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. (5.1)
`
` INVEGA® SUSTENNA® is not approved for use in patients with
`
`
`dementia-related psychosis. (5.1)
`
`
`
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------­
`INVEGA® SUSTENNA® is an atypical antipsychotic indicated for the
`
`treatment of schizophrenia (1)
`
`-----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
` For intramuscular injection only. (2.1)
`
` For deltoid injection, use 1 ½-inch 22G needle for patients  90 kg or
`
`1-inch 23G needle for patients < 90 kg. For gluteal injection, use 1 ½-inch
`
`22G needle regardless of patient weight. (2.1)
`
` 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)
`
`
` Initiate dosing with 234 mg on treatment day 1 and 156 mg one week later,
`
`both administered in the deltoid muscle. (2.2)
`
`
`
` Recommended monthly maintenance dose 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). Administer
`
`monthly maintenance doses in either the deltoid or gluteal muscle. (2.2)
`
`
` Missed Doses: To manage either a missed second initiation dose or a
`missed monthly maintenance dose, refer to the Full Prescribing
`Information. (2.3)
`
` Moderate to severe renal impairment (creatinine clearance < 50 mL/min):
`INVEGA® SUSTENNA® is not recommended. (2.5)
`
`
`
`
` Mild renal impairment (creatinine clearance  50 mL/min to < 80 mL/min):
`Administer 156 mg on treatment day 1 and 117 mg one week later, both
`administered in the deltoid muscle. Follow with monthly injections of 78
`mg in either the deltoid or gluteal muscle. (2.5).
`--------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`Extended-release injectable suspension: 39 mg, 78 mg, 117 mg, 156 mg, or
`
`
`234 mg (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)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3495576
`
`
` QT Prolongation: Avoid use with drugs that also increase QT interval and
`
`in patients with risk factors for prolonged QT interval (5.4)
`
` Tardive Dyskinesia: Discontinue drug if clinically appropriate (5.5)
`
`
` Metabolic Changes: Atypical antipsychotic drugs have been associated
`with metabolic changes that may increase cardiovascular/cerebrovascular
`risk. These metabolic changes include:
`o Hyperglycemia and Diabetes Mellitus: Monitor for symptoms of
`
`
`hyperglycemia including polydipsia, polyuria, polyphagia, and
`weakness. Monitor glucose regularly in patients with diabetes or at
`risk for diabetes. (5.6)
`o Dyslipidemia: Undesirable alterations have been observed. (5.6)
`
`
`o Weight Gain: Significant weight gain has been reported. Monitor
`
`
`
`weight gain. (5.6)
`
` Orthostatic Hypotension and Syncope: Use with caution in patients with
`known cardiovascular or cerebrovascular disease and patients predisposed
`
`to hypotension (5.7)
`
` Leukopenia, Neutropenia, and Agranulocytosis: Monitor complete blood
`count in patients with a history of a clinically significant low white blood
`
`
`cell count (WBC) or a drug-induced leukopenia/neutropenia. Consider
`
`discontinuation if clinically significant decline in WBC in the absence of
`
`other causative factors (5.8)
`
` Hyperprolactinemia: Prolactin elevations occur and persist during chronic
`administration (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)
`
`
`
`
`------------------------------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---------------------------­
`
`
` Centrally-acting drugs: Use caution when co-administering with INVEGA®
`
`SUSTENNA®. Avoid alcohol. (7.1)
`
`
`
`
` 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: It may be necessary to
`increase the dose of INVEGA® SUSTENNA® when a strong inducer of
`both CYP3A4 and P-gp (e.g., carbamazepine, rifampin, St John’s wort) is
`co-administered. Conversely, on discontinuation of the strong inducer, it
`may be necessary to decrease the dose of INVEGA® SUSTENNA®. (7.2,
`
`
`12.3)
`
`
`-----------------------USE IN SPECIFIC POPULATIONS----------------------­
`
` Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
` Nursing Mothers: Discontinue drug or nursing, taking into consideration
`the importance of drug to the mother. (8.3)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
`
`
`
`Revised: MM/YYYY
`
`
`
`
`
`
`1
`
`

