Musculoskeletal and connective tissue disorders: back pain, myalgia, pain in

extremity, joint stiffness, muscle spasms, muscle twitching, nuchal rigidity

Nervous system disorders: bradykinesia, cerebrovascular accident, convulsion,

dizziness, dizziness postural, dysarthria, hypertonia, lethargy, oromandibular dystonia,

psychomotor hyperactivity, syncope

Psychiatric disorders: agitation, nightmare

Reproductive system and breast disorders: breast discharge, erectile dysfunction,

gynecomastia, menstrual disorder, menstruation delayed, menstruation irregular, sexual

dysfunction

Respiratory, thoracic and mediastinal disorders: cough

Skin and subcutaneous tissue disorders: drug eruption, pruritus, pruritus

generalized, rash, urticaria

Vascular disorders: hypertension

Additional Adverse Reactions Reported in Clinical Trials with Oral Paliperidone

The following is a list of additional adverse reactions that have been reported in clinical

trials with oral paliperidone:

Cardiac disorders: bundle branch block left, sinus arrhythmia

Gastrointestinal disorders: abdominal pain, constipation, ﬂatulence, small intestinal

obstruction

General disorders and administration site conditions: edema, edema peripheral

Immune system disorders: anaphylactic reaction

Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain,

torticollis, trismus

Nervous system disorders: grand mal convulsion, parkinsonian gait, transient

ischemic attack

Psychiatric disorders: sleep disorder

Reproductive system and breast disorders: breast engorgement, breast tenderness/

breast pain, retrograde ejaculation

Respiratory, thoracic and mediastinal disorders: nasal congestion,

pharyngolaryngeal pain, pneumonia aspiration

Skin and subcutaneous tissue disorders: rash papular

Vascular disorders: hypotension, ischemia

6.2 Postmarketing Experience

The following adverse reactions have been identiﬁed during postapproval use of

paliperidone; because these reactions were reported voluntarily from a population of

uncertain size, it is not always possible to reliably estimate their frequency or establish a

causal relationship to drug exposure: angioedema, catatonia, ileus, somnambulism, swollen

tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary retention.

Cases of anaphylactic reaction after injection with the 1-month paliperidone palmitate

extended-release suspension have been reported during postmarketing experience in

patients who have previously tolerated oral risperidone or oral paliperidone.

Paliperidone is the major active metabolite of risperidone. Adverse reactions reported

with oral risperidone and risperidone long-acting injection can be found in the Adverse

Reactions (6) sections of the package inserts for those products.

7 DRUG INTERACTIONS

7.1 Drugs Having Clinically Important Interactions with INVEGATRINZA

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. In addition, consider the

3-month dosing interval and long half-life of INVEGA TRINZA

[see Dosage and

Administration (2.1) and Clinical Pharmacology (12.3)].

Table 11. Clinically Important Drug Interactions with INVEGATRINZA

Concomitant Drug Name

or Drug Class

Clinical Rationale

Clinical

Recommendation

Centrally Acting Drugs and

Alcohol

Given the primary CNS

effects of paliperidone,

concomitant use of

centrally acting drugs and

alcohol may modulate the

CNS effects of

INVEGA TRINZA

should

be used with caution in

combination with other

centrally acting drugs and

alcohol [see Adverse

Reactions (6.1, 6.2)].

Drugs with Potential for

Inducing Orthostatic

Hypotension

Because INVEGATRINZA

has the potential for

inducing orthostatic

hypotension,

an additive

effect may occur when

INVEGATRINZA

administered with other

therapeutic agents that

have this potential [see

Warnings and Precautions

(5.7)].

Monitor orthostatic vital

signs in patients who are

vulnerable to hypotension

[see Warnings and

Precautions (5.7)].

Strong Inducers of

CYP3A4 and P-gp (e.g.,

carbamazepine, rifampin,

or St. John’s Wort)

The concomitant use of

paliperidone and strong

inducers of CYP3A4 and

P-gp may decrease the

exposure of paliperidone

[see Clinical Pharmacology

(12.3)].

Avoid using CYP3A4

and/or P-gp inducers with

INVEGATRINZA

during

the 3-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 (2.7)].

Levodopa and Other

Dopamine Agonists

Paliperidone may

antagonize the effect of

levodopa and other

dopamine agonists.

Monitor and manage

patient as clinically

appropriate.

7.2 Drugs Having No Clinically Important Interactions with INVEGATRINZA

Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of

INVEGA TRINZA

is required when administered concomitantly with valproate [see

Clinical Pharmacology (12.3)]. Additionally, no dosage adjustment is necessary for

valproate when co-administered with INVEGATRINZA

[see Clinical Pharmacology (12.3)].

