Invega+Sustenna Pi

INVEGA SUSTENNA® INVEGA SUSTENNA® (paliperidone palmitate)
extended-release injectable suspension, for intramuscular use

(paliperidone palmitate) extended-release injectable
suspension, for intramuscular use
--------------------------- DOSAGE FORMS AND STRENGTHS----------------------------
HIGHLIGHTS OF PRESCRIBING INFORMATION Extended-release injectable suspension: 39 mg/0.25 mL, 78 mg/0.5 mL, 117 mg/0.75 mL,
These highlights do not include all the information needed to use 156 mg/mL, or 234 mg/1.5 mL (3)
INVEGA SUSTENNA® safely and effectively. See full prescribing information
for INVEGA SUSTENNA®. ----------------------------------- CONTRAINDICATIONS------------------------------------
INVEGA SUSTENNA® (paliperidone palmitate) extended-release injectable Known hypersensitivity to paliperidone, risperidone, or to any excipients in
suspension, for intramuscular use INVEGA SUSTENNA®. (4)
Initial U.S. Approval: 2006
-----------------------------WARNINGS AND PRECAUTIONS------------------------------
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS • Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with
WITH DEMENTIA-RELATED PSYCHOSIS Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse
See full prescribing information for complete boxed warning. reactions (e.g. stroke, transient ischemic attack). (5.2)
• Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of
Elderly patients with dementia-related psychosis treated with antipsychotic
drug and close monitoring. (5.3)
drugs are at an increased risk of death. INVEGA SUSTENNA® is not approved
for use in patients with dementia-related psychosis. (5.1) • 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)
-------------------------------- RECENT MAJOR CHANGES--------------------------------- • Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia
Dosage and Administration (2.5) 7/2022 and weight gain. (5.6)
• Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure
-------------------------------- INDICATIONS AND USAGE--------------------------------- and warn patients with known cardiovascular or cerebrovascular disease, and
INVEGA SUSTENNA® is an atypical antipsychotic indicated for risk of dehydration or syncope. (5.7)
• Treatment of schizophrenia in adults. (1) • Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts
• Treatment of schizoaffective disorder in adults as monotherapy and as an (CBC) in patients with pre-existing low white blood cell count (WBC) or history
adjunct to mood stabilizers or antidepressants. (1) of leukopenia or neutropenia. Consider discontinuing INVEGA SUSTENNA® if
clinically significant decline in WBC in the absence of other causative factors. (5.9)
-----------------------------DOSAGE AND ADMINISTRATION----------------------------- • Hyperprolactinemia: Prolactin elevations occur and persist during chronic
• For intramuscular injection only. (2.1) administration. (5.10)
• Each injection must be administered only by a healthcare professional. (2.1) • Potential for Cognitive and Motor Impairment: Use caution when operating
• For deltoid injection, use 1-inch 23G needle for patients weighing less than 90 kg machinery. (5.11)
or 1½-inch 22G needle for patients weighing 90 kg or more. For gluteal injection, • Seizures: Use cautiously in patients with a history of seizures or with conditions
use 1½-inch 22G needle regardless of patient weight. (2.1) that lower the seizure threshold. (5.12)
Initiation Dosing Monthly Maximum ----------------------------------- ADVERSE REACTIONS------------------------------------
Indication (deltoid) Maintenance Dosea Monthly Dose The most common adverse reactions (incidence ≥ 5% and occurring at least twice
Day 1 Day 8 (deltoid or gluteal) as often as placebo) were injection site reactions, somnolence/sedation, dizziness,
Schizophrenia (2.2) 234 mg 156 mg 39-234 mgb 234 mg akathisia, and extrapyramidal disorder. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals,
Schizoaffective
234 mg 156 mg 78-234 mgc 234 mg Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or
disorder (2.2)
www.fda.gov/medwatch
a dministered 5 weeks after the first injection.
A
b The recommended maintenance dose for treatment of schizophrenia is 117 mg. ----------------------------------- DRUG INTERACTIONS------------------------------------
Some patients may benefit from lower or higher maintenance doses within the • Drugs that may cause orthostatic hypotension: An additive effect may occur
additional available strengths (39 mg, 78 mg, 156 mg, and 234 mg). when co-administered with INVEGA SUSTENNA®. (7.1)
c Adjust dose based on tolerability and/or efficacy using available strengths. The
• Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong inducer of
39 mg strength was not studied in the long-term schizoaffective disorder study. CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John’s Wort) during a
• For patients naïve to oral paliperidone or oral or injectable risperidone, establish dosing interval for INVEGA SUSTENNA®. If administering a strong inducer is
tolerability with oral paliperidone or oral risperidone prior to initiating treatment necessary, consider managing the patient using paliperidone extended release
with INVEGA SUSTENNA®. (2.2) tablets. (2.5, 7.1, 12.3)
• Missed Doses: To manage either a missed second initiation dose or a missed ----------------------------- USE IN SPECIFIC POPULATIONS------------------------------
monthly maintenance dose, refer to the Full Prescribing Information. (2.3)
Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates
• Moderate to severe renal impairment (creatinine clearance < 50 mL/min):
with third trimester exposure. (8.1)
INVEGA SUSTENNA® is not recommended. (2.5)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient
• Mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min):
labeling.
Administer 156 mg on treatment Day 1 and 117 mg on Day 8, both in the deltoid
muscle. Follow with the recommended monthly maintenance dose of 78 mg, Revised: 7/2022
administered in the deltoid or gluteal muscle. Adjust monthly maintenance dose
based on tolerability and/or efficacy within the strengths of 39 mg, 78 mg, 117 mg,
or 156 mg. The maximum monthly dose is 156 mg for patients with mild renal
impairment. (2.5)
1
INVEGA SUSTENNA® (paliperidone palmitate) INVEGA SUSTENNA® (paliperidone palmitate)
extended-release injectable suspension, for intramuscular use extended-release injectable suspension, for intramuscular use
FULL PRESCRIBING INFORMATION: CONTENTS* 7 DRUG INTERACTIONS

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA- 7.1 Drugs Having Clinically Important Interactions with
RELATED PSYCHOSIS INVEGA SUSTENNA®
1 INDICATIONS AND USAGE 7.2 Drugs Having No Clinically Important Interactions with
2 DOSAGE AND ADMINISTRATION INVEGA SUSTENNA®
2.1 Administration Instructions 8 USE IN SPECIFIC POPULATIONS
2.2 Schizophrenia and Schizoaffective Disorder 8.1 Pregnancy
2.3 Missed Doses 8.2 Lactation
2.4 Use with Risperidone or with Oral Paliperidone 8.3 Females and Males of Reproductive Potential
2.5 Dosage Adjustments 8.4 Pediatric Use
2.6 Switching from Other Antipsychotics 8.5 Geriatric Use
2.7 Instructions for Use 8.6 Renal Impairment
3 DOSAGE FORMS AND STRENGTHS 8.7 Hepatic Impairment
8.8 Patients with Parkinson’s Disease or Lewy Body Dementia
4 CONTRAINDICATIONS
9 DRUG ABUSE AND DEPENDENCE
5 WARNINGS AND PRECAUTIONS
9.1 Controlled Substance
5.1 Increased Mortality in Elderly Patients with Dementia-Related
Psychosis 9.2 Abuse
5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly 9.3 Dependence
Patients with Dementia-Related Psychosis 10 OVERDOSAGE
5.3 Neuroleptic Malignant Syndrome 10.1 Human Experience
5.4 QT Prolongation 10.2 Management of Overdosage
5.5 Tardive Dyskinesia 11 DESCRIPTION
5.6 Metabolic Changes 12 CLINICAL PHARMACOLOGY
5.7 Orthostatic Hypotension and Syncope 12.1 Mechanism of Action
5.8 Falls 12.2 Pharmacodynamics
5.9 Leukopenia, Neutropenia, and Agranulocytosis 12.3 Pharmacokinetics
5.10 Hyperprolactinemia 13 NONCLINICAL TOXICOLOGY
5.11 Potential for Cognitive and Motor Impairment 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5.12 Seizures 13.2 Animal Toxicology and/or Pharmacology
5.13 Dysphagia 14 CLINICAL STUDIES
5.14 Priapism 14.1 Schizophrenia
5.15 Disruption of Body Temperature Regulation 14.2 Schizoaffective Disorder
6 ADVERSE REACTIONS 16 HOW SUPPLIED/STORAGE AND HANDLING
6.1 Clinical Trials Experience 17 PATIENT COUNSELING INFORMATION
6.2 Postmarketing Experience
*Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION 2.2 Schizophrenia and Schizoaffective Disorder

For patients who have never taken oral paliperidone or oral or injectable
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS risperidone, it is recommended to establish tolerability with oral paliperidone or
WITH DEMENTIA-RELATED PSYCHOSIS oral risperidone prior to initiating treatment with INVEGA SUSTENNA®.
Elderly patients with dementia-related psychosis treated with antipsychotic The recommended dosing of INVEGA SUSTENNA® for each approved indication is
drugs are at an increased risk of death. INVEGA SUSTENNA® is not approved displayed in Table 1. The recommended initiation of INVEGA SUSTENNA® is with a
for use in patients with dementia-related psychosis. [see Warnings and dose of 234 mg on treatment day 1 and 156 mg one week later, both administered
Precautions (5.1)]. in the deltoid muscle. Following the second initiation dose, monthly maintenance
doses can be administered in either the deltoid or gluteal muscle.
1 INDICATIONS AND USAGE
Table 1:
Recommended Dosing of INVEGA SUSTENNA® for Adults with
INVEGA SUSTENNA® (paliperidone palmitate) is indicated for the treatment of: Schizophrenia or Schizoaffective Disorder
• Schizophrenia in adults [see Clinical Studies (14.1)].
• Schizoaffective disorder in adults as monotherapy and as an adjunct to mood Initiation Dosing Monthly Maximum
Indication (deltoid) Maintenance Dosea Monthly Dose
stabilizers or antidepressants [see Clinical Studies (14.2)].
Day 1 Day 8 (deltoid or gluteal)
2 DOSAGE AND ADMINISTRATION
2.1 Administration Instructions Schizophrenia 234 mg 156 mg 39-234 mgb 234 mg
Each injection must be administered only by a healthcare professional. Schizoaffective
234 mg 156 mg 78-234 mgc 234 mg
Parenteral drug products should be inspected visually for foreign matter and disorder
discoloration prior to administration, whenever product and container permit. a dministered 5 weeks after the first injection.
A
INVEGA SUSTENNA® is intended for intramuscular use only. Do not administer by b The recommended maintenance dose for treatment of schizophrenia is 117 mg.
any other route. Avoid inadvertent injection into a blood vessel. Administer the Some patients may benefit from lower or higher maintenance doses within the
dose in a single injection; do not administer the dose in divided injections. Inject additional available strengths (39 mg, 78 mg, 156 mg, and 234 mg).
c Adjust dose based on tolerability and/or efficacy using available strengths. The
slowly, deep into the deltoid or gluteal muscle.
INVEGA SUSTENNA® must be administered using only the needles that are 39 mg strength was not studied in the long-term schizoaffective disorder study.
provided in the INVEGA SUSTENNA® kit. Adjustment of the maintenance dose may be made monthly. When making dose
The recommended needle size for administration of INVEGA SUSTENNA® into the adjustments, the prolonged-release characteristics of INVEGA SUSTENNA®
deltoid muscle is determined by the patient’s weight: should be considered [see Clinical Pharmacology (12.3)], as the full effect of the
dose adjustment may not be evident for several months.
• For patients weighing less than 90 kg, the 1-inch, 23 gauge needle is recommended.
• For patients weighing 90 kg or more, the 1 ½-inch, 22 gauge needle is recommended. 2.3 Missed Doses
Avoiding Missed Doses
Deltoid injections should be alternated between the two deltoid muscles.
It is recommended that the second initiation dose of INVEGA SUSTENNA® be given
The recommended needle size for administration of INVEGA SUSTENNA® into the one week after the first dose. To avoid a missed dose, patients may be given the
gluteal muscle is the 1½-inch, 22 gauge needle regardless of patient weight. second dose 4 days before or after the one-week time point. Similarly, the third and
Administer into the upper-outer quadrant of the gluteal muscle. Gluteal injections subsequent injections after the initiation regimen are recommended to be given
should be alternated between the two gluteal muscles. monthly. To avoid a missed monthly dose, patients may be given the injection up to
7 days before or after the monthly time point.
2
Management of a Missed Second Initiation Dose INVEGA SUSTENNA® is not recommended in patients with moderate or severe
If the target date for the second INVEGA SUSTENNA® injection (one week renal impairment (creatinine clearance < 50 mL/min) [see Use in Specific
± 4 days) is missed, the recommended reinitiation depends on the length of time Populations (8.6) and Clinical Pharmacology (12.3)].
which has elapsed since the patient’s first injection. In case of a missed second Coadministration with Strong CYP3A4/P-glycoprotein (P-gp) Inducers
initiation dose follow the dosing instructions provided in Table 2. Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin,
Table 2: Management of a Missed Second Initiation Dose St John’s Wort) during the 1-month dosing interval for INVEGA SUSTENNA®, if
possible. If administering a strong inducer is necessary, consider managing the
TIMING OF MISSED DOSING patient using paliperidone extended release tablets [see Drug Interactions (7.1)
SECOND INITIATION DOSE and Clinical Pharmacology (12.3)].
Less than 4 weeks since Administer the second initiation dose of 156 mg in 2.6 Switching from Other Antipsychotics
first injection the deltoid muscle as soon as possible. There are no systematically collected data to specifically address switching
1. It is recommended to administer a third injection patients with schizophrenia or schizoaffective disorder from other antipsychotics
of 117 mg in either the deltoid or gluteal muscle to INVEGA SUSTENNA®, or concerning concomitant administration with other
5 weeks after the first injection (regardless of the antipsychotics.
timing of the second injection). Switching from Oral Antipsychotics
2. Thereafter, resume regular monthly dosing in For patients who have never taken oral paliperidone or oral or injectable
either the deltoid or gluteal muscle. risperidone, tolerability should be established with oral paliperidone or oral
4 to 7 weeks since Resume dosing with two injections of 156 mg in the risperidone prior to initiating treatment with INVEGA SUSTENNA®.
first injection following manner: Previous oral antipsychotics can be gradually discontinued at the time of
1. Administer a deltoid injection as soon as possible. initiation of treatment with INVEGA SUSTENNA®. Recommended initiation of
INVEGA SUSTENNA® is with a dose of 234 mg on treatment day 1 and 156 mg
2. Administer a second deltoid injection 1 week later.
one week later, both administered in the deltoid muscle [see Dosage and
3. Thereafter, resume regular monthly dosing in Administration (2.2)]. Patients previously stabilized on different doses of INVEGA®
either the deltoid or gluteal muscle. Extended-Release tablets can attain similar paliperidone steady-state exposure
More than 7 weeks since Restart dosing with recommended initiation (see during maintenance treatment with INVEGA SUSTENNA® monthly doses as
first injection Section 2.2, Table 1): depicted in Table 4.
1. Administer a 234 mg deltoid injection on Day 1. Table 4: Doses of INVEGA® and INVEGA SUSTENNA® Needed to Attain Similar
2. Administer a 156 mg deltoid injection 1 week later. Steady-State Paliperidone Exposure During Maintenance Treatment
3. Thereafter, resume regular monthly dosing in INVEGA® INVEGA SUSTENNA®
either the deltoid or gluteal muscle. Formulation
Extended-Release Tablet Injection
Management of a Missed Maintenance Dose Dosing Frequency Once Daily Once every 4 weeks
In case of a missed maintenance dose follow the dosing instructions provided in 12 234
Table 3.
9 156
Table 3: Management of a Missed Maintenance Dose Dose (mg)
6 117
TIMING OF MISSED DOSING 3 39-78
MAINTENANCE DOSE
4 to 6 weeks since Resume regular monthly dosing as soon as Switching from Long-Acting Injectable Antipsychotics
last injection possible at the patient’s previously stabilized For patients who have never taken oral paliperidone or oral or injectable
dose, followed by injections at monthly intervals. risperidone, tolerability should be established with oral paliperidone or oral
More than 6 weeks to 6 Resume the same dose the patient was previously risperidone prior to initiating treatment with INVEGA SUSTENNA®.
months since last injection stabilized on (unless the patient was stabilized on When switching patients currently at steady-state on a long-acting injectable
a dose of 234 mg, then the first 2 injections should antipsychotic, initiate INVEGA SUSTENNA® therapy in place of the next scheduled
each be 156 mg) in the following manner: injection. INVEGA SUSTENNA® should then be continued at monthly intervals. The
one-week initiation dosing regimen as described in Section 2.2 is not required. See
1. Administer a deltoid injection as soon as possible.
Table 1 above for recommended monthly maintenance dosing. Based on previous
2. Administer a second deltoid injection 1 week clinical history of tolerability and/or efficacy, some patients may benefit from
later at the same dose. lower or higher maintenance doses within the available strengths (39 mg, 78 mg,
3. Thereafter, resume administering the previously 117 mg, 156 mg, and 234 mg). The 39 mg strength was not studied in the long-term
stabilized dose in the deltoid or gluteal muscle schizoaffective disorder study. Monthly maintenance doses can be administered
1 month after the second injection. in either the deltoid or gluteal muscle [see Dosage and Administration (2.2)].
More than 6 months since Restart dosing with recommended initiation (see If INVEGA SUSTENNA® is discontinued, its prolonged-release characteristics
last injection Section 2.2, Table 1): must be considered. As recommended with other antipsychotic medications, the
1. Administer a 234 mg deltoid injection on Day 1. need for continuing existing extrapyramidal symptoms (EPS) medication should be
re-evaluated periodically.
2. Administer a 156 mg deltoid injection 1 week later.
3. Thereafter, resume administering the previously 2.7 Instructions for Use
stabilized dose in the deltoid or gluteal muscle Each injection must be administered only by a healthcare professional.
1 month after the second injection. The kit contains a prefilled syringe and 2 safety needles (a 1 ½-inch 22 gauge needle
and a 1-inch 23 gauge needle) for intramuscular injection.
2.4 Use with Risperidone or with Oral Paliperidone
Since paliperidone is the major active metabolite of risperidone, caution should be
Prefilled Syringe
exercised when INVEGA SUSTENNA® is coadministered with risperidone or with
oral paliperidone for extended periods of time. Safety data involving concomitant
use of INVEGA SUSTENNA® with other antipsychotics is limited.
2.5 Dosage Adjustments
22G 23G x1"
Patients with Renal Impairment Gray hub Blue hub
INVEGA SUSTENNA® has not been systematically studied in patients with renal
impairment [see Clinical Pharmacology (12.3)].
For patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to
< 80 mL/min [Cockcroft-Gault Formula]), initiate INVEGA SUSTENNA® with a dose
of 156 mg on treatment Day 1 and 117 mg on Day 8, both in the deltoid muscle.
Follow with the recommended monthly maintenance dose of 78 mg, administered
in either the deltoid or gluteal muscle. Adjust monthly maintenance dose based on
tolerability and/or efficacy within the strengths of 39 mg, 78 mg, 117 mg, or 156 mg.
The maximum monthly dose is 156 mg for patients with mild renal impairment [see
Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. INVEGA SUSTENNA® is for single use only.
3
a.
Shake the syringe vigorously for a minimum of 10 seconds to ensure a f. Bring the syringe with the attached needle in upright position to de-aerate.
homogeneous suspension. De-aerate the syringe by moving the plunger rod carefully forward.
b. Select the appropriate needle.

