ERZOFRI EXTENDED-RELEASE

ERZOFRI (paliperidone palmitate) extended-release injectable suspension contains a racemic mixture of (+)- and (-)- paliperidone palmitate. Paliperidone palmitate, is an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical name is (9 RS )-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4 H -pyrido[1,2- a ]pyrimadin-9-yl hexadecanoate. Its molecular formula is C 39 H 57 FN 4 O 4 and its molecular weight is 664.89. The structural formula is: Paliperidone palmitate is very slightly soluble in ethanol and methanol, practically insoluble in water, and slightly soluble in ethyl acetate. ERZOFRI is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in the following dose strengths of paliperidone palmitate (deliverable volume) in single-dose prefilled syringes: 39 mg (0.25 mL), 78 mg (0.5 mL), 117 mg (0.75 mL), 156 mg (1 mL), 234 mg (1.5 mL), and 351 mg (2.25 mL). The drug product hydrolyzes in vivo to the active moiety, paliperidone, resulting in dose strengths of 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, and 225 mg of paliperidone, respectively. The inactive ingredients are citric acid monohydrate (5 mg/mL), dibasic sodium phosphate anhydrous (5 mg/mL), monobasic sodium phosphate monohydrate (2.5 mg/mL), polyethylene glycol 4000 (30 mg/mL), polysorbate 20 (12 mg/mL), sodium hydroxide to adjust pH, and water for injection. The drug product pH is 6.5 to 7.5. Chemical Structure

ERZOFRI is indicated for the treatment of: Schizophrenia in adults . Schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants . ERZOFRI 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 )