Pharmacokinetic interaction between lithium and INVEGATRINZA

is 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)]

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women

exposed to atypical antipsychotics, including INVEGA TRINZA

, 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 TRINZA

during pregnancy (see Clinical

Considerations). Paliperidone has been detected in plasma in adult subjects up to

INVEGA TRINZA

(paliperidone palmitate) INVEGA TRINZA

(paliperidone palmitate)

18 months after a single-dose administration of INVEGA TRINZA

[see Clinical

Pharmacology (12.3)], and the clinical signiﬁcance of INVEGA TRINZA

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/m

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/m

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 is 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 TRINZA

, during

the third trimester of pregnancy. These symptoms have varied in severity. Monitor

neonates for 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

No developmental toxicity studies were conducted with the 3-month paliperidone

palmitate extended-release injectable suspension.

There were no treatment-related effects on the offspring when pregnant rats were

injected intramuscularly with 1-month paliperidone palmitate extended-release

injectable suspension during the period of organogenesis at doses up to 250 mg/kg,

which is 3 times the MRHD of 819 mg of the 3-month paliperidone palmitate extended-

release injectable suspension based on mg/m

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/m

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/m

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/m

body surface area. When the offspring of

pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/m

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/m

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).

8.2 Lactation

Risk Summary

Limited data from published literature report the presence of paliperidone in human

breast milk. There is no information on the effects on the breastfed infant, or the

effects on milk production; however, there are reports of sedation, failure to thrive,

jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements)

in breastfed infants exposed to paliperidone’s parent compound, risperidone (see

Clinical Considerations). Paliperidone has been detected in plasma in adult subjects up

to 18 months after a single-dose administration of INVEGA TRINZA

, and the clinical

signiﬁcance on the breastfed infant is not known [see Clinical Pharmacology (12.3)].

The developmental and health beneﬁts of breastfeeding should be considered along

with the mother’s clinical need for INVEGA TRINZA

and any potential adverse effects

on the breastfed child from INVEGA TRINZA

or from the mother’s underlying condition.

Clinical Considerations

Infants exposed to INVEGA TRINZA

through breastmilk should be monitored for excess

sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and

abnormal muscle movements).

8.3 Females and Males of Reproductive Potential

Infertility

Females

Based on the pharmacologic action of paliperidone (D

receptor antagonism), treatment

with INVEGA TRINZA

may result in an increase in serum prolactin levels, which may

lead to a reversible reduction in fertility in females of reproductive potential

[see Warnings and Precautions (5.10)].

8.4 Pediatric Use

Safety and effectiveness of INVEGATRINZA

in patients less than 18 years of age have

not been established. Use of INVEGATRINZA

is not recommended in pediatric patients

because of the potential longer duration of an adverse event compared to shorter-

acting products. In clinical trials of oral paliperidone, there were notably higher

incidences of dystonia, hyperkinesia, tremor, and parkinsonism in the adolescent

population as compared to the adult studies.

Juvenile Animal Studies

No juvenile animal studies were conducted with the 3-month paliperidone palmitate

extended-release injectable suspension.

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 TRINZA

on growth and sexual maturation have not

been fully evaluated in children and adolescents.

8.5 Geriatric Use

Clinical studies of INVEGATRINZA

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, monitor renal function and adjust dosage [see Dosage and

Administration (2.5)].

8.6 Renal Impairment

Use of INVEGA TRINZA

is not recommended in patients with moderate or

severe renal impairment (creatinine clearance < 50 mL/min). Use of INVEGA TRINZA

in patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to

< 80 mL/min) is based on the previous dose of the 1-month paliperidone palmitate

extended-release injectable suspension that the patient was stabilized on prior to

initiation of INVEGA TRINZA

[see Dosage and Administration (2.5) and Clinical

Pharmacology (12.3)].

8.7 Hepatic Impairment

INVEGATRINZA

has not been studied in patients with hepatic impairment. Based on a

study with oral paliperidone, no dose adjustment is required in patients with mild or

moderate hepatic impairment. Paliperidone has not been studied in patients with

severe hepatic impairment [see Clinical Pharmacology (12.3)].

INVEGA TRINZA

(paliperidone palmitate) INVEGA TRINZA

(paliperidone palmitate)

8.8 Patients with Parkinson’s Disease or Lewy Body Dementia

Patients with Parkinson’s Disease or Dementia with Lewy Bodies can experience

increased sensitivity to INVEGA TRINZA

. Manifestations can include confusion,

obtundation, postural instability with frequent falls, extrapyramidal symptoms, and

clinical features consistent with neuroleptic malignant syndrome.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

INVEGATRINZA

(paliperidone) is not a controlled substance.

9.2 Abuse

Paliperidone

has not been systematically studied in animals or humans for its potential

for abuse.

9.3 Dependence

Paliperidone has not been systematically studied in animals or humans for its potential

for tolerance or physical dependence.

