HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`INVEGA SUSTENNA® safely and effectively. See full prescribing
`information for INVEGA SUSTENNA®.
`INVEGA SUSTENNA® (paliperidone palmitate) extended-release
`injectable suspension, for intramuscular use
`Initial U.S. Approval: 2006
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA-RELATED PSYCHOSIS
`See full prescribing information for complete boxed warning.
`Elderly patients with dementia-related psychosis treated with
`antipsychotic drugs are at an increased risk of death. INVEGA
`SUSTENNA® is not approved for use in patients with dementia-related
`psychosis. (5.1)
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Warning and Precautions (5.3, 5.5)
`2/2021
`
`----------------------------INDICATIONS AND USAGE----------------------------
`INVEGA SUSTENNA® is an atypical antipsychotic indicated for
`• Treatment of schizophrenia in adults. (1)
`• Treatment of schizoaffective disorder in adults as monotherapy and as an
`adjunct to mood stabilizers or antidepressants. (1)
`
`
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`• For intramuscular injection only. (2.1)
`• Each injection must be administered only by a healthcare professional.
`(2.1)
`• For deltoid injection, use 1-inch 23G needle for patients weighing less than
`90 kg or 1½-inch 22G needle for patients weighing 90 kg or more. For
`gluteal injection, use 1½-inch 22G needle regardless of patient weight.
`(2.1)
`
`
`Initiation Dosing
`(deltoid)
`Day 1
`Day 8
`
`Monthly
`Maintenance Dosea
`(deltoid or gluteal)
`
`Maximum
`Monthly
`Dose
`
`234 mg
`
`156 mg
`
`39-234 mgb
`
`234 mg
`
`234 mg
`
`156 mg
`
`78-234 mgc
`
`234 mg
`
`
`Indication
`
`Schizophrenia
`(2.2)
`
`a
`b
`
`c
`
`Schizoaffective
`disorder (2.2)
`Administered 5 weeks after the first injection.
`The recommended maintenance dose for treatment of schizophrenia is
`117 mg. Some patients may benefit from lower or higher maintenance
`doses within the additional available strengths (39 mg, 78 mg, 156 mg, and
`234 mg).
`Adjust dose based on tolerability and/or efficacy using available strengths.
`The 39 mg strength was not studied in the long-term schizoaffective
`disorder study.
`
`
`• For patients naïve to oral paliperidone or oral or injectable risperidone,
`establish tolerability with oral paliperidone or oral risperidone prior to
`initiating treatment with INVEGA SUSTENNA®. (2.2)
`• Missed Doses: To manage either a missed second initiation dose or a
`missed monthly maintenance dose, refer to the Full Prescribing
`Information. (2.3)
`• Moderate to severe renal impairment (creatinine clearance < 50 mL/min):
`INVEGA SUSTENNA® is not recommended. (2.5)
`
`
`
`
`
`
`1
`
`• Mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min):
`Administer 156 mg on treatment day 1 and 117 mg one week later, both
`administered in the deltoid muscle. Follow with monthly injections of
`78 mg in either the deltoid or gluteal muscle. (2.5)
`--------------------DOSAGE FORMS AND STRENGTHS----------------------
`Extended-release injectable suspension: 39 mg/0.25 mL, 78 mg/0.5 mL,
`117 mg/0.75 mL, 156 mg/mL, or 234 mg/1.5 mL (3)
`
`-------------------------------CONTRAINDICATIONS-------------------------------
`Known hypersensitivity to paliperidone, risperidone, or to any excipients in
`INVEGA SUSTENNA®. (4)
`
`---------------------------WARNINGS AND PRECAUTIONS--------------------
`• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients
`with Dementia-Related Psychosis Increased incidence of cerebrovascular
`adverse reactions (e.g. stroke, transient ischemic attack). (5.2)
`• Neuroleptic Malignant Syndrome Manage with immediate discontinuation
`of drug and close monitoring. (5 3)
`• QT Prolongation Avoid use with drugs that also increase QT interval and
`in patients with risk factors for prolonged QT interval. (5.4)
`• Tardive Dyskinesia Discontinue drug if clinically appropriate. (5.5)