For DELTOID injection:
• If the patient weighs less than 90 kg, use the 1-inch 23 gauge needle (needle g. Inject the entire contents intramuscularly slowly, deep into the selected deltoid
with blue colored hub). or gluteal muscle of the patient. Do not administer by any other route.
• If the patient weighs 90 kg or more, use the 1 ½-inch 22 gauge needle (needle h. After the injection is complete, use either thumb or finger of one hand (h1,
with gray colored hub). h2) or a flat surface (h3) to activate the needle protection system. The needle
For GLUTEAL injection: protection system is fully activated when a ‘click’ is heard. Discard the syringe
Use the 1 ½-inch 22 gauge needle (needle with gray colored hub) regardless of with needle appropriately.
patient’s weight. h1
c. While holding the syringe upright, remove the rubber tip cap with an easy
clockwise twisting motion.
h2
h3
d. Peel the safety needle pouch half way open. Grasp the needle sheath using
the plastic peel pouch. Attach the safety needle to the luer connection of the
syringe with an easy clockwise twisting motion.
3 DOSAGE FORMS AND STRENGTHS

INVEGA SUSTENNA® is available as a white to off-white aqueous extended-
release injectable suspension for intramuscular injection in dose strengths of
39 mg/0.25 mL, 78 mg/0.5 mL, 117 mg/0.75 mL, 156 mg/mL, and 234 mg/1.5 mL
paliperidone palmitate in single-dose prefilled syringes.
4 CONTRAINDICATIONS
INVEGA SUSTENNA® is contraindicated in patients with a known hyper
sensitivity to either paliperidone or risperidone, or to any of the excipients in
the INVEGA SUSTENNA® formulation. Hypersensitivity reactions, including
e. Pull the needle sheath away from the needle with a straight pull. Do not twist anaphylactic reactions and angioedema, have been reported in patients treated
the sheath as the needle may be loosened from the syringe. 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 SUSTENNA® is not approved for the treatment of
patients with dementia-related psychosis [see Boxed Warning and Warnings and
Precautions (5.2)].
4
5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients (2) for whom alternative, equally effective, but potentially less harmful treatments
with Dementia-Related Psychosis are not available or appropriate. In patients who do require chronic treatment, use
In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly the lowest dose and the shortest duration of treatment producing a satisfactory
subjects with dementia, there was a higher incidence of cerebrovascular adverse clinical response. Periodically reassess the need for continued treatment.
reactions (cerebrovascular accidents and transient ischemic attacks) including If signs and symptoms of tardive dyskinesia appear in a patient on
fatalities compared to placebo-treated subjects. No studies have been conducted INVEGA SUSTENNA®, drug discontinuation should be considered. However, some
with oral paliperidone, INVEGA SUSTENNA®, or the 3-month paliperidone palmitate patients may require treatment with INVEGA SUSTENNA® despite the presence
extended-release injectable suspension in elderly patients with dementia. These of the syndrome.
medicines are not approved for the treatment of patients with dementia-related 5.6 Metabolic Changes
psychosis [see Boxed Warning and Warnings and Precautions (5.1)].
Atypical antipsychotic drugs have been associated with metabolic changes that
5.3 Neuroleptic Malignant Syndrome may increase cardiovascular/cerebrovascular risk. These metabolic changes
Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs
been reported in association with antipsychotic drugs, including paliperidone. in the class have been shown to produce some metabolic changes, each drug has
Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental its own specific risk profile.
status including delirium, and autonomic instability (irregular pulse or blood Hyperglycemia and Diabetes Mellitus
pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may
include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and Hyperglycemia and diabetes mellitus, in some cases extreme and associated
acute renal failure. with ketoacidosis or hyperosmolar coma or death, have been reported in patients
treated with all atypical antipsychotics. These cases were, for the most part,
If NMS is suspected, immediately discontinue INVEGA SUSTENNA® and provide seen in post-marketing clinical use and epidemiologic studies, not in clinical
symptomatic treatment and monitoring. trials. Hyperglycemia and diabetes have been reported in trial subjects treated
5.4 QT Prolongation with INVEGA SUSTENNA®. Assessment of the relationship between atypical
Paliperidone causes a modest increase in the corrected QT (QTc) interval. The antipsychotic use and glucose abnormalities is complicated by the possibility of
use of paliperidone should be avoided in combination with other drugs that are an increased background risk of diabetes mellitus in patients with schizophrenia
known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III and the increasing incidence of diabetes mellitus in the general population. Given
(e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications these confounders, the relationship between atypical antipsychotic use and
(e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or hyperglycemia-related adverse events is not completely understood. However,
any other class of medications known to prolong the QTc interval. Paliperidone epidemiological studies suggest an increased risk of hyperglycemia-related
should also be avoided in patients with congenital long QT syndrome and in adverse reactions in patients treated with the atypical antipsychotics.
patients with a history of cardiac arrhythmias. Patients with an established diagnosis of diabetes mellitus who are started on
Certain circumstances may increase the risk of the occurrence of Torsades atypical antipsychotics should be monitored regularly for worsening of glucose
de pointes and/or sudden death in association with the use of drugs that prolong control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history
the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; of diabetes) who are starting treatment with atypical antipsychotics should undergo
(3) concomitant use of other drugs that prolong the QTc interval; and (4) presence fasting blood glucose testing at the beginning of treatment and periodically during
of congenital prolongation of the QT interval. treatment. Any patient treated with atypical antipsychotics should be monitored
The effects of oral paliperidone on the QT interval were evaluated in a double- for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and
blind, active-controlled (moxifloxacin 400 mg single dose), multicenter QT study in weakness. Patients who develop symptoms of hyperglycemia during treatment
adults with schizophrenia and schizoaffective disorder, and in three placebo- and with atypical antipsychotics should undergo fasting blood glucose testing. In
active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia. some cases, hyperglycemia has resolved when the atypical antipsychotic was
In the QT study (n=141), the 8 mg dose of immediate-release oral paliperidone discontinued; however, some patients required continuation of anti-diabetic
(n=50) showed a mean placebo-subtracted increase from baseline in QTcLD of treatment despite discontinuation of the suspect drug.
12.3 msec (90% CI: 8.9; 15.6) on day 8 at 1.5 hours post-dose. The mean steady- Pooled data from the four placebo-controlled (one 9-week and three 13-week),
state peak plasma concentration for this 8 mg dose of paliperidone immediate fixed-dose studies in subjects with schizophrenia are presented in Table 5.
release (Cmax ss = 113 ng/mL) was more than 2-fold the exposure observed with
the maximum recommended 234 mg dose of INVEGA SUSTENNA® administered Table 5: Change in Fasting Glucose from Four Placebo-Controlled, 9- to 13-Week,
in the deltoid muscle (predicted median Cmax ss = 50 ng/mL). In this same study, a Fixed-Dose Studies in Subjects with Schizophrenia
4 mg dose of the immediate-release oral formulation of paliperidone, for which INVEGA SUSTENNA®
Cmax ss = 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec Placebo 39 mg 78 mg 156 mg 234/39 mga 234/156 mga 234/234 mga
(90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose. Mean change from baseline (mg/dL)
In the three fixed-dose efficacy studies of oral paliperidone extended release in n=367 n=86 n=244 n=238 n=110 n=126 n=115
subjects with schizophrenia, electrocardiogram (ECG) measurements taken at Serum Glucose
various time points showed only one subject in the oral paliperidone 12 mg group Change from -1.3 1.3 3.5 0.1 3.4 1.8 -0.2
had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec). baseline
In the four fixed-dose efficacy studies of INVEGA SUSTENNA® in subjects with Proportion of Patients with Shifts
schizophrenia and in the long-term study in subjects with schizoaffective disorder, Serum Glucose
no subject experienced a change in QTcLD exceeding 60 msec and no subject had Normal to High 4.6% 6.3% 6.4% 3.9% 2.5% 7.0% 6.6%
a QTcLD value of > 500 msec at any time point. In the maintenance study in subjects (<100 mg/dL to (11/241) (4/64) (11/173) (6/154) (2/79) (6/86) (5/76)
with schizophrenia, no subject had a QTcLD change > 60 msec, and one subject ≥126 mg/dL)
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.
a I nitial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every
4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and
5.5 Tardive Dyskinesia 156 mg) are from studies involving only gluteal injection. [see Clinical Studies (14.1)].
Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary,
dyskinetic movements, may develop in patients treated with antipsychotic drugs. In a long-term open-label pharmacokinetic and safety study in subjects
Although the prevalence of the syndrome appears to be highest among the elderly, with schizophrenia in which the highest dose available (234 mg) was evaluated,
especially elderly women, it is impossible to predict which patients will develop the INVEGA SUSTENNA® was associated with a mean change in glucose of
syndrome. Whether antipsychotic drug products differ in their potential to cause -0.4 mg/dL at Week 29 (n=109) and +6.8 mg/dL at Week 53 (n=100).
tardive dyskinesia is unknown. During the initial 25-week open-label period of a long-term study in subjects with
The risk of developing tardive dyskinesia and the likelihood that it will become schizoaffective disorder, INVEGA SUSTENNA® was associated with mean change
irreversible appear to increase with the duration of treatment and the cumulative in glucose of +5.3 mg/dL (n=518). At the endpoint of the subsequent 15-month
dose. The syndrome can develop after relatively brief treatment periods, even at double-blind period of the study, INVEGA SUSTENNA® was associated with a
low doses. It may also occur after discontinuation of treatment. mean change in glucose of +0.3 mg/dL (n=131) compared with a mean change of
Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment +4.0 mg/dL in the placebo group (n=120).
is discontinued. Antipsychotic treatment, itself, however, may suppress (or Dyslipidemia
partially suppress) the signs and symptoms of the syndrome, possibly masking the Undesirable alterations in lipids have been observed in patients treated with
underlying process. The effect that symptomatic suppression has upon the long- atypical antipsychotics.
term course of the syndrome is unknown.
Pooled data from the four placebo-controlled (one 9-week and three 13-week),
Given these considerations, INVEGA SUSTENNA® should be prescribed in a fixed-dose studies in subjects with schizophrenia are presented in Table 6.
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
5
Table 6: Change in Fasting Lipids from Four Placebo-Controlled, 9- to 13-Week, Table 8: Change in Fasting Lipids from an Open-Label and Double-Blind Periods
Fixed-Dose Studies in Subjects with Schizophrenia of a Long-Term Study in Subjects with Schizoaffective Disorder
INVEGA SUSTENNA® Open-Label Period Double-Blind Period
Placebo 39 mg 78 mg 156 mg 234/39 mga 234/156 mga 234/234 mga INVEGA SUSTENNA® Placebo INVEGA SUSTENNA®
Mean change from baseline (mg/dL) Mean change from baseline (mg/dL)
Cholesterol
Change from
n=366 n=89 n=244 n=232 n=105 n=119 n=120 Cholesterol n=198 n=119 n=132
baseline -6.6 -6.4 -5.8 -7.1 -0.9 -4.2 9.4
Change from -3.9 -4.2 2.3
LDL baseline
n=275 n=80 n=164 n=141 n=104 n=117 n=108
Change from
baseline -6.0 -4.8 -5.6 -4.8 0.9 -2.4 5.2 LDL n=198 n=117 n=130
HDL Change from -2.7 -2.8 5.9