10 OVERDOSAGE

10.1 Human Experience

No cases of overdose were reported in premarketing studies with paliperidone

palmitate injection. Because INVEGA TRINZA

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 OVERDOSAGE 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 paliperidone and INVEGA TRINZA

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 TRINZA

and the long

apparent half-life of paliperidone when assessing treatment needs and recovery.

11 DESCRIPTION

INVEGA TRINZA

contains paliperidone palmitate. The active ingredient, paliperidone, is

an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives.

INVEGA TRINZA

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 C

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TRINZA

is available as a white to off-white sterile aqueous extended-release

suspension for intramuscular injection in dose strengths of 273 mg, 410 mg, 546 mg,

and 819 mg paliperidone palmitate in single-dose preﬁlled syringes. The drug product

hydrolyzes to the active moiety, paliperidone, resulting in dose strengths of 175 mg,

263 mg, 350 mg, and 525 mg of paliperidone, respectively. The inactive ingredients are

polysorbate 20 (10 mg/mL), polyethylene glycol 4000 (75 mg/mL), citric acid

monohydrate (7.5 mg/mL), sodium dihydrogen phosphate monohydrate (6 mg/mL),

sodium hydroxide (5.4 mg/mL used as an alkalizing agent to set the pH at 7), and

water for injection.

INVEGA TRINZA

is provided in a single-dose preﬁlled syringe (cyclic-oleﬁn-copolymer)

with either 175 mg (0.875 mL), 263 mg (1.315 mL), 350 mg (1.75 mL), or 525 mg

(2.625 mL) paliperidone (as 273 mg, 410 mg, 546 mg, or 819 mg paliperidone

palmitate) suspension with a plunger stopper and tip cap (bromobutyl rubber), a

backstop, and 2 types of commercially available needles: a thin walled 22G, 1 ½-inch

safety needle and a thin walled 22G, 1-inch safety needle.

12 CLINICAL PHARMACOLOGY

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 (D

) and serotonin

Type 2 (5HT

) receptor antagonism.

12.2 Pharmacodynamics

In vitro, paliperidone acts as an antagonist at the central dopamine Type 2 (D

) and

serotonin Type 2 (5HT

) receptors with binding afﬁnities (Ki values) of 1.6-2.8 nM for

and 0.8-1.2 nM for 5HT

receptors. Paliperidone is also active as an antagonist at

the α

and α

adrenergic receptors and H

histaminergic receptors, which may explain

some of the other effects of the drug. Paliperidone has no afﬁnity for cholinergic

muscarinic or β

- and β

-adrenergic receptors. The pharmacological activity of the (+)-

and (-)- paliperidone enantiomers is qualitatively and quantitatively similar in vitro.

12.3 Pharmacokinetics

Absorption and Distribution

Due to its extremely low water solubility, the 3-month formulation of paliperidone

palmitate dissolves slowly after intramuscular injection before being hydrolyzed to

paliperidone and absorbed into the systemic circulation. The release of the drug starts

as early as day 1 and lasts for as long as 18 months.

Following a single intramuscular dose of INVEGATRINZA

, the plasma concentrations

of paliperidone gradually rise to reach maximum plasma concentrations at a median

max

of 30-33 days. Following intramuscular injection of INVEGATRINZA

at doses of

273-819mg in the deltoid muscle, on average, an 11-12% higher C

max

was observed

compared with injection in the gluteal muscle. The release proﬁle and dosing regimen

of INVEGATRINZA

results in sustained therapeutic concentrations over 3 months. The

total and peak exposure of paliperidone following INVEGATRINZA

administration was

dose-proportional over a 273-819 mg dose range. The mean steady-state peak:trough

ratio for a INVEGA TRINZA

dose was 1.6 following gluteal administration and

1.7 following deltoid administration. Following administration of INVEGA TRINZA

, the

apparent volume of distribution of paliperidone is 1960L.

The plasma protein binding of racemic paliperidone is 74%.

Following administration of INVEGA TRINZA

, the (+) and (-) enantiomers of

paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.7-1.8.

Metabolism and Elimination

In a study with oral immediate-release

C-paliperidone, one week following

administration of a single oral dose of 1 mg immediate-release

C-paliperidone, 59%

of the dose was excreted unchanged into urine, indicating that paliperidone is not

extensively metabolized in the liver. Approximately 80% of the administered

radioactivity was recovered in urine and 11% in the feces. Four metabolic pathways

have been identiﬁed in vivo, none of which accounted for more than 10% of the dose:

dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although

in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of

paliperidone, there is no evidence in vivo that these isozymes play a signiﬁcant role in

the metabolism of paliperidone. Population pharmacokinetics analyses indicated

no discernible difference on the apparent clearance of paliperidone after administration

of oral paliperidone between extensive metabolizers and poor metabolizers of

CYP2D6 substrates.

