`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--------------------------
`Warnings and Precautions, Metabolic Changes (5.6)
` Month YYYY
`
`
`----------------------------INDICATIONS AND USAGE----------------------------
`INVEGA® SUSTENNA® is an atypical antipsychotic agent indicated for the
`
`
`acute and maintenance treatment of schizophrenia in adults (1)
`
`
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`
`• 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®.
`(2.1)
`
`• Initiate INVEGA® SUSTENNA® with a dose of 234 mg on treatment day 1
`
`and 156 mg one week later, both administered in the deltoid muscle. The
`
`
`recommended monthly maintenance dose is 117 mg; some patients may
`
`benefit from lower or higher maintenance doses within the recommended
`
`range of 39 mg to 234 mg based on individual patient tolerability and/or
`efficacy. Following the second dose, monthly maintenance doses can be
`administered in either the deltoid or gluteal muscle. (2.1)
`
`
`• Administer by intramuscular injection only, using appropriate needle sizes.
`For deltoid injection, use 1 ½-inch 22G needle for patients ≥ 90 kg (≥ 200
`lb) or 1-inch 23G needle for patients < 90 kg (< 200 lb). For gluteal
`
`injection, use 1 ½-inch 22G needle regardless of patient weight. (2.3)
`
`--------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`
`Prefilled syringes containing 39 mg, 78 mg, 117 mg, 156 mg, or 234 mg
`
`
`paliperidone palmitate. (3)
`
`-------------------------------CONTRAINDICATIONS-------------------------------
`Known hypersensitivity to paliperidone, risperidone, or to any components in
`the formulation (4)
`
`
`---------------------------WARNINGS AND PRECAUTIONS--------------------
`
`• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients
`with Dementia-Related Psychosis: Increased incidence of cerebrovascular
`adverse reactions (e.g. stroke, transient ischemic attack, including
`fatalities). INVEGA® SUSTENNA® is not approved for use in patients
`with dementia-related psychosis (5.2)
`
`• Neuroleptic Malignant Syndrome: Manage with immediate discontinuation
`
`
`of drug and close monitoring (5.3)
`
`• QT Prolongation: Increase in QT interval, avoid use with drugs that also
`
`increase QT interval and in patients with risk factors for prolonged QT
`interval (5.4)
`
`• Tardive Dyskinesia: Discontinue drug if clinically appropriate (5.5)
`
`
`
`• Metabolic Changes: Atypical antipsychotic drugs have been associated
`with metabolic changes that may increase cardiovascular/cerebrovascular
`risk. These metabolic changes include hyperglycemia, dyslipidemia, and
`
`weight gain. (5.6)
`o Hyperglycemia and Diabetes Mellitus: Monitor patients for
`
`
`
`symptoms of hyperglycemia including polydipsia, polyuria,
`polyphagia, and weakness. Monitor glucose regularly in patients with
`
`diabetes or at risk for diabetes. (5.6)
`
`
`
`Reference ID: 3018691
`
`o
`o
`
`
`
`
`
`
` Dyslipidemia: Undesirable alterations have been observed in patients
`treated with atypical antipsychotics. (5.6)
` Weight Gain: Significant weight gain has been reported. Monitor
`
`
`weight gain. (5.6)
`
`• Hyperprolactinemia: Prolactin elevations occur and persist during chronic
`
`administration (5.7)
`
`• Orthostatic Hypotension and Syncope: Use with caution in patients with
`
`known cardiovascular or cerebrovascular disease and patients
`
`predisposed to hypotension (5.8)
`
`• Leukopenia, Neutropenia, and Agranulocytosis: has been reported with
`antipsychotics, including INVEGA®, an oral form of paliperidone.
`
`
`
`Patients with a history of a clinically significant low white blood cell
`count (WBC) or a drug-induced leukopenia/neutropenia should have
`
`their complete blood count (CBC) monitored frequently during the first
`few months of therapy and discontinuation of INVEGA® SUSTENNA®
`
`should be considered at the first sign of a clinically significant decline in
`WBC in the absence of other causative factors. (5.9)
`
`• Potential for Cognitive and Motor Impairment: Use caution when
`
`operating machinery (5.10)
`
`• Seizures: Use cautiously in patients with a history of seizures or with
`
`conditions that lower the seizure threshold (5.11)
`
`• Suicide: Closely supervise high-risk patients (5.13)
`
`
`• Administration: For intramuscular injection only. Avoid inadvertent
`
`injection into a blood vessel. (5.17)
`
`
`------------------------------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,
`Division of Ortho-McNeil-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----------------------------
`
`• Centrally-acting drugs: Due to CNS effects, use caution in combination.
`
`Avoid alcohol. (7.1)
`
`
`• Drugs that may cause orthostatic hypotension: An additive effect may be
`observed when co-administered with INVEGA® SUSTENNA®. (7.1)
`
`• Co-administration of oral paliperidone extended release with
`
`carbamazepine decreased mean steady-state Cmax and AUC of paliperidone
`by approximately 37%. Adjust dose of INVEGA® SUSTENNA® if
`
`necessary. (7.2)
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`• Renal impairment: INVEGA® SUSTENNA® has not been systematically
`
`
`
`studied in patients with renal impairment. For 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. Thereafter, follow with monthly injections of 78 mg. in
`either the deltoid or gluteal muscle. INVEGA® SUSTENNA® is not
`
`recommended for use in patients with moderate to severe renal impairment
`(creatinine clearance < 50 mL/min). (2.5, 8.6)
`
`• Elderly: same as for younger adults (adjust dose according to renal function
`
`status). (2.5, 8.5)
`
`
`• Nursing Mothers: should not breastfeed. (8.3)
`
`• Pediatric Use: safety and effectiveness not established in patients less than
`18 years of age. (8.4)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
`
`
`
`
`
`Revised: Month YYYY
`
`
`
`1
`
`