`

`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA-RELATED PSYCHOSIS
`
` 
` 
`1
`INDICATIONS AND USAGE
` 
` 
`2 DOSAGE AND ADMINISTRATION
`
` 
` 
`Administration Instructions
`
`2.1
` 
`2.2 Recommended Dosing
`
`
` 
`2.3 Missed Doses
`
`
` 
` 
`Use with Oral Paliperidone or with Risperidone
`
`2.4
` 
` 
`Dosage Adjustments
`
`2.5
` 
` 
`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
`
` 
`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
` 
` 
`Leukopenia, Neutropenia, and Agranulocytosis
`
`5.8
` 
` 
`Hyperprolactinemia
`
`5.9
` 
` 
`5.10 Potential for Cognitive and Motor Impairment
`
` 
` 
`5.11 Seizures
`
` 
` 
`5.12 Dysphagia
`
` 
` 
`5.13 Priapism
`
` 
` 
`5.14 Disruption of Body Temperature Regulation
`
` 
` 
`6 ADVERSE REACTIONS
` 
` 
`Clinical Trials Experience
`
`6.1
` 
`6.2 Postmarketing Experience
`
`
` 
`6.3 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
`
` 
`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
`
` 
` 
`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: 3495576
`
`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 [see Warnings and Precautions (5.1)].
`INVEGA® SUSTENNA® is not approved for use in patients with dementia-related
`
` psychosis [see Warnings and Precautions (5.1)].
`
`
`
`
`
` INDICATIONS AND USAGE
`1
`
`INVEGA® SUSTENNA® (paliperidone palmitate)
`treatment of
`the
`indicated for
`is
`schizophrenia. Efficacy was established in four short-term studies and one longer-term study in
`adults [see Clinical Studies (14)].
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Administration Instructions
`Parenteral drug products should be inspected visually for foreign matter and discoloration prior
`to administration, whenever product and container permit.
`
`INVEGA® SUSTENNA®
`intramuscular use only. Do not administer
`intended for
`is
`intravascularly or subcutaneously. Avoid inadvertent injection into a blood vessel. Each injection
`must be administered only by a health care professional. Administer the dose in a single
`injection; do not administer the dose in divided injections. Inject slowly, deep into the muscle.
`
`The recommended needle size for administration of INVEGA® SUSTENNA® into the deltoid
`muscle is determined by the patient’s weight. For those  90 kg, the 1½-inch, 22 gauge needle is
`recommended. For those < 90 kg, 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. Administer into the upper-outer quadrant of the gluteal
`muscle. Gluteal injections should be alternated between the two gluteal muscles.
`
` 2.2 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
`
`3
`
`Reference ID: 3495576
`
`

`

`
`monthly maintenance dose is 117 mg; however, based on previous clinical history of tolerability
`
` and/or efficacy, some patients may benefit from lower or higher maintenance doses within the
`additional available strengths (39 mg, 78 mg, 156 mg, and 234 mg). 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.
`
` 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.
`
`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.
`
`Missed second initiation dose (< 4 weeks from first injection)
`If less than 4 weeks have elapsed since the first injection, then the patient should be administered
`the second injection of 156 mg in the deltoid muscle as soon as possible. A third INVEGA®
`
`SUSTENNA® injection of 117 mg is recommended in either the deltoid or gluteal muscle
`administered 5 weeks after the first injection (regardless of the timing of the second injection).
`The normal monthly cycle of injections in either the deltoid or gluteal muscle of 39 mg to
`234 mg based on individual patient tolerability and/or efficacy should be followed thereafter.
`
`Missed second initiation dose (4-7 weeks from first injection)
`If 4 to 7 weeks have elapsed since the first injection of INVEGA® SUSTENNA®, resume dosing
`with two injections of 156 mg in the following manner: a deltoid injection as soon as possible
`followed by another deltoid injection one week later, then resumption of the normal monthly
`cycle of injections in either the deltoid or gluteal muscle of 39 mg to 234 mg based on individual
`patient tolerability and/or efficacy.
`
`
`Missed second initiation dose (> 7 weeks from first injection)
`If more than 7 weeks have elapsed since the first injection of INVEGA® SUSTENNA®, initiate
`
`dosing as described in Section 2.2 above.
`
`4
`
`Reference ID: 3495576
`
`

`

`
`Missed Maintenance 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 Maintenance 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 Maintenance 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.
`
`2.4 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 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
`It may be necessary to increase the dose of INVEGA® SUSTENNA® when a strong inducer of
`both CYP3A4 and P-gp (e.g., carbamazepine, rifampin, St John’s wort) is co-administered.
`
`5
`
`Reference ID: 3495576
`
`