`• Metabolic Changes Monitor for hyperglycemia/diabetes mellitus,
`dyslipidemia and weight gain. (5.6)
`• Orthostatic Hypotension and Syncope Monitor heart rate and blood
`pressure and warn patients with known cardiovascular or cerebrovascular
`disease, and risk of dehydration or syncope. (5.7)
`• Leukopenia, Neutropenia, and Agranulocytosis Perform complete blood
`counts (CBC) in patients with pre-existing low white blood cell count
`(WBC) or history of leukopenia or neutropenia. Consider discontinuing
`INVEGA SUSTENNA® if clinically significant decline in WBC in the
`absence of other causative factors. (5.9)
`• Hyperprolactinemia Prolactin elevations occur and persist during chronic
`administration. (5.10)
`• Potential for Cognitive and Motor Impairment Use caution when
`operating machinery. (5.11)
`• Seizures Use cautiously in patients with a history of seizures or with
`conditions that lower the seizure threshold. (5.12)
`
`
`------------------------------ADVERSE REACTIONS------------------------------
`The most common adverse reactions (incidence ≥ 5% and occurring at least
`twice as often as placebo) were injection site reactions, somnolence/sedation,
`dizziness, akathisia, and extrapyramidal disorder. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Janssen
`Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at
`1-800-FDA-1088 or www.fda.gov/medwatch
`
`---------------------------------DRUG INTERACTIONS----------------------------
`• Drugs that may cause orthostatic hypotension An additive effect may
`occur when co-administered with INVEGA SUSTENNA®. (7.1)
`• Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong
`inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John’s
`Wort) during a dosing interval for INVEGA SUSTENNA®. If
`administering a strong inducer is necessary, consider managing the patient
`using paliperidone extended release tablets. (2.5, 7.1, 12.3)
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`Pregnancy May cause extrapyramidal and/or withdrawal symptoms in
`neonates with third trimester exposure. (8.1)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 08/2021
`
`
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA-RELATED PSYCHOSIS
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1
`Administration Instructions
`2.2
`Schizophrenia and Schizoaffective Disorder
`2.3
`Missed Doses
`2.4
`Use with Risperidone or with Oral Paliperidone
`2.5
`Dosage Adjustments
`2.6
`Switching from Other Antipsychotics
`2.7
`Instructions for Use
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Increased Mortality in Elderly Patients with
`Dementia-Related Psychosis
`5.2
`Cerebrovascular Adverse Reactions, Including
`Stroke, in Elderly Patients with Dementia-
`Related Psychosis
`Neuroleptic Malignant Syndrome
`5.3
`QT Prolongation
`5.4
`Tardive Dyskinesia
`5.5
`Metabolic Changes
`5.6
`Orthostatic Hypotension and Syncope
`5.7
`Falls
`5.8
`Leukopenia, Neutropenia, and Agranulocytosis
`5.9
`5.10 Hyperprolactinemia
`5.11 Potential for Cognitive and Motor Impairment
`5.12 Seizures
`5.13 Dysphagia
`5.14 Priapism
`5.15 Disruption of Body Temperature Regulation
`6 ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`
`7 DRUG INTERACTIONS
`7.1
`Drugs Having Clinically Important Interactions
`with INVEGA SUSTENNA®
`7.2
`Drugs Having No Clinically Important
`Interactions with INVEGA SUSTENNA®
`8 USE IN SPECIFIC POPULATIONS
`Pregnancy
`8.1
`8.2
`Lactation
`8.3
`Females and Males of Reproductive Potential
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Renal Impairment
`8.7
`Hepatic Impairment
`8.8
`Patients with Parkinson’s Disease or Lewy Body
`Dementia
`9 DRUG ABUSE AND DEPENDENCE
`Controlled Substance
`9.1
`9.2
`Abuse
`9.3
`Dependence
`10 OVERDOSAGE
`10.1 Human Experience
`10.2 Management of Overdosage
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1 Schizophrenia
`14.2 Schizoaffective Disorder
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`2
`
`
`
`