n=286 n=89 n=165 n=150 n=105 n=118 n=115 baseline
Change from
baseline 0.7 2.1 0.6 0.3 1.5 1.1 0.0
HDL n=198 n=119 n=131
Triglycerides n=366 n=89 n=244 n=232 n=105 n=119 n=120
Change from Change from -2.7 -0.9 -0.7
baseline -16.7 7.6 -9.0 -11.5 -14.1 -20.0 11.9 baseline
Proportion of Patients with Shifts Triglycerides n=198 n=119 n=132
Cholesterol Change from 7.0 2.5 -12.3
Normal to High 3.2% 2.0% 2.0% 2.1% 0% 3.1% 7.1% baseline
(<200 mg/dL to (7/222) (1/51) (3/147) (3/141) (0/69) (2/65) (6/84)
≥240 mg/dL)
Weight Gain
LDL Weight gain has been observed with atypical antipsychotic use. Clinical monitoring
Normal to High 1.1% 0% 0% 0% 0% 0% 0% of weight is recommended.
(<100 mg/dL to (1/95) (0/29) (0/67) (0/46) (0/41) (0/37) (0/44) Data on mean changes in body weight and the proportion of subjects meeting a
≥160 mg/dL)
weight gain criterion of ≥ 7% of body weight from the four placebo-controlled (one
HDL 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are
Normal to Low 13.8% 14.8% 9.6% 14.2% 12.7% 10.5% 16.0% presented in Table 9.
(≥40 mg/dL to (28/203) (9/61) (11/115) (15/106) (9/71) (8/76) (13/81)
<40 mg/dL) Table 9: Mean Change in Body Weight (kg) and the Proportion of Subjects with
≥ 7% Gain in Body Weight from Four Placebo-Controlled, 9- to 13-Week,
Triglycerides Fixed-Dose Studies in Subjects with Schizophrenia
Normal to High 3.6% 6.1% 9.2% 7.2% 1.3% 3.7% 10.7%
(<150 mg/dL to (8/221) (3/49) (14/153) (10/139) (1/79) (3/82) (9/84) INVEGA SUSTENNA®
≥200 mg/dL)
Placebo 39 mg 78 mg 156 mg 234/39 mga 234/156 mga 234/234 mga
a I nitial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg
every 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, n=451 n=116 n=280 n=267 n=137 n=144 n=145
and 156 mg) are from studies involving only gluteal injection. [see Clinical Weight (kg)
Studies (14.1)]. Change from -0.4 0.4 0.8 1.4 0.4 0.7 1.4
In a long-term open-label pharmacokinetic and safety study in subjects with baseline
schizophrenia in which the highest dose available (234 mg) was evaluated, the
Weight Gain
mean changes from baseline in lipid values are presented in Table 7. ≥ 7% increase 3.3% 6.0% 8.9% 9.0% 5.8% 8.3% 13.1%
Table 7: Change in Fasting Lipids from Long-term Open-label Pharmacokinetic from baseline
and Safety Study in Subjects with Schizophrenia a I nitial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every
4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and
INVEGA SUSTENNA® 234 mg
156 mg) are from studies involving only gluteal injection. [see Clinical Studies (14.1)].
Week 29 Week 53
In a long-term open-label pharmacokinetic and safety study in which the highest
Mean change from baseline (mg/dL) dose available (234 mg) was evaluated, INVEGA SUSTENNA® was associated
with a mean change in weight of +2.4 kg at Week 29 (n=134) and +4.3 kg at
Cholesterol n=112 n=100 Week 53 (n=113).
Change from baseline -1.2 0.1 During the initial 25-week open-label period of a long-term study in subjects
with schizoaffective disorder, INVEGA SUSTENNA® was associated with a mean
LDL n=107 n=89 change in weight of +2.2 kg and 18.4% of subjects had an increase in body weight
of ≥ 7% (n=653). At the endpoint of the subsequent 15-month double-blind period of
Change from baseline -2.7 -2.3 the study, INVEGA SUSTENNA® was associated with a mean change in weight of
HDL n=112 n=98 -0.2 kg and 13.0% of subjects had an increase in body weight of ≥ 7% (n=161); the
placebo group had a mean change in weight of -0.8 kg and 6.0% of subjects had an
Change from baseline -0.8 -2.6 increase in body weight of ≥ 7% (n=168).
Triglycerides n=112 n=100 5.7 Orthostatic Hypotension and Syncope
Paliperidone can induce orthostatic hypotension and syncope in some patients
Change from baseline 16.2 37.4 because of its alpha-adrenergic blocking activity. Syncope was reported in < 1%
(4/1293) of subjects treated with INVEGA SUSTENNA® in the recommended dose
The mean changes from baseline in lipid values during the initial 25-week open- range of 39 mg to 234 mg in the four fixed-dose, double-blind, placebo-controlled
label period and at the endpoint of the subsequent 15-month double-blind period in trials compared with 0% (0/510) of subjects treated with placebo. In the four fixed-
a long-term study in subjects with schizoaffective disorder are presented in Table 8. dose efficacy studies in subjects with schizophrenia, orthostatic hypotension
was reported as an adverse event by < 1% (2/1293) of INVEGA SUSTENNA®-
treated subjects compared to 0% (0/510) with placebo. Incidences of orthostatic
hypotension and syncope in the long-term studies in subjects with schizophrenia
and schizoaffective disorder were similar to those observed in the short-term
studies.
INVEGA SUSTENNA® should be used with caution in patients with known
cardiovascular disease (e.g., heart failure, history of myocardial infarction or
ischemia, conduction abnormalities), cerebrovascular disease, or conditions
that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and
treatment with antihypertensive medications). Monitoring of orthostatic vital signs
should be considered in patients who are vulnerable to hypotension.
6
5.8 Falls the INVEGA SUSTENNA® group than those in the placebo group in males (55.6%
Somnolence, postural hypotension, motor and sensory instability have been vs. 23.2%) and in females (44.3% vs. 25.0%). During the 15-month double-blind
reported with the use of antipsychotics, including INVEGA SUSTENNA®, which phase, 11 females (13.9%) in the INVEGA SUSTENNA® group had 14 potentially
may lead to falls and, consequently, fractures or other fall-related injuries. For prolactin-related adverse reactions (hyperprolactinemia N=3; blood prolactin
patients, particularly the elderly, with diseases, conditions, or medications that increased N=4; libido decreased N=1; amenorrhea N=3; galactorrhea N=3), while
could exacerbate these effects, assess the risk of falls when initiating antipsychotic 5 females (5.8%) in the placebo group had 6 potentially prolactin-related adverse
treatment and recurrently for patients on long-term antipsychotic therapy. reactions (hyperprolactinemia N=2; blood prolactin increased N=1; amenorrhea
5.9 Leukopenia, Neutropenia, and Agranulocytosis N=2; galactorrhea N=1). Six males (7.1%) in the INVEGA SUSTENNA® group
experienced 6 potentially prolactin-related adverse reactions (hyperprolactinemia
In clinical trial and/or postmarketing experience, events of leukopenia and N=4; libido decreased N=1; erectile dysfunction N=1), while 1 male (1.2%) in the
neutropenia have been reported temporally related to antipsychotic agents, placebo group experienced adverse reaction of blood prolactin increased.
including INVEGA SUSTENNA®. Agranulocytosis has also been reported.
Prior to the 15-month double-blind phase (during the 25-week open-label phase of
Possible risk factors for leukopenia/neutropenia include pre-existing low the long-term maintenance trial), the mean (SD) serum prolactin values at baseline
white blood cell count (WBC)/absolute neutrophil count (ANC) and history of were 14.6 (14.0) ng/mL in males (N=352) and 39.1 (44.6) ng/mL in females (N=302). At
drug-induced leukopenia/neutropenia. In patients with a history of a clinically the end of the open-label phase, mean (SD) prolactin values were 32.8 (17.2) ng/mL
significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform a in males (N=275) and 72.4 (46.5) ng/mL in females (N=239). During the open-label
complete blood count (CBC) frequently during the first few months of therapy. In phase, 48.9% of females and 53.3% of males experienced elevations of prolactin
such patients, consider discontinuation of INVEGA SUSTENNA® at the first sign of above the reference range relative to baseline, and a higher proportion of females
a clinically significant decline in WBC in the absence of other causative factors. experienced potentially prolactin-related adverse reactions compared to males
Monitor patients with clinically significant neutropenia for fever or other (10.0% vs. 9.0%). Amenorrhea (5.8%) and galactorrhea (2.9%) in females and libido
symptoms or signs of infection and treat promptly if such symptoms or signs occur. decrease (2.8%) and erectile dysfunction (2.5%) in males were observed with a
Discontinue INVEGA SUSTENNA® in patients with severe neutropenia (absolute rate greater than 2%.
neutrophil count < 1000/mm3) and follow their WBC until recovery.
5.11 Potential for Cognitive and Motor Impairment
5.10 Hyperprolactinemia Somnolence, sedation, and dizziness were reported as adverse reactions in
Like other drugs that antagonize dopamine D2 receptors, paliperidone elevates subjects treated with INVEGA SUSTENNA® [see Adverse Reactions (6.1)].
prolactin levels and the elevation persists during chronic administration. Paliperidone Antipsychotics, including INVEGA SUSTENNA®, have the potential to impair
has a prolactin-elevating effect similar to that seen with risperidone, a drug that is judgment, thinking, or motor skills. Patients should be cautioned about performing
associated with higher levels of prolactin than other antipsychotic drugs. activities requiring mental alertness, such as operating hazardous machinery
Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, or operating a motor vehicle, until they are reasonably certain that paliperidone
resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit therapy does not adversely affect them.
reproductive function by impairing gonadal steroidogenesis in both female and 5.12 Seizures
male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have In the four fixed-dose double-blind placebo-controlled studies in subjects with
been reported in patients receiving prolactin-elevating compounds. Long-standing schizophrenia, <1% (1/1293) of subjects treated with INVEGA SUSTENNA® in
hyperprolactinemia when associated with hypogonadism may lead to decreased the recommended dose range of 39 mg to 234 mg experienced an adverse event
bone density in both female and male subjects. of convulsion compared with <1% (1/510) of placebo-treated subjects who
Tissue culture experiments indicate that approximately one-third of human breast experienced an adverse event of grand mal convulsion.
cancers are prolactin dependent in vitro, a factor of potential importance if the Like other antipsychotic drugs, INVEGA SUSTENNA® should be used cautiously
prescription of these drugs is considered in a patient with previously detected in patients with a history of seizures or other conditions that potentially lower
breast cancer. An increase in the incidence of pituitary gland, mammary gland, the seizure threshold. Conditions that lower the seizure threshold may be more
and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and prevalent in patients 65 years or older.
pancreatic adenomas) was observed in the risperidone carcinogenicity studies
conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Neither clinical 5.13 Dysphagia
studies nor epidemiologic studies conducted to date have shown an association Esophageal dysmotility and aspiration have been associated with antipsychotic
between chronic administration of this class of drugs and tumorigenesis in drug use. INVEGA SUSTENNA® and other antipsychotic drugs should be used
humans, but the available evidence is too limited to be conclusive. cautiously in patients at risk for aspiration pneumonia.
Prolactin data from two long-term, double-blind, placebo-controlled studies with 5.14 Priapism
INVEGA SUSTENNA® are presented below; one study was in a population of Drugs with alpha-adrenergic blocking effects have been reported to induce
patients with schizophrenia; the second study was in patients with schizoaffective priapism. Although no cases of priapism have been reported in clinical trials with
disorder. INVEGA SUSTENNA®, priapism has been reported with oral paliperidone during
Schizophrenia postmarketing surveillance. Severe priapism may require surgical intervention.
In a long-term maintenance trial of INVEGA SUSTENNA® in schizophrenia patients 5.15 Disruption of Body Temperature Regulation
(Study PSY-3001), see Clinical Studies (14.1), elevations of prolactin to above Disruption of the body’s ability to reduce core body temperature has been
the reference range (> 18 ng/mL in males and > 30 ng/mL in females) relative to attributed to antipsychotic agents. Appropriate care is advised when prescribing
open-label baseline at any time during the double-blind phase were noted in a INVEGA SUSTENNA® to patients who will be experiencing conditions which may
higher percentage of the patients in the INVEGA SUSTENNA® group than those contribute to an elevation in core body temperature, e.g., exercising strenuously,
in the placebo group in males (51.9% vs. 29.0%) and in females (50.5% vs. 42.9%). exposure to extreme heat, receiving concomitant medication with anticholinergic
During the double-blind phase, 4 females (4.2%) in the INVEGA SUSTENNA® activity, or being subject to dehydration.
group experienced potentially prolactin-related adverse reactions (amenorrhea 6 ADVERSE REACTIONS
N=2; galactorrhea N=1; menstruation irregular N=1), while 2 females (2.2%) in The following are discussed in more detail in other sections of the labeling:
the placebo group experienced potentially prolactin-related adverse reactions
(amenorrhea N=1; breast pain N=1). One male (0.9%) in the INVEGA SUSTENNA® • Increased mortality in elderly patients with dementia-related psychosis [see
group experienced erectile dysfunction and 1 male (0.9%) in placebo group Boxed Warning and Warnings and Precautions (5.1)]
experienced gynecomastia. • Cerebrovascular adverse reactions, including stroke, in elderly patients with
Prior to the double-blind phase (during the 33-week open-label phase of the long- dementia-related psychosis [see Warnings and Precautions (5.2)]
term maintenance trial), the mean (SD) serum prolactin values at baseline were • Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
14.9 (22.3) ng/mL in males (N=490) and 35.2 (39.6) ng/mL in females (N=358). At the • QT prolongation [see Warnings and Precautions (5.4)]
end of the open-label phase, mean (SD) prolactin values were 24.7 (22.5) ng/mL • Tardive dyskinesia [see Warnings and Precautions (5.5)]
in males (N=470) and 59.5 (38.1) ng/mL in females (N=333). During the open-label • Metabolic changes [see Warnings and Precautions (5.6)]
phases 49.2% of females and 47.7% of males experienced elevations of prolactin • Orthostatic hypotension and syncope [see Warnings and Precautions (5.7)]
above the reference range relative to baseline, and a higher proportion of females • Falls [see Warnings and Precautions (5.8)]
experienced potentially prolactin-related adverse reactions compared to males • Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.9)]
(5.3% vs. 1.8%). Amenorrhea (2.5%) in females and no single potentially prolactin-
related adverse reaction in males were observed with a rate greater than 2%. • Hyperprolactinemia [see Warnings and Precautions (5.10)]
• Potential for cognitive and motor impairment [see Warnings and Precautions (5.11)]
Schizoaffective Disorder • Seizures [see Warnings and Precautions (5.12)]
In a long-term maintenance trial of INVEGA SUSTENNA® in patients with • Dysphagia [see Warnings and Precautions (5.13)]
schizoaffective disorder (Study SCA-3004) see Clinical Studies (14.2), elevations
• Priapism [see Warnings and Precautions (5.14)]
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 • Disruption of body temperature regulation [see Warnings and Precautions (5.15)]
15-month double-blind phase were noted in a higher percentage of patients in
7
6.1 Clinical Trials Experience Table 10: Incidences of Adverse Reactions 2% or More of INVEGA SUSTENNA®-
Because clinical trials are conducted under widely varying conditions, adverse Treated Patients (and Greater than Placebo) with Schizophrenia in
reaction rates observed in the clinical trials of a drug cannot be directly compared Four Fixed-Dose, Double-Blind, Placebo-Controlled Trials
to rates in the clinical trials of another drug and may not reflect the rates observed INVEGA SUSTENNA®
in clinical practice. System Organ Placeboa 39 mg 78 mg 156 mg 234/39 mgb 234/156 mgb 234/234 mgb
Class (N=510) (N=130) (N=302) (N=312) (N=160) (N=165) (N=163)
Patient Exposure Adverse
The data described in this section are derived from a clinical trial database Reactions
consisting of a total of 3817 subjects (approximately 1705 patient-years exposure) Total percentage 70 75 68 69 63 60 63
with schizophrenia who received at least one dose of INVEGA SUSTENNA® in of subjects
the recommended dose range of 39 mg to 234 mg and a total of 510 subjects with with adverse
reactions
schizophrenia who received placebo. Among the 3817 INVEGA SUSTENNA®-
Gastrointestinal disorders
treated subjects, 1293 received INVEGA SUSTENNA® in four fixed-dose, double-
Abdominal 2 2 4 4 1 2 4
blind, placebo-controlled trials (one 9-week and three 13-week studies), 849 discomfort/
received INVEGA SUSTENNA® in the maintenance trial (median exposure 229 days abdominal pain
during the initial 33-week open-label phase of this study, of whom 205 continued to upper
receive INVEGA SUSTENNA® during the double-blind placebo-controlled phase of Diarrhea 2 0 3 2 1 2 2
this study [median exposure 171 days]), and 1675 received INVEGA SUSTENNA® Dry mouth 1 3 1 0 1 1 1
in five non-placebo controlled trials (three noninferiority active-comparator trials, Nausea 3 4 4 3 2 2 2
one long-term open-label pharmacokinetic and safety study, and an injection site Toothache 1 1 1 3 1 2 3
[deltoid-gluteal] cross-over trial). One of the 13-week studies included a 234 mg Vomiting 4 5 4 2 3 2 2
INVEGA SUSTENNA® initiation dose followed by treatment with either 39 mg, General disorders and administration site conditions
156 mg, or 234 mg every 4 weeks. Asthenia 0 2 1 <1 0 1 1
The safety of INVEGA SUSTENNA® was also evaluated in a 15-month, long- Fatigue 1 1 2 2 1 2 1
term study comparing INVEGA SUSTENNA® to selected oral antipsychotic Injection site 2 0 4 6 9 7 10
reactions
therapies in adult subjects with schizophrenia. A total of 226 subjects received
Infections and infestations
INVEGA SUSTENNA® during the 15-month, open-label period of this study;
Nasopharyngitis 2 0 2 2 4 2 2
218 subjects received selected oral antipsychotic therapies. The safety of
Upper 2 2 2 2 1 2 4
INVEGA SUSTENNA® was similar to that seen in previous double-blind, placebo- respiratory tract
controlled clinical trials in adult subjects with schizophrenia. The safety of infection
INVEGA SUSTENNA® was also evaluated in a long-term study in adult subjects Urinary tract 1 0 1 <1 1 1 2
with schizoaffective disorder. A total of 667 subjects received INVEGA SUSTENNA® infection
during the initial 25-week open-label period of this study (median exposure 147 days); Investigations
164 subjects continued to receive INVEGA SUSTENNA® during the 15-month double- Weight 1 4 4 1 1 1 2
blind placebo-controlled period of this study (median exposure 446 days). Adverse increased
reactions that occurred more frequently in the INVEGA SUSTENNA® than the Musculoskeletal and connective tissue disorders
placebo group (a 2% difference or more between groups) were weight increased, Back pain 2 2 1 3 1 1 1
nasopharyngitis, headache, hyperprolactinemia, and pyrexia. Musculoskeletal 1 1 <1 <1 1 1 2
stiffness
Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials Myalgia 1 2 1 <1 1 0 2
Commonly Observed Adverse Reactions: The most common (at least 5% in any Pain in 1 0 2 2 2 3 0
INVEGA SUSTENNA® group) and likely drug-related (adverse events for which the extremity
drug rate is at least twice the placebo rate) adverse reactions from the double- Nervous system disorders
blind, placebo-controlled trials in subjects with schizophrenia were injection site Akathisia 3 2 2 3 1 5 6
reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder. Dizziness 1 6 2 4 1 4 2
No occurrences of adverse events reached this threshold in the long-term double- Extrapyramidal 1 5 2 3 1 0 0
blind, placebo-controlled study in subjects with schizoaffective disorder. disorder
Discontinuation of Treatment Due to Adverse Events: The percentage of subjects Headache 12 11 11 15 11 7 6
who discontinued due to adverse events in the four fixed-dose, double-blind, Somnolence/ 3 5 7 4 1 5 5
sedation
placebo-controlled schizophrenia trials were similar for INVEGA SUSTENNA®-
Psychiatric disorders
and placebo-treated subjects.
Agitation 7 10 5 9 8 5 4
The percentage of subjects who discontinued due to adverse events in the open- Anxiety 7 8 5 3 5 6 6
label period of the long-term study in subjects with schizoaffective disorder Nightmare <1 2 0 0 0 0 0
was 7.5%. During the double-blind, placebo-controlled period of that study, the Respiratory, thoracic and mediastinal disorders
percentages of subjects who discontinued due to adverse events were 5.5% and Cough 1 2 3 1 0 1 1
1.8% in INVEGA SUSTENNA®- and placebo-treated subjects, respectively. Vascular disorders
Dose-Related Adverse Reactions: Based on the pooled data from the four fixed- Hypertension 1 2 1 1 1 1 0