The median apparent half-life of paliperidone following INVEGATRINZA

administration

over the dose range of 273-819 mg ranged from 84-95 days following deltoid

injections and 118-139 days following gluteal injections. The concentration of

paliperidone remaining in the circulation 18 months after dosing of 819 mg

INVEGATRINZA

is stopped is estimated to be 3% (following deltoid injection) or 7%

(following gluteal injection) of the average steady-state levels.

Long-acting 3-month paliperidone palmitate injection versus other paliperidone

formulations

INVEGA TRINZA

is designed to deliver paliperidone over a 3-month period, while

1-month paliperidone palmitate injection is administered on a monthly basis.

INVEGA TRINZA

, when administered at doses that are 3.5-fold higher than the

corresponding dose of 1-month paliperidone palmitate injection, results in paliperidone

exposures similar to those obtained with corresponding monthly doses of 1-month

paliperidone palmitate injection and corresponding once daily doses of paliperidone

extended-release tablets. The exposure range for INVEGA TRINZA

is encompassed

within the exposure range for the approved dose strengths of paliperidone extended-

release tablets.

INVEGA TRINZA

(paliperidone palmitate) INVEGA TRINZA

(paliperidone palmitate)

The between-subject variability for paliperidone pharmacokinetics following delivery

from INVEGA TRINZA

was similar to the variability for paliperidone extended-release

tablets. Because of the difference in median pharmacokinetic proﬁles among the three

formulations, caution should be exercised when making a direct comparison of their

pharmacokinetic properties.

Drug Interaction Studies

No speciﬁc drug interaction studies have been performed with INVEGA TRINZA

. The

information below is obtained from studies with oral paliperidone.

Effects of other drugs on the exposures of INVEGA TRINZA

are summarized in

Figure 1. After oral administration of 20 mg/day of paroxetine (a potent CYP2D6

inhibitor), an increase in mean C

max

and AUC values at steady-state was observed (see

Figure 1). Higher doses of paroxetine have not been studied. The clinical relevance is

unknown. After oral administration, a decrease in mean C

max

and AUC values at steady

state is expected when patients are treated with carbamazepine, a strong inducer of

both CYP3A4 and P-gp [see Drug Interactions (7.1)]. This decrease is caused, to a

substantial degree, by a 35% increase in renal clearance of paliperidone.

Figure 1: The effects of other drugs on INVEGATRINZA

pharmacokinetics.

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; they contribute to only a small

fraction of total body clearance. In vitro studies demonstrated that paliperidone is a

substrate of P-glycoprotein (P-gp) [see Drug Interactions (7.2)].

In vitro studies in human liver microsomes demonstrated that paliperidone does not

substantially inhibit the metabolism of drugs metabolized by cytochrome P450

isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and

CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are

metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone

is also not expected to have enzyme inducing properties.

Paliperidone is a weak inhibitor of P-gp at high concentrations. No in vivo data are

available, and the clinical relevance is unknown.

The effects of INVEGA TRINZA

on the exposures of other drugs are summarized in

Figure 2.

After oral administration of paliperidone, the steady-state C

max

and AUC of valproate

were not affected in 13 patients stabilized on valproate. In a clinical study, subjects on

stable doses of valproate had comparable valproate average plasma concentrations

when oral paliperidone extended-release tablets 3-15 mg/day was added to their

existing valproate treatment [see Drug Interactions (7.1)].

Figure 2: The effects of INVEGATRINZA

on pharmacokinetics of other drugs.

Studies in Specific Populations

No speciﬁc pharmacokinetic studies have been performed with INVEGA TRINZA

speciﬁc populations. All the information is obtained from studies with oral paliperidone

or is based on the population pharmacokinetic modelling of oral paliperidone and

INVEGATRINZA

. Exposures of paliperidone in speciﬁc populations (renal impairment,

hepatic impairment and elderly) are summarized in Figure 3 [see Dosage and

Administration (2.5) and Use in Speciﬁc Populations (8.6)].

After oral administration of paliperidone in patients with moderate hepatic impairment,

the plasma concentrations of free paliperidone were similar to those of healthy

subjects, although total paliperidone exposure decreased because of a decrease in

protein binding. Paliperidone has not been studied in patients with severe hepatic

impairment [see Use in Speciﬁc Populations (8.7)].

After oral administration of paliperidone in elderly subjects, the C

max

and AUC increased

1.2-fold compared to young subjects. However, there may be age-related decreases in

creatinine clearance [see Dosage and Administration (2.5) and Use in Speciﬁc

Populations (8.5)].

Figure 3: Effects of intrinsic factors on paliperidone pharmacokinetics.

Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate

for CYP1A2;smoking should, therefore, not have an effect on the pharmacokinetics of

paliperidone. Slower absorption was observed in females in a population

pharmacokinetic analysis. At apparent steady-state with INVEGA TRINZA

, the trough

concentrations were similar between males and females.