`

`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`3
`
`
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-
`RELATED PSYCHOSIS
`Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
`increased risk of death. INVEGA SUSTENNA® is not approved for use in patients with
`dementia-related psychosis. [see Warnings and Precautions (5.1)].
`
` 1
`
`INDICATIONS AND USAGE
`
`INVEGA SUSTENNA® (paliperidone palmitate) is indicated for the treatment of:
`• Schizophrenia in adults [see Clinical Studies (14.1)].
`• Schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or
`antidepressants [see Clinical Studies (14.2)].
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Administration Instructions
`Each injection must be administered only by a healthcare professional.
`
`Parenteral drug products should be inspected visually for foreign matter and discoloration prior to
`administration, whenever product and container permit.
`
`INVEGA SUSTENNA® is intended for intramuscular use only. Do not administer by any other
`route. Avoid inadvertent injection into a blood vessel. Administer the dose in a single injection;
`do not administer the dose in divided injections. Inject slowly, deep into the deltoid or gluteal
`muscle.
`
`INVEGA SUSTENNA® must be administered using only the needles that are provided in the
`INVEGA SUSTENNA® kit.
`
`The recommended needle size for administration of INVEGA SUSTENNA® into the deltoid
`muscle is determined by the patient’s weight:
`
`• For patients weighing less than 90 kg, the 1-inch, 23 gauge needle is recommended.
`
`• For patients weighing 90 kg or more, the 1½-inch, 22 gauge needle is recommended.
`
`Deltoid injections should be alternated between the two deltoid muscles.
`
`The recommended needle size for administration of INVEGA SUSTENNA® into the gluteal
`muscle is the 1½-inch, 22 gauge needle regardless of patient weight.
`
`Administer into the upper-outer quadrant of the gluteal muscle. Gluteal injections should be
`alternated between the two gluteal muscles.
`
`4
`
`
`
`

`

`
`2.2 Schizophrenia and Schizoaffective Disorder
`For patients who have never taken oral paliperidone or oral or injectable risperidone, it is
`recommended to establish tolerability with oral paliperidone or oral risperidone prior to initiating
`treatment with INVEGA SUSTENNA®.
`
`The recommended dosing of INVEGA SUSTENNA® for each approved indication is displayed in
`Table 1. The recommended initiation of INVEGA SUSTENNA® is with a dose of 234 mg on
`treatment day 1 and 156 mg one week later, both administered in the deltoid muscle. Following
`the second initiation dose, monthly maintenance doses can be administered in either the deltoid or
`gluteal muscle.
`
`
`
`Table 1:
`
`Indication
`
`Schizophrenia
`
`234 mg
`
`156 mg
`
`Recommended Dosing of INVEGA SUSTENNA for Adults with Schizophrenia or
`Schizoaffective Disorder
`Initiation Dosing
`(deltoid)
`Day 1
`Day 8
`
`Monthly
`Maintenance Dosea
`(deltoid or gluteal)
`39-234 mgb
`
`
`Maximum
`Monthly Dose
`
`234 mg
`
`234 mg
`
`Schizoaffective disorder
`
`234 mg
`
`156 mg
`
`78-234 mgc
`
`a Administered 5 weeks after the first injection.
`The recommended maintenance dose for treatment of schizophrenia is 117 mg. Some patients may benefit
`b
`from lower or higher maintenance doses within the 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 39 mg strength was not
`studied in the long-term schizoaffective disorder study.
`
`
`Adjustment of the maintenance dose may be made monthly. When making dose adjustments, the
`prolonged-release characteristics of INVEGA SUSTENNA® should be considered [see Clinical
`Pharmacology (12.3)], as the full effect of the dose adjustment may not be evident for several
`months.
`
`2.3 Missed Doses
`Avoiding Missed Doses
`It is recommended that the second initiation dose of INVEGA SUSTENNA® be given one week
`after the first dose. To avoid a missed dose, patients may be given the second dose 4 days before
`or after the one-week time point. Similarly, the third and subsequent injections after the initiation
`regimen are recommended to be given monthly. To avoid a missed monthly dose, patients may be
`given the injection up to 7 days before or after the monthly time point.
`
`5
`
`
`
`