dose, double-blind, placebo-controlled trials in subjects with schizophrenia, among Percentages are rounded to whole numbers. Table includes adverse reactions that
the adverse reactions that occurred with ≥ 2% incidence in the subjects treated were reported in 2% or more of subjects in any of the INVEGA SUSTENNA® dose
with INVEGA SUSTENNA®, only akathisia increased with dose. Hyperprolactinemia groups and which occurred at greater incidence than in the placebo group.
a Placebo group is pooled from all studies and included either deltoid or gluteal
also exhibited a dose relationship, but did not occur at ≥ 2% incidence in
INVEGA SUSTENNA®-treated subjects from the four fixed-dose studies. injection depending on study design.
b Initial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every
Adverse Reactions Occurring at an Incidence of 2% or More in INVEGA SUSTENNA®- 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and 156 mg)
Treated Patients: Table 10 lists the adverse reactions reported in 2% or more of are from studies involving only gluteal injection. [see Clinical Studies (14.1)]
INVEGA SUSTENNA®-treated subjects and at a greater proportion than in the
placebo group with schizophrenia in the four fixed-dose, double-blind, placebo- Adverse reactions for which the INVEGA SUSTENNA® incidence was equal to or
controlled trials. less than placebo are not listed in the table, but included the following: dyspepsia,
psychotic disorder, schizophrenia, and tremor. The following terms were combined:
somnolence/sedation, breast tenderness/breast pain, abdominal discomfort/
abdominal pain upper/stomach discomfort, and tachycardia/sinus tachycardia/
heart rate increased. All injection site reaction-related adverse reactions were
collapsed and are grouped under “Injection site reactions”.
Other Adverse Reactions Observed During the Clinical Trial Evaluation of
INVEGA SUSTENNA®
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, or 4) which were not considered to have significant
clinical implications.
8
Cardiac disorders: atrioventricular block first degree, bradycardia, bundle branch The results across all phases of the maintenance trial in subjects with schizophrenia
block, palpitations, postural orthostatic tachycardia syndrome, tachycardia exhibited comparable findings. In the 9-week, fixed-dose, double-blind, placebo-
Ear and labyrinth disorders: vertigo controlled trial, the proportions of parkinsonism and akathisia assessed by
Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurred incidence of rating scales were higher in the INVEGA SUSTENNA® 156 mg
group (18% and 11%, respectively) than in the INVEGA SUSTENNA® 78 mg group
Gastrointestinal disorders: constipation, dyspepsia, flatulence, salivary hypersecretion (9% and 5%, respectively) and placebo group (7% and 4%, respectively).
Immune system disorders: hypersensitivity
In the 13-week study in subjects with schizophrenia involving 234 mg initiation
Investigations: alanine aminotransferase increased, aspartate aminotransferase dosing, the incidence of any EPS was similar to that of the placebo group (8%), but
increased, electrocardiogram abnormal exhibited a dose-related pattern with 6%, 10%, and 11% in the INVEGA SUSTENNA®
Metabolism and nutrition disorders: decreased appetite, hyperinsulinemia, 234/39 mg, 234/156 mg, and 234/234 mg groups, respectively. Hyperkinesia was
increased appetite the most frequent category of EPS-related adverse events in this study, and was
Musculoskeletal and connective tissue disorders: arthralgia, joint stiffness, reported at a similar rate between the placebo (4.9%) and INVEGA SUSTENNA®
muscle rigidity, muscle spasms, muscle tightness, muscle twitching, nuchal rigidity 234/156 mg (4.8%) and 234/234 mg (5.5%) groups, but at a lower rate in the 234/39 mg
Nervous system disorders: bradykinesia, cerebrovascular accident, cogwheel group (1.3%).
rigidity, convulsion, dizziness postural, drooling, dysarthria, dyskinesia, dystonia, In the long-term study in subjects with schizoaffective disorder, EPS reported during
hypertonia, lethargy, oromandibular dystonia, parkinsonism, psychomotor the 25-week open-label INVEGA SUSTENNA® treatment included hyperkinesia
hyperactivity, syncope (12.3%), parkinsonism (8.7%), tremor (3.4%), dyskinesia (2.5%), and dystonia (2.1%).
Psychiatric disorders: insomnia, libido decreased, restlessness During the 15-month double-blind treatment, the incidence of any EPS was similar to
Reproductive system and breast disorders: amenorrhea, breast discharge, that of the placebo group (8.5% and 7.1% respectively). The most commonly reported
breast enlargement/breast swelling, breast tenderness/breast pain, ejaculation treatment-emergent EPS-related adverse events (> 2%) in any treatment group in
disorder, erectile dysfunction, galactorrhea, gynecomastia, menstrual disorder, the double-blind phase of the study (INVEGA SUSTENNA® versus placebo) were
menstruation delayed, menstruation irregular, sexual dysfunction hyperkinesia (3.7% vs. 2.9%), parkinsonism (3.0% vs. 1.8%), and tremor (1.2% vs. 2.4%).
Respiratory, thoracic and mediastinal disorders: nasal congestion Dystonia
Skin and subcutaneous tissue disorders: drug eruption, pruritus, pruritus Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may
generalized, rash, urticaria occur in susceptible individuals during the first few days of treatment. Dystonic
symptoms include: spasm of the neck muscles, sometimes progressing to tightness
Demographic Differences of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the
An examination of population subgroups in the double-blind placebo-controlled trials tongue. While these symptoms can occur at low doses, they occur more frequently
did not reveal any evidence of differences in safety on the basis of age, gender, or and with greater severity with high potency and at higher doses of first generation
race alone; however, there were few subjects 65 years of age and older. antipsychotic drugs. An elevated risk of acute dystonia is observed in males and
Extrapyramidal Symptoms (EPS) younger age groups.
Pooled data from the two double-blind, placebo-controlled, 13-week, fixed-dose Pain Assessment and Local Injection Site Reactions
trials in adult subjects with schizophrenia provided information regarding EPS. In the pooled data from the two 13-week, fixed-dose, double-blind, placebo-
Several methods were used to measure EPS: (1) the Simpson-Angus global score controlled trials in subjects with schizophrenia, the mean intensity of injection pain
which broadly evaluates parkinsonism, (2) the Barnes Akathisia Rating Scale reported by subjects using a visual analog scale (0 = no pain to 100 = unbearably
global clinical rating score which evaluates akathisia, (3) the Abnormal Involuntary painful) decreased in all treatment groups from the first to the last injection
Movement Scale scores which evaluates dyskinesia, and (4) use of anticholinergic (placebo: 10.9 to 9.8; 39 mg: 10.3 to 7.7; 78 mg: 10.0 to 9.2; 156 mg: 11.1 to 8.8). The
medications to treat EPS (Table 11), and (5) incidence of spontaneous reports of results from both the 9-week, fixed-dose, double-blind, placebo-controlled trial
EPS (Table 12). and the double-blind phase of the maintenance trial exhibited comparable findings.
Table 11: Extrapyramidal Symptoms (EPS) Assessed by Incidence of Rating Scales In the 13-week study involving 234 mg initiation dosing in subjects with
and Use of Anticholinergic Medication – Schizophrenia Studies in Adults schizophrenia, occurrences of induration, redness, or swelling, as assessed
Percentage of Subjects by blinded study personnel, were infrequent, generally mild, decreased over
INVEGA SUSTENNA® time, and similar in incidence between the INVEGA SUSTENNA® and placebo
Placebo 39 mg 78 mg 156 mg groups. Investigator ratings of injection pain were similar for the placebo and
Scale (N=262) (N=130) (N=223) (N=228) INVEGA SUSTENNA® groups. Investigator evaluations of the injection site after
the first injection for redness, swelling, induration, and pain were rated as absent
Parkinsonisma 9 12 10 6 for 69-100% of subjects in both the INVEGA SUSTENNA® and placebo groups. At
Akathisiab 5 5 6 5 Day 92, investigators rated absence of redness, swelling, induration, and pain in
Dyskinesiac 3 4 6 4 95-100% of subjects in both the INVEGA SUSTENNA® and placebo groups.
Use of Anticholinergic Medicationsd 12 10 12 11 Additional Adverse Reactions Reported in Clinical Trials with Oral Paliperidone
a For parkinsonism, percent of subjects with Simpson-Angus Total score > 0.3 at
The following is a list of additional adverse reactions that have been reported in
endpoint (Total score defined as total sum of items score divided by the number clinical trials with oral paliperidone:
of items) Cardiac disorders: bundle branch block left, sinus arrhythmia
b For Akathisia, percent of subjects with Barnes Akathisia Rating Scale global score
≥ 2 at endpoint Gastrointestinal disorders: abdominal pain, small intestinal obstruction
c For Dyskinesia, percent of subjects with a score ≥ 3 on any of the first 7 items or General disorders and administration site conditions: edema, edema peripheral
a score ≥ 2 on two or more of any of the first 7 items of the Abnormal Involuntary Immune system disorders: anaphylactic reaction
Movement Scale at endpoint Infections and infestations: rhinitis
d Percent of subjects who received anticholinergic medications to treat EPS Musculoskeletal and connective tissue disorders: musculoskeletal pain,
torticollis, trismus
Table 12: E xtrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred
Term – Schizophrenia Studies in Adults Nervous system disorders: grand mal convulsion, parkinsonian gait, transient
ischemic attack
Percentage of Subjects Psychiatric disorders: sleep disorder
INVEGA SUSTENNA® Reproductive system and breast disorders: breast engorgement
Placebo 39 mg 78 mg 156 mg Respiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain,
EPS Group (N=262) (N=130) (N=223) (N=228) pneumonia aspiration
Overall percentage of subjects 10 12 11 11 Skin and subcutaneous tissue disorders: rash papular
with EPS-related adverse events Vascular disorders: hypotension, ischemia
Parkinsonism 5 6 6 4 6.2 Postmarketing Experience
Hyperkinesia 2 2 2 4 The following adverse reactions have been identified during postapproval use of
Tremor 3 2 2 3 paliperidone; because these reactions were reported voluntarily from a population
Dyskinesia 1 2 3 1 of uncertain size, it is not always possible to reliably estimate their frequency or
Dystonia 0 1 1 2 establish a causal relationship to drug exposure: angioedema, catatonia, ileus,
somnambulism, swollen tongue, thrombotic thrombocytopenic purpura, urinary
Parkinsonism group includes: Extrapyramidal disorder, hypertonia, musculoskeletal incontinence, and urinary retention.
stiffness, parkinsonism, drooling, masked facies, muscle tightness, hypokinesia
Cases of anaphylactic reaction after injection with INVEGA SUSTENNA® have
Hyperkinesia group includes: Akathisia, restless legs syndrome, restlessness
been reported during postmarketing experience in patients who have previously
Dyskinesia group includes: Dyskinesia, choreoathetosis, muscle twitching,
tolerated oral risperidone or oral paliperidone.
myoclonus, tardive dyskinesia
Dystonia group includes: Dystonia, muscle spasms
9
Paliperidone is the major active metabolite of risperidone. Adverse reactions Paliperidone has been detected in plasma in adult subjects up to 126 days after
reported with oral risperidone and risperidone long-acting injection can be found a single-dose administration of INVEGA SUSTENNA® [see Clinical Pharmacology
in the Adverse Reactions (6) sections of the package inserts for those products. (12.3)], and the clinical significance of INVEGA SUSTENNA® administered before
7 DRUG INTERACTIONS pregnancy or anytime during pregnancy is not known.
7.1 Drugs Having Clinically Important Interactions with INVEGA SUSTENNA® The estimated background risk of major birth defects and miscarriage for the
Because paliperidone palmitate is hydrolyzed to paliperidone [see Clinical indicated population is unknown. All pregnancies have a background risk of
Pharmacology (12.3)], results from studies with oral paliperidone should be taken birth defects, loss, or other adverse outcomes. In the U.S. general population,
into consideration when assessing drug-drug interaction potential. the estimated background risk of major birth defects and miscarriage in clinically
recognized pregnancies is 2-4% and 15-20%, respectively.
Table 13. C
linically Important Drug Interactions with INVEGA SUSTENNA® In animal reproduction studies, there were no treatment related effects on the
Concomitant offspring when pregnant rats were injected intramuscularly with paliperidone
Drug Name or Clinical Rationale Clinical Recommendation palmitate during the period of organogenesis at doses up to 10 times the
maximum recommended human dose (MRHD) of 234 mg paliperidone based on
Drug Class
mg/m2 body surface area. There were no increases in fetal abnormalities when
Centrally Acting Given the primary CNS INVEGA SUSTENNA® pregnant rats and rabbits were treated orally with paliperidone during the period
Drugs and effects of paliperidone, should be used with caution of organogenesis with up to 8 times the MRHD of 12 mg of paliperidone based
Alcohol concomitant use of centrally in combination with other on mg/m2 body surface area. Additional reproduction toxicity studies were
acting drugs and alcohol may centrally acting drugs conducted with orally administered risperidone, which is extensively converted to
modulate the CNS effects of and alcohol [see Adverse paliperidone (see Animal data).
INVEGA SUSTENNA®. Reactions (6.1, 6.2)]. Clinical Considerations
Drugs with Because INVEGA SUSTENNA® Monitor orthostatic vital signs Disease-associated maternal and/or embryo/fetal risk
Potential has the potential for inducing in patients who are vulnerable There is a risk to the mother from untreated schizophrenia, including increased risk
for Inducing orthostatic hypotension, an to hypotension [see Warnings of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are
Orthostatic additive effect may occur and Precautions (5.7)]. associated with increased adverse perinatal outcomes, including preterm birth. It
Hypotension when INVEGA SUSTENNA® is not known if this is a direct result of the illness or other comorbid factors.
is administered with other Fetal/Neonatal Adverse Reactions
therapeutic agents that have
Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia,
this potential [see Warnings hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have
and Precautions (5.7)]. been reported in neonates who were exposed to antipsychotic drugs, including
Strong Inducers The concomitant use of Avoid using CYP3A4 and/ INVEGA SUSTENNA®, during the third trimester of pregnancy. These symptoms
of CYP3A4 paliperidone and strong or P-gp inducers with have varied in severity. Monitor neonates exhibiting extrapyramidal and/or
and P-gp (e.g., inducers of CYP3A4 and P-gp INVEGA SUSTENNA® during withdrawal symptoms and manage symptoms appropriately. Some neonates
carbamazepine, may decrease the exposure the 1-month dosing interval, recovered within hours or days without specific treatment; others required
rifampin, or St. of paliperidone [see Clinical if possible. If administering a prolonged hospitalization.
John’s Wort) Pharmacology (12.3)]. strong inducer is necessary, Data
consider managing the patient Human Data
using paliperidone extended-
Published data from observational studies, birth registries, and case reports on the
release tablets [see Dosage
use of atypical antipsychotics during pregnancy do not report a clear association
and Administration (2.5)]. with antipsychotics and major birth defects. A prospective observational study
Levodopa and Paliperidone may antagonize Monitor and manage patient including 6 women treated with risperidone, the parent compound of paliperidone,
Other Dopamine the effect of levodopa and as clinically appropriate. demonstrated placental passage of risperidone and paliperidone. A retrospective
Agonists other dopamine agonists. 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.
7.2 Drugs Having No Clinically Important Interactions with INVEGA SUSTENNA® There was a small increase in the risk of major birth defects (RR= 1.26, 95% CI
Clinically meaningful pharmacokinetic interaction between INVEGA SUSTENNA® 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88-1.81) in a subgroup
and valproate (including valproic acid and divalproex sodium) is not expected. of 1566 women exposed to the parent compound of paliperidone, risperidone,
Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment during the first trimester of pregnancy; however, there is no mechanism of action
to explain the difference in malformation rates.
of INVEGA SUSTENNA® is required when administered with valproate [see
Clinical Pharmacology (12.3)]. Additionally, no dosage adjustment is necessary Animal Data
for valproate when co-administered with INVEGA SUSTENNA® [See Clinical There were no treatment-related effects on the offspring when pregnant rats were
Pharmacology (12.3)]. injected intramuscularly with paliperidone palmitate extended-release injectable
suspension during the period of organogenesis at doses up to 250 mg/kg, which is
Pharmacokinetic interaction between lithium and INVEGA SUSTENNA® is also 10 times MRHD of 234 mg paliperidone based on mg/m2 body surface area.
unlikely.
In animal reproduction studies, there were no increases in fetal abnormalities
Paliperidone is not expected to cause clinically important pharmacokinetic when pregnant rats and rabbits were treated orally with paliperidone during the
interactions with drugs that are metabolized by cytochrome P450 isozymes. period of organogenesis with up to 8 times the MRHD of 12 mg based on mg/m2
In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone body surface area.
metabolism; however, there is no evidence in vivo that inhibitors of these enzymes Additional reproduction toxicity studies were conducted with orally administered
significantly affect the metabolism of paliperidone. Paliperidone is not a substrate risperidone, which is extensively converted to paliperidone. Cleft palate was
of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or observed in the offspring of pregnant mice treated with risperidone at 3 to 4
inducers of these isozymes is unlikely. [see Clinical Pharmacology (12.3)] times the MRHD of 16 mg based on mg/m2 body surface area; maternal toxicity
occurred at 4 times the MHRD. There was no evidence of teratogenicity in embryo-
8 USE IN SPECIFIC POPULATIONS fetal developmental toxicity studies with risperidone in rats and rabbits at doses
8.1 Pregnancy up to 6 times the MRHD of 16 mg/day risperidone based on mg/m2 body surface
Pregnancy Exposure Registry area. When the offspring of pregnant rats, treated with risperidone at 0.6 times
There is a pregnancy exposure registry that monitors pregnancy outcomes in the MRHD based on mg/m2 body surface area, reached adulthood, learning was
women exposed to atypical antipsychotics, including INVEGA SUSTENNA®, impaired. Increased neuronal cell death occurred in the fetal brains of the offspring
during pregnancy. Healthcare providers are encouraged to register patients of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development
by contacting the National Pregnancy Registry for Atypical Antipsychotics at and growth of the offspring was delayed.
1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research- In rat reproduction studies with risperidone, pup deaths occurred at oral doses
programs/pregnancyregistry/. which are less than the MRHD of risperidone based on mg/m2 body surface area;
Risk Summary it is not known whether these deaths were due to a direct effect on the fetuses or
Neonates exposed to antipsychotic drugs during the third trimester of pups or, to effects on the dams (see RISPERDAL® package insert).
pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following 8.2 Lactation
delivery (see Clinical Considerations). Overall, available data from published Risk Summary
epidemiologic studies of pregnant women exposed to paliperidone have not
established a drug-associated risk for major birth defects, miscarriage, or Limited data from published literature report the presence of paliperidone in
adverse maternal or fetal outcomes (see Data). There are risks to the mother human breast milk. There is no information on the effects on the breastfed infant
associated with untreated schizophrenia and with exposure to antipsychotics, or the effects on milk production; however, there are reports of sedation, failure
including INVEGA SUSTENNA®, during pregnancy (see Clinical Considerations). to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle
movements) in breastfed infants exposed to paliperidone’s parent compound,
10
risperidone (see Clinical Considerations). Paliperidone has been detected 10 OVERDOSAGE