Lower C

max

was observed in overweight and obese subjects. At apparent steady-state

with INVEGA TRINZA

, the trough concentrations were similar among normal,

overweight, and obese subjects.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No carcinogenicity studies were conducted with the 3-month paliperidone palmitate

extended-release injectable suspension.

The carcinogenic potential of intramuscularly injected 1-month paliperidone palmitate

extended-release injectable suspension was assessed in rats. There was an increase in

mammary gland adenocarcinomas in female rats at 16, 47, and 94 mg/kg/month,

which is 0.2, 0.6, and 1 times, respectively, the MRHD of 819 mg of INVEGA TRINZA

based on mg/m

body surface area. A no-effect dose was not established. Male rats

showed an increase in mammary gland adenomas, ﬁbroadenomas, and carcinomas at

0.6 and 1 times the MRHD based on mg/m

body surface area. A carcinogenicity study

in mice has not been conducted with paliperidone palmitate.

Carcinogenicity studies with risperidone, which is extensively converted to paliperidone

in rats, mice, and humans, were conducted in Swiss albino mice and Wistar rats.

Risperidone was administered in the diet at daily doses of 0.63, 2.5, and 10 mg/kg for

18 months to mice and for 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-effect dose for these tumors was less than or equal to the maximum recommended

human dose of risperidone based on mg/m

body surface area (see risperidone

package insert). An increase in mammary, pituitary, and endocrine pancreas neoplasms

has been found in rodents after chronic administration of other antipsychotic drugs and

is considered to be mediated by prolonged dopamine D2 antagonism and

hyperprolactinemia. The relevance of these tumor ﬁndings in rodents to human risk is

unclear [see Warnings and Precautions (5.7)].

Mutagenesis

No mutagenesis studies were conducted with the 3-month paliperidone palmitate

extended-release injectable suspension.

Paliperidone palmitate showed no genotoxicity in the in vitro Ames bacterial reverse

mutation test or the mouse lymphoma assay. Paliperidone was not genotoxic in the

in vitro Ames bacterial reverse mutation test, the mouse lymphoma assay or the in vivo

rat bone marrow micronucleus test.

INVEGA TRINZA

(paliperidone palmitate) INVEGA TRINZA

(paliperidone palmitate)

Effect

other

drugs

INVEGA

TRINZA

pharmacokinetics

INVEGA

TRINZA

Fold

Change

and

90%

inhibitor

Paroxetine

Cmax

inducer

Carbamazepine

AUC

Cmax

Divalproex

Sodium

AUC

T T

0.0

2.0

Change

Relative

Reference

(without

interacting

drug)

Effect

INVEGA

TRINZA

pharmacokinetics

other

drugs

Fold

Change

and

90%

Divalproex

Sodium

AUC

Cmax

T T

0.0

1.0

2.0

Change

Relative

Reference

(without

interacting

drug)

Effect

intrinsic

factors

INVEGA

TRINZA

pharmacokinetics

INVEGA

TRINZA

Fold

Change

and

90%

Renal

Impairment

Mild

Normal

AUC

Moderate

Normal

Severe

Normal

Hepatic

Impairment

Moderate

Normal

AUC

Age

AUC

Change

Relative

Reference

Impairment of Fertility

No fertility studies were conducted with the 3-month paliperidone palmitate extended-

release injectable suspension.

In an oral paliperidone study of fertility, the percentage of treated female rats that

became pregnant was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day

which is 2 times the MRHD based on mg/m

body surface area. However, pre- and

post-implantation loss was increased, and the number of live embryos was slightly

decreased, at 2.5 mg/kg, a dose that also caused slight maternal toxicity. These

parameters were not affected at a dose of 0.63 mg/kg, which is half of the MRHD

based on mg/m

body surface area.

The fertility of male rats was not affected at oral doses of paliperidone of up to 2 times

the MRHD of 12 mg/day based on mg/m

body surface area, although sperm count and

sperm viability studies were not conducted with paliperidone. In a subchronic study in

Beagle dogs with risperidone, which is extensively converted to paliperidone in dogs

and humans, all doses tested (0.31 mg/kg - 5.0 mg/kg) resulted in decreases in serum

testosterone and in sperm motility and concentration (0.6 to 10 times the MRHD of

16 mg/day for risperidone, based on mg/m

body surface area). Serum testosterone

and sperm parameters partially recovered, but remained decreased after the last

observation (two months after treatment was discontinued).

13.2 Animal Toxicology and/or Pharmacology

Injection site toxicity was assessed in minipigs injected intramuscularly with the

3-month paliperidone palmitate extended-release injectable suspension at doses up to

819 mg, which is equal to the MRHD. Injection site inﬂammatory reactions were

greater and more advanced than reactions to the 1-month paliperidone palmitate

extended-release injectable suspension. Reversibility of these ﬁndings was not

examined.