`

`
`Management of a Missed Second Initiation Dose
`If the target date for the second INVEGA SUSTENNA® injection (one week ± 4 days) is missed,
`the recommended reinitiation depends on the length of time which has elapsed since the patient's
`first injection. In case of a missed second initiation dose follow the dosing instructions provided
`in Table 2.
`
`
`
`Table 2:
`
`Management of a Missed Second Initiation Dose
`
`DOSING
`
`TIMING OF MISSED SECOND
`INITIATION DOSE
`Less than 4 weeks since first injection
`
`4 to 7 weeks since first injection
`
`Administer the second initiation dose of 156 mg in the deltoid
`muscle as soon as possible.
`It is recommended to administer a third injection of 117 mg in
`1.
`either the deltoid or gluteal muscle 5 weeks after the first injection
`(regardless of the timing of the second injection).
`2. Thereafter, resume regular monthly dosing in either the deltoid or
`gluteal muscle.
`Resume dosing with two injections of 156 mg in the following
`manner:
`1. Administer a deltoid injection as soon as possible.
`2. Administer a second deltoid injection 1 week later.
`3. Thereafter, resume regular monthly dosing in either the
`deltoid or gluteal muscle.
`More than 7 weeks since first injection Restart dosing with recommended initiation (see Section 2.2,
`Table 1):
`1. Administer a 234 mg deltoid injection on Day 1.
`2. Administer a 156 mg deltoid injection 1 week later.
`3. Thereafter, resume regular monthly dosing in either the
`deltoid or gluteal muscle.
`
`
`Management of a Missed Maintenance Dose
`In case of a missed maintenance dose follow the dosing instructions provided in Table 3.
`
`
`
`Management of a Missed Maintenance Dose
`Table 3:
`TIMING OF MISSED
`MAINTENANCE DOSE
`4 to 6 weeks since last injection
`
`DOSING
`
`Resume regular monthly dosing as soon as possible at the patient’s
`previously stabilized dose, followed by injections at monthly
`intervals.
`
`6
`
`
`
`

`

`
`
`
`
`More than 6 weeks to 6 months since
`last injection
`
`Resume the same dose the patient was previously stabilized on
`(unless the patient was stabilized on a dose of 234 mg, then the first
`2 injections should each be 156 mg) in the following manner:
`1. Administer a deltoid injection as soon as possible.
`2. Administer a second deltoid injection 1 week later at the same
`dose.
`3. Thereafter, resume administering the previously stabilized
`dose in the deltoid or gluteal muscle 1 month after the second
`injection.
`More than 6 months since last injection Restart dosing with recommended initiation (see Section 2.2,
`Table 1):
`1. Administer a 234 mg deltoid injection on Day 1.
`2. Administer a 156 mg deltoid injection 1 week later.
`3. Thereafter, resume administering the previously stabilized
`dose in the deltoid or gluteal muscle 1 month after the second
`injection.
`
`2.4 Use with Risperidone or with Oral Paliperidone
`Since paliperidone is the major active metabolite of risperidone, caution should be exercised when
`INVEGA SUSTENNA® is coadministered with risperidone or with oral paliperidone for extended
`periods of time. Safety data involving concomitant use of INVEGA SUSTENNA® with other
`antipsychotics is limited.
`
`2.5 Dosage Adjustments
`Renal Impairment
`INVEGA SUSTENNA® has not been systematically studied in patients with renal impairment [see
`Clinical Pharmacology (12.3)]. For patients with mild renal impairment (creatinine clearance ≥
`50 mL/min to < 80 mL/min [Cockcroft-Gault Formula]), initiate INVEGA SUSTENNA® with a
`dose of 156 mg on treatment day 1 and 117 mg one week later. Administer both doses in the deltoid
`muscle. Thereafter, follow with monthly injections of 78 mg in either the deltoid or gluteal muscle
`[see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
`
`INVEGA SUSTENNA® is not recommended in patients with moderate or severe renal impairment
`(creatinine clearance < 50 mL/min) [see Use in Specific Populations (8.6) and Clinical
`Pharmacology (12.3)].
`
`Coadministration with Strong CYP3A4/P-glycoprotein (P-gp) Inducers
`Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John’s
`Wort) during the 1-month dosing interval for INVEGA SUSTENNA®, if possible. If administering
`a strong inducer is necessary, consider managing the patient using paliperidone extended release
`
`7
`
`
`
`