For patients naïve to oral or injectable paliperidone, or oral or injectable risperidone, establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with ERZOFRI. ( 2.1 ) Each injection must be administered by a healthcare professional. ( 2.1 ) Initiate ERZOFRI by intramuscular injection in the deltoid muscle. Following the initial dose, monthly doses can be administered in either the gluteal or deltoid muscle. Do not administer by any other route. ( 2.1 ) Dosage recommendations: Indication Initial Dose (deltoid) Day 1 Monthly Dosage Administered 4 weeks after the first injection. (deltoid or gluteal) Maximum Monthly Dosage Schizophrenia ( 2.1 ) 351 mg 39 mg to 234 mg Recommended monthly dosage for treatment of schizophrenia is 117 mg. Some patients may benefit from lower or higher monthly doses within the additional available strengths (39 mg, 78 mg, 156 mg, and 234 mg). 234 mg Schizoaffective disorder ( 2.1 ) 351 mg 78 mg to 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. 234 mg Missed dose: Refer to the Full Prescribing Information. ( 2.2 ) Mild renal impairment: Administer 234 mg on treatment Day 1 in the deltoid muscle. Follow with the recommended monthly maintenance dose of 78 mg, administered in the deltoid or gluteal muscle. Adjust monthly maintenance dose based on tolerability and/or efficacy within the strengths of 39 mg, 78 mg, 117 mg, or 156 mg. The maximum monthly dosage is 156 mg for patients with mild renal impairment. ( 2.4 ) See Full Prescribing Information for important preparation and administration information. ( 2.7 ) 2.1 Recommended Dosage For patients who have never taken oral or injectable paliperidone, or oral or injectable risperidone, establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with ERZOFRI. ERZOFRI must be administered by a healthcare professional as an intramuscular injection. Do not administer ERZOFRI by any other route. For detailed preparation and administration instructions, see Dosage and Administration (2.7) . See Table 1 for dosage recommendations for ERZOFRI in the treatment of schizophrenia in adults or the treatment of schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants. The initial dosage of ERZOFRI is 351 mg on treatment Day 1 administered in the deltoid muscle. Following the initial dose, monthly doses can be administered in either the deltoid or gluteal muscle [see Clinical Pharmacology (12.3) ] . Table 1: Dosage Recommendations for ERZOFRI Indication Initial Dose (deltoid) Day 1 Monthly Dosage Administered 4 weeks after the first injection. (deltoid or gluteal) Maximum Monthly Dosage Schizophrenia 351 mg 39 mg to 234 mg The recommended monthly dosage for treatment of schizophrenia is 117 mg. Some patients may benefit from lower or higher monthly doses within the additional available strengths (39 mg, 78 mg, 156 mg, and 234 mg). 234 mg Schizoaffective disorder 351 mg 78 mg to 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. 234 mg Adjust dosage monthly depending on clinical response and tolerability. When making dose adjustments, the pharmacokinetic profile of ERZOFRI should be considered [see Clinical Pharmacology (12.3) ] , as the full effect of the dose adjustment may not be apparent for several months. 2.2 Missed Doses Dosing Window To avoid a missed monthly dose, patients may be given the injection up to 7 days before or after the monthly time point. Missed Dose If a dose of ERZOFRI is missed, follow the dosing instructions provided in Table 2. Table 2: Management of a Missed Dose of ERZOFRI TIMING OF MISSED DOSE DOSING 4 to 6 weeks since last injection Resume regular monthly dosing as soon as possible at the patient's previously stabilized dose, followed by injections at monthly intervals. 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: Administer a deltoid injection as soon as possible. Administer a second deltoid injection 1 week later at the same dose. 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 2.1, Table 1 ) : Administer a 351 mg deltoid injection on Day 1. Thereafter, resume administering the previously stabilized dose in the deltoid or gluteal muscle 1 month after the initial injection. 2.3 Use with Risperidone or with Oral Paliperidone Paliperidone is the major active metabolite of risperidone. Exercise caution if ERZOFRI is co-administered with risperidone or with oral paliperidone for extended periods of time. Safety data involving concomitant use of ERZOFRI with other antipsychotics is limited. 2.4 Dosage Recommendations for Patients with Renal Impairment For patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min [Cockcroft-Gault Formula]), initiate ERZOFRI with a dose of 234 mg on treatment Day 1 in the deltoid muscle. Follow with the recommended monthly dosage of 78 mg, administered in either the deltoid or gluteal muscle. Adjust monthly dosage based on tolerability and/or response within the strengths of 39 mg, 78 mg, 117 mg, or 156 mg. The maximum monthly dosage is 156 mg for patients with mild renal impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . ERZOFRI is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]. 2.5 Dosage Modifications for Concomitant Use with Strong CYP3A4 Inducers and/or P-gp Inducers Avoid using a strong inducer of CYP3A4 and/or P-gp during the one-month dosing interval for ERZOFRI, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release 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 ERZOFRI or concerning concomitant administration with other antipsychotics. Switching from Oral Antipsychotics Previous oral antipsychotics can be gradually discontinued at the time of initiation of treatment with ERZOFRI. The recommended initial dosage of ERZOFRI is 351 mg on treatment Day 1, administered in the deltoid muscle [see Dosage and Administration (2.1) ] . See Table 3 for subsequent monthly dosage recommendations for ERZOFRI in patients switching from oral extended-release paliperidone tablets. Table 3: Dosage Recommendations Following Initial Dose of ERZOFRI in Patients Switching from Oral Extended-Release Paliperidone Tablets Paliperidone Extended-Release Tablet ERZOFRI Dosing Frequency Once Daily Once every 4 weeks 12 mg 234 mg Dose 9 mg 156 mg 6 mg 117 mg 3 mg 39 mg to 78 mg Switching from Long-Acting Injectable Antipsychotics When switching patients currently at steady-state on a long-acting injectable antipsychotic, initiate ERZOFRI therapy in place of the next scheduled injection. Continue ERZOFRI at monthly intervals. The initial dosing regimen as described in Section 2.1 is not required. See Table 1 for recommended monthly dosing. Based on previous clinical response and tolerability, some patients may benefit from lower or higher doses within the available strengths (39 mg, 78 mg, 117 mg, 156 mg, and 234 mg). If ERZOFRI is discontinued, its pharmacokinetic characteristics must be considered. As recommended with other antipsychotic medications, the need for continuing existing extrapyramidal symptoms (EPS) medication should be re-evaluated periodically. 2.7 Preparation and Administration Instructions To be prepared and administered by a healthcare professional only. Read the instructions for preparation and administration below for preparation and administration considerations. For deltoid or gluteal intramuscular injection only. Do not inject by any other route. Administer the initial dosage of ERZOFRI in the deltoid muscle. Subsequent monthly dosages may be administered in the deltoid or gluteal muscle. As a universal precaution, always wear gloves. Do not substitute any component of the drug kit. The kit contains a prefilled syringe and 2 safety needles (a 1 ½-inch 22 gauge needle and a 1-inch 23 gauge needle). ERZOFRI is for single use only. Step 1. Select Needle For Deltoid injection For Gluteal injection If the patient weighs less than 90 kg, use the 1-inch 23 gauge needle (needle with blue colored hub) Use the 1 ½-inch 22 gauge needle (needle with gray colored hub) regardless of patient's weight If the patient weighs 90 kg or more, use the 1 ½-inch 22 gauge needle (needle with gray colored hub) Step 2. Prepare for Injection a. Open needle pouch b. Shake vigorously for at least 10 seconds c. Remove cap First, peel the safety needle pouch half way open. Place on a clean surface. Shake the syringe vigorously for a minimum of 10 seconds to ensure a homogeneous suspension. While holding the syringe upright, remove the rubber tip cap with an easy counterclockwise twisting motion. Do not touch syringe tip. d. Attach needle e. Remove needle sheath f. Remove air bubbles 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. Do not remove the pouch until the syringe and needle are securely attached. 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. Bring the syringe with the attached needle in upright position to de-aerate. De-aerate the syringe by moving the plunger rod carefully forward. Step 3. Inject Inject the entire contents intramuscularly slowly, deep into the selected deltoid or gluteal muscle of the patient. Do not administer by any other route. Step 4. After Injection Secure Needle Dispose properly a Dispose of the syringe and unused needle in an approved sharps container. b c After the injection is complete, use either thumb or finger of one hand (a, b) or a flat surface (c) to activate the needle protection system. The needle protection system is fully activated when a 'click' is heard. Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image

ERZOFRI is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the ERZOFRI formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone [see Adverse Reactions (6.1 , 6.2) ] . Known hypersensitivity to paliperidone, risperidone, or to any excipients in ERZOFRI. ( 4 )