14 CLINICAL STUDIES

The efﬁcacy of INVEGA TRINZA

for the treatment of schizophrenia in patients who

have been adequately treated for at least 4 months with INVEGASUSTENNA

(1-month

paliperidone palmitate extended-release injectable suspension) was evaluated in a

long-term double-blind, placebo-controlled randomized-withdrawal trial designed to

evaluate time to relapse involving adult subjects who met DSM-IV-TR criteria for

schizophrenia.

Patients could enter the study with acute symptoms (if previously treated with oral

antipsychotics) or be clinically stable (if treated with long-acting injectable

antipsychotics [LAI]). All patients who previously received oral antipsychotics received

the paliperidone palmitate 1-month initiation regimen (deltoid injections of 234 mg and

156 mg one week apart), while those patients switching from LAI medication were

treated with the 1-month paliperidone palmitate extended-release injectable

suspension in place of the next scheduled injection. Speciﬁcally:

• For patients entering the study who were already being treated with the 1-month

paliperidone palmitate extended-release injectable suspension, their dosing

remained unchanged. Patients who were currently receiving the 39 mg dose of

1-month paliperidone palmitate were not eligible to enroll in the study.

• Patients entering the study who were being treated with 25 mg, 37.5 mg, or 50 mg

of RISPERDAL CONSTA

(risperidone long-acting injection) were switched to 78 mg,

117 mg, or 156 mg, respectively, of the 1-month paliperidone palmitate

administered in the deltoid muscle.

• Patients entering the study who were being treated with any other LAI product were

switched to 234 mg of the 1-month paliperidone palmitate administered in the

deltoid muscle.

This study consisted of the following three treatment periods:

• A 17-week ﬂexible-dose open-label period with the 1-month paliperidone palmitate

(ﬁrst part of a 29-week open-label stabilization phase). A total of 506 patients

entered this phase of the study. Dosing of the 1-month paliperidone palmitate was

individualized based on symptom response, tolerability, and previous medication

history. Speciﬁcally, the dose could be adjusted at the week 5 and 9 injections and

the injection site could be deltoid or gluteal. The week 13 dose had to be the same

as the week 9 dose. Patients had to be clinically stable at the end of this period

before receiving INVEGATRINZA

at the week 17 visit. Clinical stability was deﬁned

as achieving a PANSS total score <70 at week 17. 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.

• A 12-week open-label treatment period with INVEGA TRINZA

(second part of a

29-week open-label stabilization phase). A total of 379 patients received a single-

dose of INVEGATRINZA

which was a 3.5 multiple of the last dose of the 1-month

paliperidone palmitate. Patients had to remain clinically stable before entry into the

next period (double-blind). Clinical stability was deﬁned as achieving a PANSS total

score <70 and scores of ≤ 4 for seven speciﬁc PANSS items.

• A variable length double-blind treatment period. In this period, 305 stabilized

patients were randomized 1:1 to continue treatment with INVEGA TRINZA

placebo until relapse, early withdrawal, or the end of study. Patients were

randomized to the same dose of INVEGA TRINZA

they received during the open-

label phase (i.e., 273 mg, 410 mg, 546mg, or 819 mg) or to placebo administered

every 12 weeks. The numbers (%) of patients entering double-blind on each of the

dose levels were 6 (4%) for 273 mg, 15 (9%) for 410mg, 78(49%) for 546 mg, and

61 (38%) for 819 mg.

The primary efﬁcacy variable was time to ﬁrst relapse. Relapse was pre-deﬁned as

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.

A pre-planned interim analysis showed a statistically signiﬁcantly longer time to

relapse in patients treated with INVEGA TRINZA

compared to placebo, and the study

was stopped early because efﬁcacy was demonstrated. The most common reason for

relapse observed across both treatment groups was increase in the PANSS total score

value, followed by psychiatric hospitalization.

Twenty-three percent (23%) of patients in the placebo group and 7.4% of patients in

the INVEGA TRINZA

group experienced a relapse event. The time to relapse was

statistically signiﬁcantly longer in patients randomized to the INVEGA TRINZA

group

than compared to placebo-treated patients. A Kaplan-Meier plot of time to relapse by

treatment group is shown in Figure 4.

An examination of population subgroups did not reveal any clinically signiﬁcant

differences in responsiveness on the basis of gender, age, or race.

Figure 4: Kaplan-Meier Plot of Cumulative Proportion of Patients with Relapse

Over

Time – Interim Analysis.

Time (days) since Randomization

28 56 84 112 140 168 196 224 252 280 308 336 364 392 420

Estimated Percent of Subjects With Relapse

Placebo (N=135)

INVEGA TRINZA (N=148)

The median time to relapse in the placebo group was 274 days. The median time to

relapse in the INVEGATRINZA

group could not be estimated due to low percentage

(7.4%) of subjects with relapse.