`

`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNINGS – INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA-RELATED PSYCHOSIS
` 
` 
`1
`INDICATIONS AND USAGE
` 
` 
`2 DOSAGE AND ADMINISTRATION
`
` 
` 
`Recommended Dosing
`2.1
` 
` 
`2.2
`Missed Doses
` 
` 
`2.3
`Administration Instructions
` 
` 
`2.4
`Use with Oral Paliperidone or with Risperidone
` 
` 
`2.5
`Dosage in Special Populations
` 
` 
`2.6
`Maintenance Therapy
` 
` 
`2.7
`Switching from Other Antipsychotics
` 
` 
`2.8
`Instructions for Use
` 
` 
`3 DOSAGE FORMS AND STRENGTHS
` 
` 
`4 CONTRAINDICATIONS
` 
` 
`5 WARNINGS AND PRECAUTIONS
` 
`Increased Mortality in Elderly Patients with
`5.1
` 
`Dementia-Related Psychosis
` 
`Cerebrovascular Adverse Events, Including
`5.2
`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
` 
` 
`Hyperprolactinemia
`5.7
` 
` 
`Orthostatic Hypotension and Syncope
`5.8
` 
` 
`Leukopenia, Neutropenia, and Agranulocytosis
`5.9
` 
` 
`5.10 Potential for Cognitive and Motor Impairment
` 
` 
`5.11 Seizures
` 
` 
`5.12 Dysphagia
` 
` 
`5.13 Suicide
` 
` 
`5.14 Priapism
` 
` 
`5.15 Thrombotic Thrombocytopenic Purpura (TTP)
` 
` 
`5.16 Body Temperature Regulation
` 
` 
`5.17 Administration
` 
` 
`5.18 Antiemetic Effect
` 
` 
`5.19 Use in Patients with Concomitant Illness
` 
` 
`5.20 Monitoring: Laboratory Tests
` 
` 
`6 ADVERSE REACTIONS
` 
`Commonly-Observed Adverse Events in
`6.1
` 
`Double-Blind, Placebo-Controlled Clinical Trials
` 
`6.2
`Adverse Reactions Observed During the
`Clinical Trial Evaluation of INVEGA®
`
` 
` SUSTENNA® and Not Listed in Table 2
`
` 
`Discontinuations Due to Adverse Events
`
` 
`Dose-Related Adverse Reactions
`
` 
`Demographic Differences
`
` 
`Extrapyramidal Symptoms (EPS)
`
` 
`Laboratory Test Abnormalities
`
`
` 
`6.3
` 
`6.4
` 
`6.5
` 
`6.6
` 
`6.7
`
`
`
` 
`6.8
` 
`6.9
`
`Pain Assessment and Local Injection Site
` 
`Reactions
`Adverse Reactions Reported in Clinical Trials
` 
`with Oral Paliperidone
` 
` 
`6.10 Postmarketing Experience
` 
` 
`6.11 Adverse Reactions Reported With Risperidone
` 
` 
`7 DRUG INTERACTIONS
`
` 
`Potential for INVEGA® SUSTENNA® to Affect
`
`7.1
` 
`Other Drugs
`
` 
`Potential for Other Drugs to Affect INVEGA®
`
`7.2
`
` 
`SUSTENNA®
`
` 
` 
`8 USE IN SPECIFIC POPULATIONS