in plasma in adult subjects up to 126 days after a single-dose administration 10.1 Human Experience
of INVEGA SUSTENNA® [see Clinical Pharmacology (12.3)], and the clinical No cases of overdose were reported in premarketing studies with
significance on the breastfed infant is not known. The developmental and health INVEGA SUSTENNA®. Because INVEGA SUSTENNA® is to be administered by
benefits of breastfeeding should be considered along with the mother’s clinical healthcare professionals, the potential for overdosage by patients is low.
need for INVEGA SUSTENNA® and any potential adverse effects on the breastfed
child from INVEGA SUSTENNA® or from the mother’s underlying condition. While experience with paliperidone overdose is limited, among the few cases of
overdose reported in premarketing trials with oral paliperidone, the highest estimated
Clinical Considerations ingestion was 405 mg. Observed signs and symptoms included extrapyramidal
Infants exposed to INVEGA SUSTENNA® through breastmilk should be monitored symptoms and gait unsteadiness. Other potential signs and symptoms include those
for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms resulting from an exaggeration of paliperidone’s known pharmacological effects,
(tremors and abnormal muscle movements). i.e., drowsiness and sedation, tachycardia and hypotension, and QT prolongation.
8.3 Females and Males of Reproductive Potential Torsades de pointes and ventricular fibrillation have been reported in a patient in
the setting of overdose with oral paliperidone.
Infertility
Paliperidone is the major active metabolite of risperidone. Overdose experience
Females reported with risperidone can be found in the OVERDOSAGE section of the
Based on the pharmacologic action of paliperidone (D2 receptor antagonism), risperidone package insert.
treatment with INVEGA SUSTENNA® may result in an increase in serum
prolactin levels, which may lead to a reversible reduction in fertility in females of 10.2 Management of Overdosage
reproductive potential [see Warnings and Precautions (5.10)]. Contact a Certified Poison Control Center for the most up to date information
on the management of INVEGA SUSTENNA® overdosage (1-800-222-1222 or
8.4 Pediatric Use www.poison.org). Provide supportive care, including close medical supervision
Safety and effectiveness of INVEGA SUSTENNA® in patients < 18 years of age and monitoring. Treatment should consist of general measures employed in the
have not been established. management of overdosage with any drug. Consider the possibility of multiple drug
Juvenile Animal Studies overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor
In a study in which juvenile rats were treated with oral paliperidone from days 24 to cardiac rhythm and vital signs. Use supportive and symptomatic measures. There
73 of age, a reversible impairment of performance in a test of learning and memory is no specific antidote to paliperidone.
was seen, in females only, with a no-effect dose of 0.63 mg/kg/day, which produced Consider the prolonged-release characteristics of INVEGA SUSTENNA® and
plasma levels (AUC) of paliperidone similar to those in adolescents dosed at the long apparent half-life of paliperidone when assessing treatment needs and
12 mg/day. No other consistent effects on neurobehavioral or reproductive recovery.
development were seen up to the highest dose tested (2.5 mg/kg/day), which
11 DESCRIPTION
produced plasma levels of paliperidone 2-3 times those in adolescents.
INVEGA SUSTENNA® contains paliperidone palmitate. The active ingredient,
Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively paliperidone, is an atypical antipsychotic belonging to the chemical class of
metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or benzisoxazole derivatives. INVEGA SUSTENNA® contains a racemic mixture of
5 mg/kg/day. Decreased bone length and density were seen with a no-effect (+)- and (-)- paliperidone palmitate. The chemical name is (9RS)-3-[2-[4-(6-Fluoro-
dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus 1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-
paliperidone which were similar to those in children and adolescents receiving pyrido[1,2-a]pyrimadin-9-yl hexadecanoate. Its molecular formula is C39H57FN4O4
the MRHD of risperidone. In addition, a delay in sexual maturation was seen at all and its molecular weight is 664.89. The structural formula is:
doses in both males and females. The above effects showed little or no reversibility
in females after a 12-week drug-free recovery period.
The long-term effects of INVEGA SUSTENNA® on growth and sexual maturation
have not been fully evaluated in children and adolescents.
8.5 Geriatric Use
Clinical studies of INVEGA SUSTENNA® did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from
younger subjects. Other reported clinical experience has not identified differences
in responses between the elderly and younger patients.
This drug is known to be substantially excreted by the kidney and clearance is Paliperidone palmitate is very slightly soluble in ethanol and methanol, practically
decreased in patients with renal impairment [see Clinical Pharmacology (12.3)], insoluble in polyethylene glycol 400 and propylene glycol, and slightly soluble in
who should be given reduced doses. Because elderly patients are more likely to ethyl acetate.
have decreased renal function, adjust dose based on renal function [see Dosage INVEGA SUSTENNA® is available as a white to off-white sterile aqueous
and Administration (2.5)]. extended-release suspension for intramuscular injection in the following dose
8.6 Renal Impairment strengths of paliperidone palmitate (and deliverable volumes) of the single-
Use of INVEGA SUSTENNA® is not recommended in patients with moderate dose prefilled syringes: 39 mg (0.25 mL), 78 mg (0.5 mL), 117 mg (0.75 mL), 156 mg
or severe renal impairment (creatinine clearance < 50 mL/min). Dose reduction (1.0 mL), and 234 mg (1.5 mL). The drug product hydrolyzes to the active moiety,
is recommended for patients with mild renal impairment (creatinine clearance paliperidone, resulting in dose strengths of 25 mg, 50 mg, 75 mg, 100 mg, and
≥ 50 mL/min to < 80 mL/min) [see Dosage and Administration (2.5) and Clinical 150 mg of paliperidone, respectively. The inactive ingredients are polysorbate
Pharmacology (12.3)]. 20 (12 mg/mL), polyethylene glycol 4000 (30 mg/mL), citric acid monohydrate
8.7 Hepatic Impairment (5 mg/mL), disodium hydrogen phosphate anhydrous (5 mg/mL), sodium dihydrogen
phosphate monohydrate (2.5 mg/mL), sodium hydroxide (2.84 mg/mL used as an
INVEGA SUSTENNA® has not been studied in patients with hepatic impairment. alkalizing agent to set pH at 7), and water for injection.
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 INVEGA SUSTENNA® is provided in a single-dose prefilled syringe (cyclic-olefin-
patients with severe hepatic impairment [Clinical Pharmacology (12.3)]. copolymer) with a plunger stopper and tip cap (bromobutyl rubber). The kit also
contains 2 safety needles (a 1 ½-inch 22 gauge safety needle and a 1-inch 23 gauge
8.8 Patients with Parkinson’s Disease or Lewy Body Dementia safety needle).
Patients with Parkinson’s Disease or Dementia with Lewy Bodies can experience
increased sensitivity to INVEGA SUSTENNA®. Manifestations can include 12 CLINICAL PHARMACOLOGY
confusion, obtundation, postural instability with frequent falls, extrapyramidal 12.1 Mechanism of Action
symptoms, and clinical features consistent with neuroleptic malignant syndrome. Paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology
9 DRUG ABUSE AND DEPENDENCE (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
9.1 Controlled Substance schizophrenia could be mediated through a combination of central dopamine
INVEGA SUSTENNA® (paliperidone) is not a controlled substance. Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.
9.2 Abuse 12.2 Pharmacodynamics
Paliperidone has not been systematically studied in animals or humans for its In vitro, paliperidone acts as an antagonist at the central dopamine Type 2 (D2)
potential for abuse. and serotonin Type 2 (5HT2A) receptors with binding affinities (Ki values) of 1.6-
9.3 Dependence 2.8 nM for D2 and 0.8-1.2 nM for 5HT2A receptors. Paliperidone is also active
Paliperidone has not been systematically studied in animals or humans for its as an antagonist at the α1 and α2 adrenergic receptors and H1 histaminergic
potential for tolerance or physical dependence. receptors, which may explain some of the other effects of the drug. Paliperidone
has no affinity for cholinergic muscarinic or β1- and β2-adrenergic receptors.
The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is
qualitatively and quantitatively similar in vitro.
11
12.3 Pharmacokinetics Figure 1: The effects of other drugs on paliperidone pharmacokinetics.