`

`
`tablets [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
`
`2.6 Switching from Other Antipsychotics
`There are no systematically collected data to specifically address switching patients with
`schizophrenia or schizoaffective disorder from other antipsychotics to INVEGA SUSTENNA®, or
`concerning concomitant administration with other antipsychotics.
`
`Switching from Oral Antipsychotics
`For patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability
`should be established with oral paliperidone or oral risperidone prior to initiating treatment with
`INVEGA SUSTENNA®.
`
`Previous oral antipsychotics can be gradually discontinued at the time of initiation of treatment
`with INVEGA SUSTENNA®. Recommended initiation of INVEGA SUSTENNA® is with a dose
`of 234 mg on treatment day 1 and 156 mg one week later, both administered in the deltoid muscle
`[see Dosage and Administration (2.2)]. Patients previously stabilized on different doses of
`INVEGA® Extended-Release tablets can attain similar paliperidone steady-state exposure during
`maintenance treatment with INVEGA SUSTENNA® monthly doses as depicted in Table 4.
`
`Table 4:
`
`
`
`
`
`Doses of INVEGA and INVEGA SUSTENNA Needed to Attain Similar Steady-State
`Paliperidone Exposure During Maintenance Treatment
`Formulation
`INVEGA®
`Extended-Release Tablet
`Once Daily
`12
`9
`6
`3
`
`INVEGA SUSTENNA®
`Injection
`Once every 4 weeks
`234
`156
`117
`39-78
`
`Dosing Frequency
`
`Dose (mg)
`
`Switching from Long-Acting Injectable Antipsychotics
`For patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability
`should be established with oral paliperidone or oral risperidone prior to initiating treatment with
`INVEGA SUSTENNA®.
`
`When switching patients currently at steady-state on a long-acting injectable antipsychotic, initiate
`INVEGA SUSTENNA® therapy in place of the next scheduled injection. INVEGA SUSTENNA®
`should then be continued at monthly intervals. The one-week initiation dosing regimen as
`described in Section 2.2 is not required. See Table 1 above for recommended monthly maintenance
`dosing. Based on previous clinical history of tolerability and/or efficacy, some patients may benefit
`from lower or higher maintenance doses within the available strengths (39 mg, 78 mg, 117 mg,
`
`8
`
`
`
`

`

`
`156 mg, and 234 mg). The 39 mg strength was not studied in the long-term schizoaffective disorder
`study. Monthly maintenance doses can be administered in either the deltoid or gluteal muscle [see
`Dosage and Administration (2.2)].
`
`If INVEGA SUSTENNA® is discontinued, its prolonged-release characteristics must be
`considered. As recommended with other antipsychotic medications, the need for continuing
`existing extrapyramidal symptoms (EPS) medication should be re-evaluated periodically.
`
`Instructions for Use
`2.7
`Each injection must be administered only by a healthcare professional.
`
`The kit contains a prefilled syringe and 2 safety needles (a 1 ½-inch 22 gauge needle and a 1-inch
`23 gauge needle) for intramuscular injection.
`
`INVEGA SUSTENNA® is for single use only.
`
`
`
`
`
`a. Shake the syringe vigorously for a minimum of 10 seconds to ensure a homogeneous
`suspension.
`
`9
`
`
`
`