`
` 
` 
`8.1
`Pregnancy
`
` 
` 
`8.2
`Labor and Delivery
`
` 
` 
`8.3
`Nursing Mothers
`
` 
` 
`8.4
`Pediatric Use
`
` 
` 
`8.5
`Geriatric Use
`
` 
` 
`8.6
`Renal Impairment
`
` 
` 
`8.7
`Hepatic Impairment
`
` 
` 
`9 DRUG ABUSE AND DEPENDENCE
`
` 
` 
`9.1
`Controlled Substance
`
` 
` 
`9.2
`Abuse
`
` 
` 
`9.3
`Dependence
`
` 
` 
`10 OVERDOSAGE
`
` 
` 
`10.1 Human Experience
`
` 
` 
`10.2 Management of Overdosage
`
`
` 
` 
`11 DESCRIPTION
`
` 
` 
`12 CLINICAL PHARMACOLOGY
`
` 
` 
`12.1 Mechanism of Action
`
` 
` 
`12.2 Pharmacodynamics
`
` 
` 
`12.3 Pharmacokinetics
`
` 
` 
`13 NONCLINICAL TOXICOLOGY
`
` 
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`
` 
`Fertility
`
` 
` 
`14 CLINICAL STUDIES
`
` 
` 
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
` 
` 
`17 PATIENT COUNSELING INFORMATION
`
`
` 
` 
`17.1 Orthostatic Hypotension
`
` 
`17.2
`Interference with Cognitive and Motor
`
` 
`Performance
`
` 
` 
`17.3 Pregnancy
`
` 
` 
`17.4 Nursing
`
` 
` 
`17.5 Concomitant Medication
`
` 
` 
`17.6 Alcohol
`
` 
` 
`17.7 Heat Exposure and Dehydration
`
` 
`Information for Patients and Caregivers
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`listed
`
`Reference ID: 3018691
`
`2
`
`

`

`
`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. 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®
`treatment of patients with
`(paliperidone palmitate)
`is not approved
`for
`the
`
` dementia-related psychosis. [See Warnings and Precautions (5.1)]
`
`
`INDICATIONS AND USAGE
`1
`INVEGA® SUSTENNA® (paliperidone palmitate) is indicated for the acute and maintenance
`treatment of schizophrenia in adults [see Clinical Studies (14)].
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`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®.
`
`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. The recommended
`monthly maintenance dose is 117 mg; some patients may benefit from lower or higher
`maintenance doses within the recommended range of 39 to 234 mg based on individual patient
`tolerability and/or efficacy. Following the second dose, monthly maintenance doses can be
`administered in either the deltoid or gluteal muscle.
`
`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.
`
`3
`
`Reference ID: 3018691
`
`