`

`
`Conversely, on discontinuation of the strong inducer, it may be necessary to decrease the dose of
`
` INVEGA® SUSTENNA® [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
`
`
`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.
`
`Switching from Other Antipsychotics
`2.7
`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®. 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 1.
`
`Table 1.
`
`Dosing Frequency
`
`Dose (mg)
`
`
` Doses of INVEGA® and INVEGA® SUSTENNA® needed to attain similar steady-state
`
`paliperidone exposure during maintenance treatment
`INVEGA®
`
`Formulation
`
`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® .
`
`
`Reference ID: 3495576
`
`6
`
`

`

`
`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. The recommended monthly maintenance
`
` dose is 117 mg; however, based on previous clinical history of tolerability and/or efficacy, some
`
` patients may benefit from lower or higher maintenance doses within the additional available
`strengths (39 mg, 78 mg, 156 mg, and 234 mg). 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
`2.8
`
`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
`
`a. Shake the syringe vigorously for a minimum of 10 seconds to ensure a homogeneous
`
`suspension.
`
`Reference ID: 3495576
`
`7
`
`

`

`
`
`
`
`b. 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).
`
`c. While holding the syringe upright, remove the rubber tip cap with an easy clockwise twisting
`motion.
`
`
`
`Reference ID: 3495576
`
`8
`
`

`

`
`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.
`
`
`
`
`
`9
`
`Reference ID: 3495576
`
`

`

`
`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 into the selected deltoid or gluteal muscle of the
`patient. Do not administer intravascularly or subcutaneously.
`
`
`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
`
`
`
`
`
` 10
`
`Reference ID: 3495576
`
`

`

`
`
`
`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, 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
`
`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
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`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® (paliperidone palmitate) is not approved for the treatment of patients
`
`with dementia-related psychosis [see Boxed Warning].
`
`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. 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 Boxed Warning and Warnings and Precautions (5.1)].
`
`5.3 Neuroleptic Malignant Syndrome
`A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome
`
`(NMS) has been reported in association with antipsychotic drugs, including paliperidone.
`
`Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and
`evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis,
`and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase,
`myoglobinuria (rhabdomyolysis), and acute renal failure.
`
`The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
`diagnosis, it is important to identify cases in which the clinical presentation includes both serious
`
`medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
`extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
`diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
`nervous system pathology.
`
`The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs
`and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and
`medical monitoring; and (3) treatment of any concomitant serious medical problems for which
`specific treatments are available. There is no general agreement about specific pharmacological
`treatment regimens for uncomplicated NMS.
`
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` If a patient appears to require antipsychotic drug treatment after recovery from NMS,
`
`reintroduction of drug therapy should be closely monitored, since recurrences of NMS have been
`reported.
`
`5.4 QT Prolongation
`Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of
`paliperidone should be avoided in combination with other drugs that are known to prolong QTc
`including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol)
`antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine),
`antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong
`the QTc interval. Paliperidone should also be avoided in patients with congenital long QT
`syndrome and in patients with a history of cardiac arrhythmias.
`
`
`Certain circumstances may increase the risk of the occurrence of Torsades de pointes and/or
`sudden death in association with the use of drugs that prolong the QTc interval, including
`(1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that
`prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.
`
`The effects of oral paliperidone on the QT interval were evaluated in a double-blind,
`active-controlled (moxifloxacin 400 mg single dose), multicenter QT study in adults with
`schizophrenia and schizoaffective disorder, and in three placebo- and active-controlled 6-week,
`
`fixed-dose efficacy trials in adults with schizophrenia.
`
`In the QT study (n = 141), the 8 mg dose of immediate-release oral paliperidone (n=50) showed
`a mean placebo-subtracted increase from baseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on
`
`day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg
`dose of paliperidone immediate release (Cmax ss = 113 ng/mL) was more than 2-fold the exposure
`observed with the maximum recommended 234 mg dose of INVEGA® SUSTENNA®
`
`administered in the deltoid muscle (predicted median Cmax ss = 50 ng/mL). In this same study, a
`
`4 mg dose of
`the
`immediate-release oral formulation of paliperidone, for which
`Cmax ss = 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6;
`
`10.1) on day 2 at 1.5 hours post-dose.
`
`In the three fixed-dose efficacy studies of oral paliperidone extended release, 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
`
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`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®
`
`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.
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`Reference ID: 3495576
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`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 diabete