`

`
`
`b. Select the appropriate needle.
`
`For DELTOID injection:
`
`
`
`•
`
`•
`
`If the patient weighs less than 90 kg, use the 1-inch 23 gauge needle (needle with blue
`colored hub).
`
`If the patient weighs 90 kg or more, use the 1 ½-inch 22 gauge needle (needle with gray
`colored hub).
`
`For GLUTEAL injection:
`
`Use the 1 ½-inch 22 gauge needle (needle with gray colored hub) regardless of patient’s
`weight.
`
`
`
`c. While holding the syringe upright, remove the rubber tip cap with an easy clockwise twisting
`motion.
`
`
`
`10
`
`
`
`

`

`
`d. Peel the safety needle pouch half way open. Grasp the needle sheath using the plastic peel
`pouch. Attach the safety needle to the luer connection of the syringe with an easy clockwise
`twisting motion.
`
`e. Pull the needle sheath away from the needle with a straight pull. Do not twist the sheath as the
`needle may be loosened from the syringe.
`
`
`
`
`
`11
`
`
`
`

`

`
`f. Bring the syringe with the attached needle in upright position to de-aerate. De-aerate the
`syringe by moving the plunger rod carefully forward.
`
`
`
`g. Inject the entire contents intramuscularly slowly, deep into the selected deltoid or gluteal
`muscle of the patient. Do not administer by any other route.
`
`h. After the injection is complete, use either thumb or finger of one hand (h1, h2) or a flat surface
`(h3) to activate the needle protection system. The needle protection system is fully activated
`when a ‘click’ is heard. Discard the syringe with needle appropriately.
`
`h1
`
`
`
`12
`
`
`
`

`

`
`
`h2
`
`h3
`
`
`
`
`
`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 hypersensitivity to either
`paliperidone or risperidone, or to any of the excipients in the INVEGA SUSTENNA® formulation.
`Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported
`in patients treated with risperidone and in patients treated with paliperidone. Paliperidone palmitate
`is converted to paliperidone, which is a metabolite of risperidone.
`
`5 WARNINGS AND PRECAUTIONS
`5.1
`Increased Mortality in Elderly Patients with Dementia-Related Psychosis
`Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
`increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks),
`
`13
`
`
`
`