`

`
`2.2 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 2 days
`
` before or after the one-week timepoint. 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 timepoint.
`
`Missed Dose (1 Month to 6 Weeks)
`After initiation, the recommended injection cycle of INVEGA® SUSTENNA® is monthly. If less
`than 6 weeks have elapsed since the last injection, then the previously stabilized dose should be
`administered as soon as possible, followed by injections at monthly intervals.
`
`Missed Dose (> 6 Weeks to 6 Months)
`If more than 6 weeks have elapsed since the last injection of INVEGA® SUSTENNA®, resume
`the same dose the patient was previously stabilized on (unless the patient was stabilized on
`
` a dose of 234 mg, then the first two injections should each be 156 mg) in the following
`manner: 1) a deltoid injection as soon as practically possible, followed by 2) another deltoid
`injection (same dose) one week later, and 3) resumption of either deltoid or gluteal dosing at
`
`monthly intervals.
`
`Missed Dose (> 6 Months)
`If more than 6 months have elapsed since the last injection of INVEGA® SUSTENNA®, initiate
`dosing as described in Section 2.1 above.
`
`2.3 Administration Instructions
`INVEGA® SUSTENNA® is intended for intramuscular use only. Inject slowly, deep into the
`muscle. Care should be taken to avoid inadvertent injection into a blood vessel. Each injection
`should be administered by a health care professional. Administration should be in a single
`injection. Do not administer the dose in divided injections. Do not administer intravascularly or
`
`subcutaneously.
`
`The recommended needle size for administration of INVEGA® SUSTENNA® into the deltoid
`muscle is determined by the patient’s weight. For those ≥ 90 kg (≥ 200 lb), the 1½-inch,
`22 gauge needle is recommended. For those < 90 kg (< 200 lb), the 1-inch, 23 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. Administration should be made into the upper-outer
`
`Reference ID: 3018691
`
`4
`
`

`

`
`quadrant of the gluteal area. Gluteal injections should be alternated between the two gluteal
`muscles.
`
`2.4 Use with Oral Paliperidone or with Risperidone
`Concomitant use of INVEGA® SUSTENNA® with oral paliperidone or oral or injectable
`
` risperidone has not been studied. Since paliperidone is the major active metabolite of
`risperidone, consideration should be given to the additive paliperidone exposure if any of these
`medications are coadministered with INVEGA® SUSTENNA®.
`
`2.5 Dosage in Special Populations
`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), recommended initiation of INVEGA® SUSTENNA® is
`
`
` with a dose of 156 mg on treatment day 1 and 117 mg one week later, both administered in the
`
` deltoid muscle. Thereafter, follow with monthly injections of 78 mg in either the deltoid or
`gluteal muscle.
`
`INVEGA® SUSTENNA® is not recommended in patients with moderate or severe renal
`impairment (creatinine clearance < 50 mL/min).
`
`Hepatic Impairment
`INVEGA® SUSTENNA® has not been studied in patients with hepatic impairment. Based on a
`
`study with oral paliperidone, no dose adjustment is required in patients with mild or moderate
`hepatic impairment. Paliperidone has not been studied in patients with severe hepatic
`impairment. [See Clinical Pharmacology (12.3)]
`
`
`Elderly
`In general, recommended dosing of INVEGA® SUSTENNA® for elderly patients with normal
`
`renal function is the same as for younger adult patients with normal renal function. As elderly
`patients may have reduced renal function, see Renal Impairment above for dosing
`recommendations in patients with renal impairment.
`
`2.6 Maintenance Therapy
`
`INVEGA® SUSTENNA® has been shown to be effective in delaying time to relapse of symptoms
`
`
`of schizophrenia in long-term use. It is recommended that responding patients be continued on
`
`treatment at the lowest dose needed. Patients should be periodically reassessed to determine the
`need for continued treatment.
`
`Reference ID: 3018691
`
`5
`
`