16 HOW SUPPLIED/STORAGE AND HANDLING

INVEGATRINZA

is available as a white to off-white sterile aqueous extended-release

suspension for intramuscular injection in dose strengths of 273 mg/0.88 mL,

410 mg/1.32 mL, 546 mg/1.75 mL, and 819 mg/2.63 mL paliperidone palmitate in

single-dose preﬁlled syringes. The single-use kit contains a preﬁlled syringe and

2 safety needles (a thin walled 22G, 1-inch safety needle and a thin walled 22G,

1½-inch safety needle).

273 mg paliperidone palmitate kit (NDC 50458-606-01)

410 mg paliperidone palmitate kit (NDC 50458-607-01)

546 mg paliperidone palmitate kit (NDC 50458-608-01)

819 mg paliperidone palmitate kit (NDC 50458-609-01)

Storage and Handling

Store at room temperature 20°C to 25°C (68°F to 77°F); excursions between 15°C and

30°C (59°F and 86°F) are permitted. Do not mix with any other product or diluent.

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 adverse reaction, Neuroleptic Malignant

Syndrome (NMS), that has been reported in association with administration of

antipsychotic drugs. Advise patients, family members, or caregivers to contact their

healthcare provider or report to the emergency room if they experience signs and

symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status

including delirium, and evidence of autonomic instability (irregular pulse or blood

pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and

Precautions (5.3)].

INVEGA TRINZA

(paliperidone palmitate) INVEGA TRINZA

(paliperidone palmitate)

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 and diabetes mellitus, 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 and syncope, 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 that they should have their CBC monitored while taking INVEGA TRINZA

[see Warnings and Precautions (5.9)].

Hyperprolactinemia

Counsel patients on signs and symptoms of hyperprolactinemia that may be associated

with chronic use of INVEGA TRINZA

. 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

Caution patients about performing activities requiring mental alertness, such as

operating hazardous machinery, or operating a motor vehicle until they are reasonably

certain that INVEGA TRINZA

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

[Warnings and Precautions (5.14)].

Heat Exposure and Dehydration

Counsel patients regarding appropriate care in 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 medications, because there is a potential for

clinically signiﬁcant interactions [see Drug Interactions (7)].

Alcohol

Advise patients to avoid alcohol during treatment with INVEGA TRINZA

[see Drug

Interactions (7.1)].

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to

become pregnant during treatment with INVEGA TRINZA

. Advise patients that

INVEGATRINZA

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TRINZA

during pregnancy [see Use in Speciﬁc Populations

(8.1)].

Lactation

Advise breastfeeding women using INVEGATRINZA

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TRINZA

may impair fertility due

to an increase in serum prolactin levels. The effects on fertility are reversible [see Use

in Speciﬁc Populations (8.3)].

INVEGATRINZA

(paliperidone palmitate) Extended-Release Injectable Suspension

INVEGA SUSTENNA

, RISPERDAL

, and RISPERDAL CONSTA

are trademarks of

Janssen Pharmaceuticals, Inc.

Product of Ireland

Manufactured by:

Janssen Pharmaceutica NV

Beerse, Belgium

Manufactured for:

Janssen Pharmaceuticals, Inc.

Titusville, NJ 08560

INVEGA TRINZA

(paliperidone palmitate)

PATIENT INFORMATION

INVEGATRINZA

(in-VAY-guh TRIN-zuh)

(paliperidone palmitate)

Extended-Release Injectable Suspension

What is the most important information I should know about INVEGATRINZA

INVEGATRINZA

can cause serious side effects, including:

• Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related

psychosis). INVEGATRINZA

is not for treating dementia-related psychosis.

What is INVEGATRINZA

INVEGATRINZA

is a prescription medicine given by injection by a healthcare professional and used to treat schizophrenia.

INVEGATRINZA

is used in people who have been treated with INVEGASUSTENNA

1 time a month injections for at least 4 months.

It is not known if INVEGATRINZA

is safe and effective in children under 18 years of age.

Who should not receive INVEGATRINZA

Do not receive INVEGATRINZA

if you:

• are allergic to paliperidone palmitate, risperidone, or any of the ingredients in INVEGA TRINZA

. See the end of this Patient Information

leaﬂet for a complete list of ingredients in INVEGATRINZA

What should I tell my healthcare provider before receiving INVEGATRINZA

Before you receive INVEGATRINZA

, tell your healthcare provider about all your medical conditions, including if you:

• have had Neuroleptic Malignant Syndrome (NMS)

• have or have had heart problems, including a heart attack, heart failure, abnormal heart rhythm, or long QT syndrome

• have or have had low levels of potassium or magnesium in your blood

• have or have had uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia)

• have or have had kidney or liver problems

• have diabetes or have a family history of diabetes

• have had a low white blood cell count

• have had problems with dizziness or fainting or are being treated for high blood pressure

• have or have had seizures or epilepsy

• have any other medical conditions

• are pregnant or plan to become pregnant. It is not known if INVEGATRINZA

will harm your unborn baby.