`

`
`largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated
`patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course
`of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%,
`compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied,
`most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or
`infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical
`antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The
`extent to which the findings of increased mortality in observational studies may be attributed to
`the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. INVEGA
`SUSTENNA® is not approved for the treatment of patients with dementia-related psychosis [see
`Boxed Warning and Warnings and Precautions (5.2)].
`
`5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients
`with Dementia-Related Psychosis
`In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with
`dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular
`accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects.
`No studies have been conducted with oral paliperidone, INVEGA SUSTENNA®, or the 3-month
`paliperidone palmitate extended-release injectable suspension in elderly patients with dementia.
`These medicines are not approved for the treatment of patients with dementia-related psychosis
`[see Boxed Warning and Warnings and Precautions (5.1)].
`
`5.3 Neuroleptic Malignant Syndrome
`Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported
`in association with antipsychotic drugs, including paliperidone.
`
`Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including
`delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis,
`and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase,
`myoglobinuria (rhabdomyolysis), and acute renal failure.
`
`If NMS is suspected, immediately discontinue INVEGA SUSTENNA® and provide symptomatic
`treatment and monitoring.
`
`5.4 QT Prolongation
`Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone
`should be avoided in combination with other drugs that are known to prolong QTc including Class
`1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic
`medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g.,
`
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`gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval.
`Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients
`with a history of cardiac arrhythmias.
`
`Certain circumstances may increase the risk of the occurrence of Torsades de pointes and/or
`sudden death in association with the use of drugs that prolong the QTc interval, including
`(1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that
`prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.
`
`The effects of oral paliperidone on the QT interval were evaluated in a double-blind,
`active-controlled (moxifloxacin 400 mg single dose), multicenter QT study in adults with
`schizophrenia and schizoaffective disorder, and in three placebo- and active-controlled 6-week,
`fixed-dose efficacy trials in adults with schizophrenia.
`
`In the QT study (n=141), the 8 mg dose of immediate-release oral paliperidone (n=50) showed a
`mean placebo-subtracted increase from baseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on
`day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg dose
`of paliperidone immediate release (Cmax ss = 113 ng/mL) was more than 2-fold the exposure
`observed with the maximum recommended 234 mg dose of INVEGA SUSTENNA® administered
`in the deltoid muscle (predicted median Cmax ss = 50 ng/mL). In this same study, a 4 mg dose of
`the immediate-release oral formulation of paliperidone, for which Cmax ss = 35 ng/mL, showed an
`increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-
`dose.
`
`In the three fixed-dose efficacy studies of oral paliperidone extended release in subjects with
`schizophrenia, electrocardiogram (ECG) measurements taken at various time points showed only
`one subject in the oral paliperidone 12 mg group had a change exceeding 60 msec at one time-
`point on Day 6 (increase of 62 msec).
`
`In the four fixed-dose efficacy studies of INVEGA SUSTENNA® in subjects with schizophrenia
`and in the long-term study in subjects with schizoaffective disorder, no subject experienced a
`change in QTcLD exceeding 60 msec and no subject had a QTcLD value of > 500 msec at any
`time point. In the maintenance study in subjects with schizophrenia, no subject had a QTcLD
`change > 60 msec, and one subject had a QTcLD value of 507 msec (Bazett’s QT corrected interval
`[QTcB] value of 483 msec); this latter subject also had a heart rate of 45 beats per minute.
`
`5.5 Tardive Dyskinesia
`Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic
`movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of
`the syndrome appears to be highest among the elderly, especially elderly women, it is impossible
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`to predict which patients will develop the syndrome. Whether antipsychotic drug products differ
`in their potential to cause tardive dyskinesia is unknown.
`
`The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear
`to increase with the duration of treatment and the cumulative dose. The syndrome can develop
`after relatively brief treatment periods, even at low doses. It may also occur after discontinuation
`of treatment.
`
`Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued.
`Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and
`symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic
`suppression has upon the long-term course of the syndrome is unknown.
`
`Given these considerations, INVEGA SUSTENNA® should be prescribed in a manner that is most
`likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should
`generally be reserved for patients: (1) who suffer from a chronic illness that is known to respond
`to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful
`treatments are not available or appropriate. In patients who do require chronic treatment, use the
`lowest dose and the shortest duration of treatment producing a satisfactory clinical response.
`Periodically reassess the need for continued treatment.
`
`If signs and symptoms of tardive dyskinesia appear in a patient on INVEGA SUSTENNA®, drug
`discontinuation should be considered. However, some patients may require treatment with
`INVEGA SUSTENNA® despite the presence of the syndrome.
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`5.6 Metabolic Changes
`Atypical antipsychotic drugs have been associated with metabolic changes that may increase
`cardiovascular/cerebrovascular
`risk. These metabolic changes
`include hyperglycemia,
`dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce
`some metabolic changes, each drug has its own specific risk profile.
`
`Hyperglycemia and Diabetes Mellitus
`Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or
`hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics.
`These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies,
`not in clinical trials. Hyperglycemia and diabetes have been reported in trial subjects treated with
`INVEGA SUSTENNA®. Assessment of the relationship between atypical antipsychotic use and
`glucose abnormalities is complicated by the possibility of an increased background risk of diabetes
`mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the
`general population. Given these confounders, the relationship between atypical antipsychotic use
`and hyperglycemia-related adverse events
`is not completely understood. However,
`epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in
`patients treated with the atypical antipsychotics.
`
`Patients with an established diagnosis of diabetes mellitus who are started on atypical
`antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk
`factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment
`with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of
`treatment and periodically during treatment. Any patient treated with atypical antipsychotics
`should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia,
`and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical
`ant