`

`
`2.7 Switching from Other Antipsychotics
`There are no systematically collected data to specifically address switching patients with
`schizophrenia 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 discontinued at the time of initiation of treatment with
`INVEGA® SUSTENNA®. INVEGA® SUSTENNA® should be initiated as described in Section
`2.1. 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 1.
`
`Table 1.
`
`Dosing Frequency
`
`Dose (mg)
`
`
`
`Doses of INVEGA® and INVEGA® SUSTENNA® needed to attain similar paliperidone exposure
`
`at steady-state
`Formulation
`
`INVEGA®
`
`Extended-Release Tablet
`
`Once Daily
`12
`6
`3
`
`INVEGA® SUSTENNA®
`
`Injection
`
`Once every 4 weeks
`234
`117
`39-78
`
` Switching from Long-Acting Injectable Antipsychotics
`
` For patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability
`
`should be established with oral paliperidone or oral risperidone prior to initiating treatment with
`INVEGA® SUSTENNA®.
`
`
`When switching patients from previous long-acting injectable antipsychotics, 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 2.1 is not required.
`
` 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.
`
`Reference ID: 3018691
`
`6
`
`

`

`
`Instructions for Use
`2.8
`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.
`
`
`
`Prefilled Syringe
`
`22Gx1½”
`Gray hub
`
`23Gx1”
`
`Blue hub
`
`
`
`INVEGA® SUSTENNA® is for single use only.
`
`Hub
`
`Tip cap
`
`
`1. Shake the syringe vigorously for a minimum of 10 seconds to ensure a homogeneous
`suspension.
`
`
`
`
`
`7
`
`Reference ID: 3018691
`
`

`

`
`2. Select the appropriate needle.
`
`For DELTOID injection, if the patient weighs < 200 lb (< 90 kg), use the 1-inch 23 gauge
`needle (needle with blue colored hub); if the patient weighs ≥ 200 lb (≥ 90 kg), 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).
`
`3. While holding the syringe upright, remove the rubber tip cap with an easy clockwise twisting
`motion.
`
`4. 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.
`
`
`
`Reference ID: 3018691
`
`8
`
`

`

`
`5. 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.
`
`
`
`6. Bring the syringe with the attached needle in upright position to de-aerate. De-aerate the
`
`syringe by moving the plunger rod carefully forward.
`
`
`
`
`
`7. Inject the entire contents intramuscularly into the selected deltoid or gluteal muscle of the
`patient. Do not administer intravascularly or subcutaneously.
`
`
`
`
`Reference ID: 3018691
`
`9
`
`

`

`
`8. After the injection is complete, use either thumb or finger of one hand (8a, 8b) or a flat
`
` surface (8c) to activate the needle protection system. The needle protection system is fully
`activated when a ‘click’ is heard. Discard the syringe with needle appropriately.
`
`8a
`
`
`8b
`
`
`
`8c
`
`
`
`
`
`
`
`
`
`Reference ID: 3018691
`
`10
`
`

`

`
`3 DOSAGE FORMS AND STRENGTHS
`INVEGA® SUSTENNA® is available as a white to off-white aqueous extended-release
`suspension for intramuscular injection in dose strengths of 39 mg, 78 mg, 117 mg, 156 mg, and
`234 mg paliperidone palmitate.
`
`4 CONTRAINDICATIONS
`Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been
`observed in patients treated with risperidone and paliperidone. Paliperidone palmitate is
`converted to paliperidone, which is a metabolite of risperidone and is therefore contraindicated
`in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the
`
`excipients in the INVEGA® SUSTENNA® formulation.
`
`
`5 WARNINGS AND PRECAUTIONS
` Increased Mortality in Elderly Patients with Dementia-Related Psychosis
`5.1
`
`Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs
`
` are at an increased risk of death compared to placebo. INVEGA® SUSTENNA®
`(paliperidone palmitate) is not approved for the treatment of dementia-related psychosis
`[see Boxed Warning].
`
`5.2 Cerebrovascular Adverse Events, 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 events (cerebrovascular
`accidents and transient ischemic attacks) including fatalities compared to placebo-treated
`subjects. Oral paliperidone and INVEGA® SUSTENNA® were not marketed at the time these
`studies were performed and are not approved for the treatment of patients with dementia-related
`
`
`psychosis [see also Boxed Warning and Warnings and Precautions (5.1)].
`
`5.3 Neuroleptic Malignant Syndrome
`
`A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome
`
`(NMS) has been reported in association with antipsychotic drugs, including paliperidone.
`Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and
`evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis,
`and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase,
`myoglobinuria (rhabdomyolysis), and acute renal failure.
`
`The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
`diagnosis, it is important to identify cases in which the clinical presentation includes both serious
`medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
`
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`