◦ If you become pregnant while taking INVEGA TRINZA

, talk to your healthcare provider about registering with the National Pregnancy

Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-

research-programs/pregnancyregistry/.

◦ Infants born to women who are treated with INVEGA TRINZA

may experience symptoms such as tremors, irritability, excessive

sleepiness, eye twitching, muscle spasms, decreased appetite, difﬁculty breathing, or abnormal movement of arms and legs. Let your

healthcare provider know if these symptoms occur.

• are breastfeeding or plan to breastfeed. INVEGA TRINZA

can pass into your breast milk. Talk to your healthcare provider about the best

way to feed your baby if you receive INVEGA TRINZA

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal

supplements.

Know the medicines you take. Keep a list of them to show to your healthcare provider or pharmacist when you get a new medicine.

How will I receive INVEGATRINZA

• Follow your INVEGATRINZA

treatment schedule exactly as your healthcare provider tells you to.

• Your healthcare provider will tell you how much INVEGATRINZA

you will receive and when you will receive it.

• INVEGATRINZA

is given as an injection by your healthcare provider into the muscle (intramuscularly) of your arm or your buttocks, 1 time

every 3 months.

What should I avoid while receiving INVEGATRINZA

• INVEGATRINZA

may affect your ability to make decisions, think clearly, or react quickly. Do not drive, operate heavy machinery, or do

other dangerous activities until you know how INVEGATRINZA

affects you.

• Avoid getting overheated or dehydrated.

What are the possible side effects of INVEGATRINZA

INVEGATRINZA

may cause serious side effects, including:

• See “What is the most important information I should know about INVEGATRINZA

?”

• stroke in elderly people (cerebrovascular problems) that can lead to death

• Neuroleptic Malignant Syndrome (NMS). NMS is a rare but very serious problem that can happen in people who receive

INVEGATRINZA

. NMS can cause death and must be treated in a hospital. Call your healthcare provider right away if you become severely

ill and have any of these symptoms:

◦ high fever

◦ severe muscle stiffness

◦ confusion

◦ loss of consciousness

◦ changes in your breathing, heartbeat and blood pressure

• problems with your heartbeat. These heart problems can cause death. Call your healthcare provider right away if you have any of these

symptoms:

◦ passing out or feeling like you will pass out

◦ dizziness

◦ feeling as if your heart is pounding or missing beats

• uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia)

• metabolic changes. Metabolic changes may include high blood sugar (hyperglycemia), diabetes mellitus and changes in the fat levels in

your blood (dyslipidemia), and weight gain.

• low blood pressure and fainting

• changes in your blood cell counts

• high level of prolactin in your blood (hyperprolactinemia). INVEGA TRINZA

may cause a rise in the blood levels of a hormone called

prolactin (hyperprolactinemia) that may cause side effects including missed menstrual periods, leakage of milk from the breasts, development

of breasts in men, or problems with erection.

• problems thinking clearly and moving your body

• seizures

• difﬁculty swallowing that can cause food or liquid to get into your lungs

• prolonged or painful erection lasting more than 4 hours. Call your healthcare provider or go to your nearest emergency room right

away if you have an erection that lasts more than 4 hours.

• problems with control of your body temperature especially when you exercise a lot or spend time doing things that make you

warm. It is important for you to drink water to avoid dehydration.

The most common side effects of INVEGATRINZA

include: injection site reactions, weight gain, headache, upper respiratory tract infections,

feeling restlessness or difﬁculty sitting still, slow movements, tremors, stiffness and shufﬂing walk.

Tell your healthcare provider if you have any side effect that bothers you or does not go away.

These are not all the possible side effects of INVEGATRINZA

. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of INVEGATRINZA

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaﬂet. Do not use INVEGA TRINZA

for a

condition for which it was not prescribed. Do not give INVEGATRINZA

to other people, even if they have the same symptoms that you have. It

may harm them. You can ask your pharmacist or healthcare provider for information about INVEGA TRINZA

that is written for health

professionals.

This Patient Information leaﬂet summarizes the most important information about INVEGATRINZA

. If you would like more information, talk

with your healthcare provider.

You can ask your healthcare provider or pharmacist for more information that is written for healthcare professionals. For more information,

go to www.invegatrinzahcp.com or call 1-800-526-7736.

What are the ingredients in INVEGATRINZA

Active ingredient: paliperidone palmitate

Inactive ingredients: polysorbate 20, polyethylene glycol 4000, citric acid monohydrate, sodium dihydrogen phosphate monohydrate, sodium

hydroxide, and water for injection

Revised: 07/2018

Manufactured by: Janssen Pharmaceutica NV Beerse, Belgium

Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560

cp-64090v8

INVEGA TRINZA

(paliperidone palmitate)