Absorption and Distribution paliperidone Fold Change and 90%
Due to its extremely low water solubility, the 1-month formulation of paliperidone inhibitor
palmitate dissolves slowly after intramuscular injection before being hydrolyzed Paroxetine
to paliperidone and absorbed into the systemic circulation. Following a single 4
intramuscular dose, the plasma concentrations of paliperidone gradually rise to CYP3A4 inducer
reach maximum plasma concentrations at a median Tmax of 13 days. The release of Carbamazepine AUG
the drug starts as early as day 1 and lasts for as long as 126 days.
Following intramuscular injection of single doses (39 mg - 234 mg) in the deltoid Divalproex Sodium ER
muscle, on average, a 28% higher Cmax was observed compared with injection in
the gluteal muscle. The two initial deltoid intramuscular injections of 234 mg on Cmax 4
day 1 and 156 mg on day 8 help attain therapeutic concentrations rapidly. T T T T

The release profile and dosing regimen of INVEGA SUSTENNA® results in 0.0 1.0 15 20
sustained therapeutic concentrations. The AUC of paliperidone following Change Relative to Reference
INVEGA SUSTENNA® administration was dose-proportional over a 39 mg-234 mg (without interacting drug)
dose range, and less than dose-proportional for Cmax for doses exceeding 78 mg. Clinically meaningful pharmacokinetic interaction between INVEGA SUSTENNA®
The mean steady-state peak:trough ratio for an INVEGA SUSTENNA® dose of and valproate (including valproic acid and divalproex sodium) is not expected.
156 mg was 1.8 following gluteal administration and 2.2 following deltoid Oral administration of divalproex sodium extended-release tablets (two 500 mg
administration. tablets once daily at steady-state) with oral paliperidone extended-release tablets
Following administration of paliperidone palmitate the (+) and (-) enantiomers of resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone.
paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6–1.8. After oral administration of paliperidone, the steady-state Cmax and AUC of
Based on a population analysis, the apparent volume of distribution of paliperidone divalproex sodium extended-release tablets were not affected in 13 patients
is 391 L. The plasma protein binding of racemic paliperidone is 74%. stabilized on divalproex sodium extended-release tablets. In a clinical study,
Metabolism and Elimination subjects on stable doses of divalproex sodium extended-release tablets had
In a study with oral immediate-release 14C-paliperidone, one week following comparable valproate average plasma concentrations when oral paliperidone
administration of a single oral dose of 1 mg immediate-release 14C-paliperidone, extended-release tablets 3-15 mg/day was added to their existing divalproex
59% of the dose was excreted unchanged into urine, indicating that paliperidone sodium extended-release tablets treatment [see Drug Interactions (7.2)].
is not extensively metabolized in the liver. Approximately 80% of the administered In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone
radioactivity was recovered in urine and 11% in the feces. Four metabolic pathways metabolism, however, there is no evidence in vivo that inhibitors of these enzymes
have been identified in vivo, none of which accounted for more than 10% of the significantly affect the metabolism of paliperidone; they contribute to only a small
dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. fraction of total body clearance. In vitro studies demonstrated that paliperidone is
Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism a substrate of P-glycoprotein (P-gp) [see Drug Interactions (7.2)].
of paliperidone, there is no evidence in vivo that these isozymes play a significant In vitro studies in human liver microsomes demonstrated that paliperidone does
role in the metabolism of paliperidone. Population pharmacokinetics analyses not substantially inhibit the metabolism of drugs metabolized by cytochrome P450
indicated no discernible difference on the apparent clearance of paliperidone isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4,
after administration of oral paliperidone between extensive metabolizers and poor and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs
metabolizers of CYP2D6 substrates. that are metabolized by these metabolic pathways in a clinically relevant manner.
The median apparent half-life of paliperidone following INVEGA SUSTENNA® Paliperidone is also not expected to have enzyme inducing properties.
single-dose administration over the dose range of 39 mg - 234 mg ranged from Paliperidone is a weak inhibitor of P-gp at high concentrations. No in vivo data are
25 days - 49 days. available, and the clinical relevance is unknown.
Long-Acting Paliperidone Palmitate Injection versus Oral Extended-Release Studies in Specific Populations
Paliperidone No specific pharmacokinetic studies have been performed with INVEGA SUSTENNA®
INVEGA SUSTENNA® is designed to deliver paliperidone over a monthly period in specific populations. All the information is obtained from studies with oral
while extended-release oral paliperidone is administered on a daily basis. paliperidone or is based on the population pharmacokinetic modelling of oral
The initiation regimen for INVEGA SUSTENNA® (234 mg/156 mg in the deltoid paliperidone and INVEGA SUSTENNA®. Exposures of paliperidone in specific
muscle on Day 1/Day 8) was designed to rapidly attain steady-state paliperidone populations (renal impairment, hepatic impairment and elderly) are summarized in
concentrations when initiating therapy without the use of oral supplementation. Figure 2 [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)].
In general, overall initiation plasma levels with INVEGA SUSTENNA® were within After oral administration of paliperidone in patients with moderate hepatic
the exposure range observed with 6-12 mg extended-release oral paliperidone. The impairment, the plasma concentrations of free paliperidone were similar to those
use of the INVEGA SUSTENNA® initiation regimen allowed patients to stay in this of healthy subjects, although total paliperidone exposure decreased because of
exposure window of 6-12 mg extended-release oral paliperidone even on trough a decrease in protein binding. Paliperidone has not been studied in patients with
pre-dose days (Day 8 and Day 36). The intersubject variability for paliperidone severe hepatic impairment [see Use in Specific Populations (8.7)].
pharmacokinetics following delivery from INVEGA SUSTENNA® was lower relative After oral administration of paliperidone in elderly subjects, the Cmax and AUC
to the variability determined from extended-release oral paliperidone tablets. increased 1.2-fold compared to young subjects. However, there may be age-
Because of the difference in median pharmacokinetic profiles between the two related decreases in creatinine clearance [see Dosage and Administration (2.5)
products, caution should be exercised when making a direct comparison of their and Use in Specific Populations (8.5)].
pharmacokinetic properties. Figure 2: Effects of intrinsic factors on paliperidone pharmacokinetics.
Drug Interaction Studies Effect of intrinsic factors on paliperidone pharmacokinetics
No specific drug interaction studies have been performed with paliperidone Fold Change and 90% Cl
INVEGA SUSTENNA®. The information below is obtained from studies with oral
paliperidone. Renal Impairment
Effects of other drugs on the exposures of paliperidone are summarized in Mild vs Normal AUC
Figure 1. After oral administration of 20 mg/day of paroxetine (a potent CYP2D6 Moderate vs Normal AUC
Severe vs Normal AUC
inhibitor), an increase in mean Cmax and AUC values at steady-state was observed Hepatic Impairment
(see Figure 1). Higher doses of paroxetine have not been studied. The clinical Moderate vs Normal
relevance is unknown. After oral administration, a decrease in mean Cmax and AUC
4
Age
values at steady state is expected when patients are treated with carbamazepine, AUC 4
a strong inducer of both CYP3A4 and P-gp [see Drug Interactions (7.1)]. This Cmax
decrease is caused, to a substantial degree, by a 35% increase in renal clearance T T T T T T
of paliperidone. 1 2 3 4 5 6
Change Relative to Reference
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 SUSTENNA®, the trough
concentrations were similar between males and females.
12
Lower Cmax was observed in overweight and obese subjects. At apparent steady- In Study 2 (PSY-3003), another 13-week study (n=349) comparing three fixed doses
state with INVEGA SUSTENNA®, the trough concentrations were similar among of INVEGA SUSTENNA® (78 mg/4 weeks, 156 mg/4 weeks, and 234 mg/4 weeks) to
normal, overweight, and obese subjects. placebo, only 156 mg/4 weeks of INVEGA SUSTENNA® was superior to placebo in
13 NONCLINICAL TOXICOLOGY improving the PANSS total score.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In Study 3 (PSY-3004), a third 13-week study (n=513) comparing three fixed doses
Carcinogenesis of INVEGA SUSTENNA® (39 mg/4 weeks, 78 mg/4 weeks, and 156 mg/4 weeks)
to placebo, all three doses of INVEGA SUSTENNA® were superior to placebo in
The carcinogenic potential of intramuscularly injected paliperidone palmitate was improving the PANSS total score.
assessed in rats. There was an increase in mammary gland adenocarcinomas in
female rats at 16, 47, and 94 mg/kg/month, which is 0.6, 2, and 4 times, respectively, In Study 4 (SCH-201), the 9-week study (n=197) comparing two fixed doses of
the MRHD of 234 mg of INVEGA SUSTENNA® based on mg/m2 body surface area. INVEGA SUSTENNA® (78 mg/4 weeks and 156 mg/4 weeks) to placebo, both doses
A no-effect dose was not established. Male rats showed an increase in mammary of INVEGA SUSTENNA® were superior to placebo in improving PANSS total score.
gland adenomas, fibroadenomas, and carcinomas at 2 and 4 times the MRHD A summary of the mean baseline PANSS scores along with the mean changes from
based on mg/m2 body surface area. A carcinogenicity study in mice has not been baseline in the four short-term acute schizophrenia studies are provided in Table 14.
conducted with paliperidone palmitate.
Table 14: Schizophrenia Short-term Studies
Carcinogenicity studies with risperidone, which is extensively converted to
paliperidone in rats, mice, and humans, were conducted in Swiss albino mice and Study Treatment Group Primary Efficacy Measure: PANSS Total Score
Wistar rats. Risperidone was administered in the diet at daily doses of 0.63, 2.5, Number
and 10 mg/kg for 18 months to mice and for 25 months to rats. A maximum tolerated Mean LS Mean Placebo-
dose was not achieved in male mice. There were statistically significant increases Baseline Change from subtracted
in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland Score (SD) Baseline (SE) Differencea
adenocarcinomas. The no-effect dose for these tumors was less than or equal (95% CI)
to the maximum recommended human dose of risperidone based on mg/m2 body
surface area (see risperidone package insert). An increase in mammary, pituitary, Study 1 INVEGA SUSTENNA® 86.9 (11.99) -11.2 (1.69) -5.1
and endocrine pancreas neoplasms has been found in rodents after chronic (39 mg/4 weeks)* (-9.01, -1.10)
administration of other antipsychotic drugs and is considered to be mediated INVEGA SUSTENNA® 86.2 (10.77) -14.8 (1.68) -8.7
by prolonged dopamine D2 antagonism and hyperprolactinemia. The relevance (156 mg/4 weeks)* (-12.62, -4.78)
of these tumor findings in rodents to human risk is unclear [see Warnings and
Precautions (5.7)]. INVEGA SUSTENNA® 88.4 (11.70) -15.9 (1.70) -9.8
(234 mg/4 weeks)* (-13.71, -5.85)
Mutagenesis
Paliperidone palmitate showed no genotoxicity in the in vitro Ames bacterial reverse Placebo 86.8 (10.31) -6.1 (1.69) --
mutation test or the mouse lymphoma assay. Paliperidone was not genotoxic in the Study 2b INVEGA SUSTENNA® 89.9 (10.78) -6.9 (2.50) -3.5
in vitro Ames bacterial reverse mutation test, the mouse lymphoma assay, or the (78 mg/4 weeks) (-8.73, 1.77)
in vivo rat bone marrow micronucleus test. INVEGA SUSTENNA® 90.1 (11.66) -10.4 (2.47) -6.9
Impairment of Fertility (156 mg/4 weeks)* (-12.12, -1.68)
No fertility studies were conducted with paliperidone palmitate. Placebo 92.4 (12.55) -3.5 (2.15) --
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 Study 3 INVEGA SUSTENNA® 90.7 (12.25) -19.8 (2.19) -6.6
2.5 mg/kg/day which is 2 times the MRHD based on mg/m2 body surface area. (39 mg/4 weeks)* (-11.40, -1.73)
However, pre- and post-implantation loss was increased, and the number of live INVEGA SUSTENNA® 91.2 (12.02) -19.2 (2.19) -5.9
embryos was slightly decreased, at 2.5 mg/kg, a dose that also caused slight (78 mg/4 weeks)* (-10.76, -1.07)
maternal toxicity. These parameters were not affected at a dose of 0.63 mg/kg, INVEGA SUSTENNA® 90.8 (11.70) -22.5 (2.18) -9.2
which is half of the MRHD based on mg/m2 body surface area. (156 mg/4 weeks)* (-14.07, -4.43)
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/m2 body surface area, although Placebo 90.7 (12.22) -13.3 (2.21) --
sperm count and sperm viability studies were not conducted with paliperidone. Study 4 INVEGA SUSTENNA® 88.0 (12.39) -4.6 (2.43) -11.2
In a subchronic study in Beagle dogs with risperidone, which is extensively (78 mg/4 weeks)* (-16.85, -5.57)
converted to paliperidone in dogs and humans, all doses tested (0.31 mg/kg - INVEGA SUSTENNA® 85.2 (11.09) -7.4 (2.45) -14.0
5.0 mg/kg) resulted in decreases in serum testosterone and in sperm motility and (156 mg/4 weeks)* (-19.51, -8.58)
concentration (0.6 to 10 times the MRHD of 16 mg/day for risperidone, based on
mg/m2 body surface area). Serum testosterone and sperm parameters partially Placebo 87.8 (13.90) 6.6 (2.45) --
recovered, but remained decreased after the last observation (two months after SD: standard deviation; SE: standard error; LS Mean: least-squares mean;
treatment was discontinued). CI: unadjusted confidence interval.
13.2 Animal Toxicology and/or Pharmacology a Difference (drug minus placebo) in least-squares mean change from baseline.
b Because an insufficient number of subjects received the 234 mg/4 weeks dose,
Injection site toxicity was assessed in minipigs injected intramuscularly with the
3-month paliperidone palmitate extended-release injectable suspension at doses results from this group are not included.
up to 819 mg, which is equal to the MRHD. Injection site inflammatory reactions * p<0.05 (Doses statistically significantly superior to placebo).
were greater and more advanced than reactions to the 1-month paliperidone
palmitate extended-release injectable suspension. Reversibility of these findings Maintenance Monotherapy Treatment (Study 5: PSY-3001)
was not examined. The efficacy of INVEGA SUSTENNA® in maintaining symptomatic control in
schizophrenia was established in a longer-term double-blind, placebo-controlled,
14 CLINICAL STUDIES flexible-dose study involving adult subjects who met DSM-IV criteria for
14.1 Schizophrenia schizophrenia. This study included a minimum 12-week, fixed-dose stabilization
Short-Term Monotherapy (Studies 1, 2, 3, 4) phase, and a randomized, placebo-controlled phase to observe for relapse. During
The efficacy of INVEGA SUSTENNA® in the acute treatment of schizophrenia the double-blind phase, patients were randomized to either the same dose of
INVEGA SUSTENNA® they received during the stabilization phase, i.e., 39 mg,
was evaluated in four short-term (one 9-week and three 13-week) double- 78 mg, or 156 mg administered every 4 weeks, or to placebo. A total of 410 stabilized
blind, randomized, placebo-controlled, fixed-dose studies of acutely relapsed patients were randomized to either INVEGA SUSTENNA® or to placebo until they
adult inpatients who met DSM-IV criteria for schizophrenia. The fixed doses experienced a relapse of schizophrenia symptoms. Relapse was pre-defined as
of INVEGA SUSTENNA® in these studies were given on days 1, 8, and 36 in the time to first emergence of one or more of the following: psychiatric hospitalization,
9-week study, and additionally on day 64 of the 13-week studies, i.e., at a weekly ≥ 25% increase (if the baseline score was > 40) or a 10-point increase (if the
interval for the initial two doses and then every 4 weeks for maintenance. baseline score was ≤ 40) in total PANSS score on two consecutive assessments,
Efficacy was evaluated using the total score on the Positive and Negative deliberate self-injury, violent behavior, suicidal/homicidal ideation, or a score
Syndrome Scale (PANSS). The PANSS is a 30-item scale that measures positive of ≥ 5 (if the maximum baseline score was ≤ 3) or ≥ 6 (if the maximum baseline
symptoms of schizophrenia (7 items), negative symptoms of schizophrenia score was 4) on two consecutive assessments of the specific PANSS items. The
(7 items), and general psychopathology (16 items), each rated on a scale of 1 primary efficacy variable was time to relapse. A pre-planned interim analysis
(absent) to 7 (extreme); total PANSS scores range from 30 to 210. showed a statistically significantly longer time to relapse in patients treated with
In Study 1 (PSY-3007), a 13-week study (n=636) comparing three fixed doses of INVEGA SUSTENNA® compared to placebo, and the study was stopped early
INVEGA SUSTENNA® (initial deltoid injection of 234 mg followed by 3 gluteal or because maintenance of efficacy was demonstrated. Thirty-four percent (34%) of
deltoid doses of either 39 mg/4 weeks, 156 mg/4 weeks or 234 mg/4 weeks) to subjects in the placebo group and 10% of subjects in the INVEGA SUSTENNA®
placebo, all three doses of INVEGA SUSTENNA® were superior to placebo in group experienced a relapse event. There was a statistically significant difference
improving the PANSS total score. between the treatment groups in favor of INVEGA SUSTENNA®. A Kaplan-Meier
plot of time to relapse by treatment group is shown in Figure 3. The time to relapse
13
for subjects in the placebo group was statistically significantly shorter than for Table 15: Components of Composite Endpoint in a Long-Term, Randomized,
the INVEGA SUSTENNA® group. An examination of population subgroups did Flexible-Dose Study in Subjects with Schizophrenia and a History of
not reveal any clinically significant differences in responsiveness on the basis of Incarceration (Schizophrenia Study 6)
gender, age, or race.
INVEGA Oral
Figure 3: Kaplan-Meier Plot of Cumulative Proportion of Subjects with Relapse Hazard
SUSTENNA® Antipsychotics
Over Time (Schizophrenia Study 5) Event Type Ratioa
N=226 N=218
[95% CI]
60 frequency (%) frequency (%)
First Treatment Failures 90 (39.8%) 117 (53.7%) 0.70
Estimated Percent of Subjects With Relapse
[0.53, 0.92]
*
4
50
First Treatment Failure