`
`extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
`diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
`nervous system pathology.
`
`The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs
`and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and
`medical monitoring; and (3) treatment of any concomitant serious medical problems for which
`specific treatments are available. There is no general agreement about specific pharmacological
`treatment regimens for uncomplicated NMS.
`
`If a patient appears to require antipsychotic drug treatment after recovery from NMS,
`
`reintroduction of drug therapy should be closely monitored, since recurrences of NMS have been
`reported.
`
`5.4 QT Prolongation
`Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of
`paliperidone should be avoided in combination with other drugs that are known to prolong QTc
`including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol)
`antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine),
`antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong
`the QTc interval. Paliperidone should also be avoided in patients with congenital long QT
`syndrome and in patients with a history of cardiac arrhythmias.
`
`Certain circumstances may increase the risk of the occurrence of torsade 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
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` 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, 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®, 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, no subject had a QTcLD change > 60 msec, and one
`subject had a QTcLD value of 507 msec (Bazett’s QT corrected interval [QTcB] value of 483
`msec); this latter subject also had a heart rate of 45 beats per minute.
`
`5.5 Tardive Dyskinesia
`A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in
`patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be
`highest among the elderly, especially elderly women, it is impossible to predict which patients
`
`will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause
`
`tardive dyskinesia is unknown.
`
`The risk of developing tardive dyskinesia and the likelihood that it will become irreversible
`appear to increase as the duration of treatment and the total cumulative dose of antipsychotic
`drugs administered to the patient increase, but the syndrome can develop after relatively brief
`treatment periods at low doses, although this is uncommon.
`
`There is no known treatment for established tardive dyskinesia, although the syndrome may
`remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment
`itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus
`
`mask the underlying process. The effect of symptomatic suppression on the long-term course
`of the syndrome is unknown.
`
`Given these considerations, INVEGA® SUSTENNA® should be prescribed in a manner that is
`most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment
`should generally be reserved for patients who suffer from a chronic illness that is known to
`respond to antipsychotic drugs. In patients who do require chronic treatment, the smallest dose
`and the shortest duration of treatment producing a satisfactory clinical response should be
`sought. The need for continued treatment should be reassessed periodically.
`
`If signs and symptoms of tardive dyskinesia appear in a patient treated with INVEGA®
`
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`
`SUSTENNA®, drug discontinuation should be considered. However, some patients may require
`treatment with INVEGA® SUSTENNA® despite the presence of the syndrome.
`
`5.6 Metabolic Changes
`Atypical antipsychotic drugs have been associated with metabolic changes that may increase
`cardiovascular/cerebrovascular
`risk. These metabolic changes
`include hyperglycemia,
`dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to
`produce some metabolic changes, each drug has its own specific risk profile.
`
`Hyperglycemia and Diabetes Mellitus
`
` Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or
`
` hyperosmolar coma or death, have been reported in patients treated with all atypical
`
` antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and
`
` epidemiologic studies, not in clinical trials, and there have been few reports of hyperglycemia or
`diabetes 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 treatment-
`emergent hyperglycemia-related adverse events
`in patients
`treated with
`the atypical
`antipsychotics. Because INVEGA® SUSTENNA® was not marketed at the time these studies
`
`were performed, it is not known if INVEGA® SUSTENNA® is associated with this risk.
`
`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 t