40 Component Events
• A rrest and/or incarceration 48 (21.2%) 64 (29.4%)
• Psychiatric hospitalization 18 (8.0%) 26 (11.9%)
• D iscontinuation of
antipsychotic treatment
20 15 (6.6%) 8 (3.7%)
because of safety or
tolerability
• T reatment supplementation
with another antipsychotic
5 (2.2%) 6 (2.8%)
because of inadequate
efficacy
Days since Randomization • Need for increase in level
*
median time to relapse for placebo group 163 days of psychiatric services
3 (1.3%) 4 (1.8%)
is
to prevent an imminent
Long-Term Comparative Monotherapy Treatment versus Oral Antipsychotic psychiatric hospitalization
Therapy (Study 6: SCH-3006) • D iscontinuation of
The efficacy of INVEGA SUSTENNA® in delaying time to treatment failure antipsychotic treatment
compared with selected oral antipsychotic medications was established in a long- 1 (0.4%) 9 (4.1%)
because of inadequate
term, randomized, flexible-dose study in subjects with schizophrenia and a history efficacy
of incarceration. Subjects were screened for up to 14 days followed by a 15-month • Suicide 0 0
treatment phase during which they were observed for treatment failure.
The primary endpoint was time to first treatment failure. Treatment failure Arrest and/or Incarceration
was defined as one of the following: arrest and/or incarceration; psychiatric or Psychiatric Hospitalization 76 (33.6%) 98 (45.0%) 0.70
hospitalization; discontinuation of antipsychotic treatment because of safety or Events, regardless of whether [0.52, 0.94]
tolerability; treatment supplementation with another antipsychotic because of they were first events b
inadequate efficacy; need for increase in level of psychiatric services to prevent a Hazard
ratio of INVEGA SUSTENNA® to Oral Antipsychotics based on Cox
an imminent psychiatric hospitalization; discontinuation of antipsychotic treatment regression model for time-to-event analysis. Note that the hazard ratio did not
because of inadequate efficacy; or suicide. Treatment failure was determined by appear constant throughout the trial.
an Event Monitoring Board (EMB) that was blinded to treatment assignment. A total b Analysis
results, which incorporated relevant events collected after discontinuation
of 444 subjects were randomly assigned to either INVEGA SUSTENNA® (N = 226; for those who discontinued, were consistent with the results from the pre-specified
median dose 156 mg) or one of up to seven pre-specified, flexibly-dosed, commonly analysis of this secondary endpoint.
prescribed oral antipsychotic medications (N = 218; aripiprazole, haloperidol,
olanzapine, paliperidone, perphenazine, quetiapine, or risperidone). The selection 14.2 Schizoaffective Disorder
of the oral antipsychotic medication was determined to be appropriate for the Maintenance Treatment – Monotherapy and as Adjunct to Mood Stabilizer or
patient by the investigator. A statistically significantly longer time to first treatment Antidepressant (SAff Study 1: SCA-3004)
failure was seen for INVEGA SUSTENNA® compared with oral antipsychotic The efficacy of INVEGA SUSTENNA® in maintaining symptom control in
medications. The median time to treatment failure was 416 days and 226 days schizoaffective disorder was established in a long-term double-blind, placebo-
for INVEGA SUSTENNA® and antipsychotic medications, respectively. A Kaplan- controlled, flexible-dose randomized-withdrawal study designed to delay relapse in
Meier plot of time to first treatment failure is shown in Figure 4. The frequencies adult subjects who met DSM-IV criteria for schizoaffective disorder, as confirmed
of first treatment failure events by type are shown in Table 15. The time to first by the Structured Clinical Interview for DSM-IV Disorders. The population included
arrest and/or incarceration or psychiatric hospitalization was also statistically subjects with schizoaffective bipolar and depressive types. Subjects received
significantly longer for the INVEGA SUSTENNA® group compared to the oral INVEGA SUSTENNA® either as monotherapy or as an adjunct to stable doses of
antipsychotic group. antidepressant or mood stabilizers.
Figure 4: Kaplan-Meier Plot of Time to First Treatment Failure in a Long-Term, This study included a 13-week, open-label, flexible-dose (INVEGA SUSTENNA®
Randomized, Flexible- Dose Study in Subjects with Schizophrenia and a 78 mg, 117 mg, 156 mg, or 234 mg) lead-in period which enrolled a total of 667
History of Incarceration (Schizophrenia Study 6) subjects who had 1) acute exacerbation of psychotic symptoms; 2) score ≥4 on
≥3 PANSS items of delusions, conceptual disorganization, hallucinatory behavior,
excitement, suspiciousness/persecution, hostility, uncooperativeness, tension,
and poor impulse control; and 3) prominent mood symptoms ≥16 on the Young
Mania Rating Scale (YMRS) and/or the Hamilton Rating Scale for Depression,
21-item version (HAM-D-21). Subjects were 19 to 66 years old (mean 39.5 years)
Estimated Percent of Subjects with Treatment Failure
and 53.5% were male. The mean scores at open-label enrollment of PANSS total
was 85.8 (range 42 to 128), HAM-D-21 was 20.4 (range 3 to 43), YMRS was 18.6
(range 0 to 50), and CGI-S-SCA was 4.4 (range 2 to 6).
After the 13-week open-label flexible-dose INVEGA SUSTENNA® treatment,
432 subjects met stabilization criteria (PANSS total score ≤70, YMRS ≤12, and
HAM-D-21 ≤12) and continued into the 12-week open-label fixed-dose stabilization
period.
A total of 334 subjects who met stabilization criteria for 12 consecutive weeks were
randomized (1:1) to continue the same dose of INVEGA SUSTENNA® or to placebo
in the 15-month, double-blind, maintenance period. For the 164 subjects who were
randomized to INVEGA SUSTENNA®, dose distribution was 78 mg (4.9%), 117 mg
(9.8%), 156 mg (47.0%), and 234 mg (38.4%). The primary efficacy variable was time to
relapse. Relapse was defined as the first occurrence of one or more of the following:
1) psychiatric hospitalization; 2) intervention employed to avert hospitalization;
3) clinically significant self-injury, suicidal or homicidal ideation or violent behavior;
30 60 150 180 210 240 270 300 330 360 390 420 450 4) a score of ≥6 (if the score was ≤4 at randomization) of any of the individual PANSS
Days since randomization items: delusions, conceptual disorganization, hallucinatory behavior, excitement,
* Median time to first treatment failure: 416 days with INVEGA SUSTENNA®; suspiciousness/persecution, hostility, uncooperativeness, or poor impulse control;
226 days with oral antipsychotics 5) on two consecutive assessments within 7 days: ≥25% increase (if the score at
14
randomization was >45) or ≥10-point increase (if the score at randomization was healthcare provider or report to the emergency room if they experience signs and
≤45) in total PANSS score; a score of ≥5 (if the score was ≤3 at randomization) of any symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status
of the individual PANSS items: delusions, conceptual disorganization, hallucinatory including delirium, and evidence of autonomic instability (irregular pulse or blood
behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, or pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and
poor impulse control; an increase of ≥2 points (if the score was 1 [not ill] to 3 [mildly Precautions (5.3)].
ill] at randomization) or increase of ≥1 point (if the score was ≥4 [moderately ill or Tardive Dyskinesia
worse] at randomization) in CGI-S-SCA overall score.
Counsel patients on the signs and symptoms of tardive dyskinesia and to contact
There was a statistically significant difference in time to relapse between the their healthcare provider if these abnormal movements occur [see Warnings and
treatment groups in favor of INVEGA SUSTENNA®. A Kaplan-Meier plot of time Precautions (5.5)].
to relapse by treatment group is shown in Figure 5.
Metabolic Changes
Figure 5: Kaplan-Meier Plot of Cumulative Proportion of Subjects with Relapse Educate patients about the risk of metabolic changes, how to recognize symptoms
Over Time (SAff Study 1) of hyperglycemia and diabetes mellitus, and the need for specific monitoring,
including blood glucose, lipids, and weight [see Warnings and Precautions (5.6)].
a
Estimated Percent of Subjects With Relapse
Orthostatic Hypotension
Educate patients about the risk of orthostatic hypotension and syncope, particularly
Placebo (N=170) at the time of initiating treatment, re-initiating treatment, or increasing the dose
a
INVEGA SUSTENNA (N=164) [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 SUSTENNA® [see Warnings and Precautions (5.9)].
Hyperprolactinemia
N
Counsel patients on signs and symptoms of hyperprolactinemia that may be

associated with chronic use of INVEGA SUSTENNA®. Advise them to seek medical
attention if they experience any of the following: amenorrhea or galactorrhea
in females, erectile dysfunction or gynecomastia in males [see Warnings and
Precautions (5.10)].
0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 Interference with Cognitive and Motor Performance
Days since Randomization Caution patients about performing activities requiring mental alertness, such
as operating hazardous machinery or operating a motor vehicle, until they are
Table 16 summarizes the number of subjects with relapse in the overall population, reasonably certain that INVEGA SUSTENNA® therapy does not affect them
by subgroup (monotherapy vs. adjunctive therapy), and by symptom type at the first adversely [see Warnings and Precautions (5.11)].
occurrence of relapse. Priapism
Advise patients of the possibility of painful or prolonged penile erections (priapism).
Table 16: Summary of Relapse Rates (SAff Study 1). Instruct the patient to seek immediate medical attention in the event of priapism
Number (Percent) of Subjects Who Relapsed [see Warnings and Precautions (5.14)].
Placebo INVEGA SUSTENNA® Heat Exposure and Dehydration
N=170 N=164 Counsel patients regarding appropriate care in avoiding overheating and
All Subjects 57 (33.5%) 25 (15.2%) dehydration [see Warnings and Precautions (5.15)].
Monotherapy subset N=73 N=78 Concomitant Medication
24 (32.9%) 9 (11.5%) Advise patients to inform their healthcare providers if they are taking, or plan to
Adjunct to Antidepressants N=97 N=86 take any prescription or over-the-counter medications because there is a potential
or Mood Stabilizer subset 33 (34.0%) 16 (18.6%) for clinically significant interactions [see Drug Interactions (7)].
Psychotic Symptomsa 53 (31.2%) 21 (12.8%) Alcohol
Mood Symptomsb Advise patients to avoid alcohol during treatment with INVEGA SUSTENNA® [see
Any Mood Symptoms 48 (28.2%) 18 (11.0%) Drug Interactions (7.1)].
Manic 16 (9.4%) 5 (3.0%) Pregnancy
Depressive 23 (13.5%) 8 (4.9%) Advise patients to notify their healthcare provider if they become pregnant or
Mixed 9 (5.3%) 5 (3.0%) intend to become pregnant during treatment with INVEGA SUSTENNA®. Advise
a 8 subjects experienced a relapse without psychotic symptoms. patients that INVEGA SUSTENNA® may cause extrapyramidal and/or withdrawal
b 16 subjects experienced a relapse without any mood symptoms. symptoms in a neonate. Advise patients that there is a pregnancy registry that
monitors pregnancy outcomes in women exposed to INVEGA SUSTENNA® during
16 HOW SUPPLIED/STORAGE AND HANDLING pregnancy [see Use in Specific Populations (8.1)].
INVEGA SUSTENNA® is available as a white to off-white sterile aqueous Lactation
extended-release suspension for intramuscular injection in dose strengths of Advise breastfeeding women using INVEGA SUSTENNA® to monitor infants for
39 mg/0.25 mL, 78 mg/0.5 mL, 117 mg/0.75 mL, 156 mg/mL, and 234 mg/1.5 mL somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors
paliperidone palmitate in single-dose prefilled syringes. The single-use kit contains and abnormal muscle movements) and to seek medical care if they notice these
a prefilled syringe and 2 safety needles (a 1 ½-inch 22 gauge safety needle and a signs [see Use in Specific Populations (8.2)].
1-inch 23 gauge safety needle).
Infertility
39 mg paliperidone palmitate kit (NDC 50458-560-01) Advise females of reproductive potential that INVEGA SUSTENNA® may impair
78 mg paliperidone palmitate kit (NDC 50458-561-01) fertility due to an increase in serum prolactin levels. The effects on fertility are
117 mg paliperidone palmitate kit (NDC 50458-562-01) reversible [see Use in Specific Populations (8.3)].
156 mg paliperidone palmitate kit (NDC 50458-563-01)
234 mg paliperidone palmitate kit (NDC 50458-564-01) INVEGA SUSTENNA® (paliperidone palmitate) Extended-Release Injectable
Storage and Handling Suspension
Store at room temperature (25°C, 77°F); excursions between 15°C and 30°C (between Product of Ireland
59°F and 86°F) are permitted. Do not mix with any other product or diluent.
Manufactured by:
17 PATIENT COUNSELING INFORMATION Janssen Pharmaceutica NV
Advise the patient to read the FDA-approved patient labeling (Patient Information). Beerse, Belgium
Neuroleptic Malignant Syndrome (NMS) Manufactured for:
Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Janssen Pharmaceuticals, Inc.
Syndrome (NMS), that has been reported in association with administration of Titusville, NJ 08560
antipsychotic drugs. Advise patients, family members, or caregivers to contact their © 2009 Janssen Pharmaceutical Companies
15
PATIENT INFORMATION
INVEGA SUSTENNA® (in-VAY-guh suss-TEN-uh)
(paliperidone palmitate)
Extended-Release Injectable Suspension
What is the most important information I should know about INVEGA SUSTENNA®?
INVEGA SUSTENNA® 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 SUSTENNA® is not for treating dementia-related psychosis.
What is INVEGA SUSTENNA®?

INVEGA SUSTENNA® is a prescription medicine given by injection by a healthcare professional and used to treat:
° schizophrenia in adults
° schizoaffective disorder in adults either alone or with other medicines such as mood stabilizers or antidepressants
It is not known if INVEGA SUSTENNA® is safe and effective in children under 18 years of age.
Who should not receive INVEGA SUSTENNA®?

Do not receive INVEGA SUSTENNA® if you:
• are allergic to paliperidone, paliperidone palmitate, risperidone, or any of the ingredients in INVEGA SUSTENNA®. See the end
of this Patient Information leaflet for a complete list of ingredients in INVEGA SUSTENNA®.
What should I tell my healthcare provider before receiving INVEGA SUSTENNA®?

Before you receive INVEGA SUSTENNA®, 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 SUSTENNA® will harm your unborn baby.
° If you become pregnant while taking INVEGA SUSTENNA , 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 SUSTENNA 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 SUSTENNA® can pass into your breast milk. Talk to your healthcare provider
about the best way to feed your baby if you receive INVEGA SUSTENNA®.
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.
16
INVEGA SUSTENNA® (paliperidone palmitate) extended-release injectable suspension, for intramuscular use
How will I receive INVEGA SUSTENNA®?

• Follow your INVEGA SUSTENNA® treatment schedule exactly as your healthcare provider tells you to.
• Your healthcare provider will tell you how much INVEGA SUSTENNA® you will receive and when you will receive it.
• INVEGA SUSTENNA® is given as an injection by your healthcare provider into the muscle (intramuscularly) of your arm or your
buttocks.
• When you receive your first dose of INVEGA SUSTENNA® you will need to get a second dose 1 week later. After that you will
only need to get a dose 1 time a month.
What should I avoid while receiving INVEGA SUSTENNA®?

• INVEGA SUSTENNA® 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 SUSTENNA® affects you.
• Avoid getting overheated or dehydrated.
What are the possible side effects of INVEGA SUSTENNA®?

INVEGA SUSTENNA® may cause serious side effects, including:
• See “What is the most important information I should know about INVEGA SUSTENNA®”
• 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 SUSTENNA®. 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 SUSTENNA® 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.
17
INVEGA SUSTENNA® (paliperidone palmitate) extended-release injectable suspension, for intramuscular use
The most common side effects of INVEGA SUSTENNA® include: injection site reactions, sleepiness or drowsiness, dizziness, feeling
restlessness or needing to be constantly moving, abnormal muscle movements including tremor (shaking), shuffling, uncontrolled
involuntary movements, and abnormal movements of your eyes.
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 SUSTENNA®. 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 SUSTENNA®.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
INVEGA SUSTENNA® for a condition for which it was not prescribed. Do not give INVEGA SUSTENNA® 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 SUSTENNA® that is written for healthcare professionals.
This Patient Information leaflet summarizes the most important information about INVEGA SUSTENNA®. 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.invegasustenna.com or call 1-800-526-7736.
What are the ingredients in INVEGA SUSTENNA®?

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
© 2009 Janssen Pharmaceutical Companies
cp-64086v10
18

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INVEGA SUSTENNA® INVEGA SUSTENNA® (paliperidone palmitate)

extended-release injectable suspension, for intramuscular use

FULL PRESCRIBING INFORMATION: CONTENTS* 7 DRUG INTERACTIONS

FULL PRESCRIBING INFORMATION 2.2 Schizophrenia and Schizoaffective Disorder

b. Select the appropriate needle.

3 DOSAGE FORMS AND STRENGTHS

HDL Change from -2.7 -2.8 5.9

risperidone (see Clinical Considerations). Paliperidone has been detected 10 OVERDOSAGE

12.3 Pharmacokinetics Figure 1: The effects of other drugs on paliperidone pharmacokinetics.

day 1 and 156 mg on day 8 help attain therapeutic concentrations rapidly. T T T T

Change Relative to Reference

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

First Treatment Failure

INVEGA SUSTENNA (N=164) [see Warnings and Precautions (5.7)].

Counsel patients on signs and symptoms of hyperprolactinemia that may be

What is INVEGA SUSTENNA®?

Who should not receive INVEGA SUSTENNA®?

What should I tell my healthcare provider before receiving INVEGA SUSTENNA®?

How will I receive INVEGA SUSTENNA®?

What should I avoid while receiving INVEGA SUSTENNA®?

What are the possible side effects of INVEGA SUSTENNA®?

° passing out or feeling like you will pass out

What are the ingredients in INVEGA SUSTENNA®?

Manufactured by: Janssen Pharmaceutica NV, Beerse, Belgium

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b. Select the appropriate needle.