The following are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1) ] Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2) ] Neuroleptic malignant syndrome [see Warnings and Precautions (5.3) ] QT prolongation [see Warnings and Precautions (5.4) ] Tardive dyskinesia [see Warnings and Precautions (5.5) ] Metabolic changes [see Warnings and Precautions (5.6) ] Orthostatic hypotension and syncope [see Warnings and Precautions (5.7) ] Falls [see Warnings and Precautions (5.8) ] Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.9) ] Hyperprolactinemia [see Warnings and Precautions (5.10) ] Potential for cognitive and motor impairment [see Warnings and Precautions (5.11) ] Seizures [see Warnings and Precautions (5.12) ] Dysphagia [see Warnings and Precautions (5.13) ] Priapism [see Warnings and Precautions (5.14) ] Disruption of body temperature regulation [see Warnings and Precautions (5.15) ] 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 Luye Innomind Pharma Shijiazhuang Co., Ltd. at 1-800-548-9765 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ERZOFRI for the treatment of schizophrenia in adults and schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants is based upon adequate and well-controlled studies of another once-a-month paliperidone palmitate extended-release injectable suspension (also referred to as "PP1M" in this section). Below is a display of adverse reactions with another PP1M from those adequate and well-controlled studies. Injection site reactions for ERZOFRI presented in this section (see " Pain and Injection Site Reactions with ERZOFRI " below) are based on pharmacokinetic studies. Patient Exposure The data described in this section are derived from a clinical trial database consisting of a total of 3,817 subjects (approximately 1,705 patient-years exposure) with schizophrenia who received at least one dose of PP1M in the recommended dose range of 39 mg to 234 mg and a total of 510 subjects with schizophrenia who received placebo. Among the 3,817 PP1M-treated subjects, 1,293 received PP1M in four fixed-dose, double- blind, placebo-controlled trials (one 9-week and three 13-week studies), 849 received PP1M in the maintenance trial (median exposure 229 days during the initial 33-week open-label phase of this study, of whom 205 continued to receive PP1M during the double-blind placebo-controlled phase of this study [median exposure 171 days]), and 1,675 received PP1M in five non-placebo controlled trials (three noninferiority active- comparator trials, one long-term open-label pharmacokinetic and safety study, and an injection site [deltoid-gluteal] cross-over trial). One of the 13-week studies included a 234 mg PP1M initiation dose followed by treatment with either 39 mg, 156 mg, or 234 mg every 4 weeks. The safety of PP1M was also evaluated in a 15-month, long-term study comparing the other PP1M to selected oral antipsychotic therapies in adult subjects with schizophrenia. A total of 226 subjects received PP1M during the 15-month, open-label period of this study; 218 subjects received selected oral antipsychotic therapies. The safety of PP1M was similar to that seen in previous double-blind, placebo-controlled clinical trials in adult subjects with schizophrenia. The safety of PP1M was also evaluated in a long-term study in adult subjects with schizoaffective disorder. A total of 667 subjects PP1M during the initial 25-week open-label period of this study (median exposure 147 days); 164 subjects continued to receive PP1M during the 15-month double-blind placebo-controlled period of this study (median exposure 446 days). Adverse reactions that occurred more frequently in the PP1M group than the placebo group (a 2% difference or more between groups) were weight increased, nasopharyngitis, headache, hyperprolactinemia, and pyrexia. Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials Commonly Observed Adverse Reactions : The most common (at least 5% in any PP1M group) and likely drug-related (adverse events for which the drug rate is at least twice the placebo rate) adverse reactions from the double-blind, placebo-controlled trials in subjects with schizophrenia were injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder . No occurrences of adverse events reached this threshold in the long-term double-blind, placebo-controlled study in subjects with schizoaffective disorder. Discontinuation of Treatment Due to Adverse Events : The percentage of subjects who discontinued due to adverse events in the four fixed-dose, double-blind, placebo-controlled schizophrenia trials were similar for PP1M- and placebo-treated subjects. The percentage of subjects who discontinued due to adverse events in the open-label period of the long-term study in subjects with schizoaffective disorder was 7.5%. During the double-blind, placebo-controlled period of that study, the percentages of subjects who discontinued due to adverse events were 5.5% and 1.8% in PP1M- and placebo-treated subjects, respectively. Dose-Related Adverse Reactions : Based on the pooled data from the four fixed-dose, double- blind, placebo-controlled trials in subjects with schizophrenia, among the adverse reactions that occurred with ≥ 2% incidence in the subjects treated with PP1M, only akathisia increased with dose. Hyperprolactinemia also exhibited a dose relationship, but did not occur at ≥ 2% incidence in PP1M-treated subjects from the four fixed-dose studies. Adverse Reactions Occurring at an Incidence of 2% or More in a once-a-month paliperidone palmitate extended-release injectable suspension-Treated Patients: Table 9 lists the adverse reactions reported in 2% or more of PP1M -treated subjects and at a greater proportion than in the placebo group with schizophrenia in the four fixed-dose, double-blind, placebo-controlled trials. Table 9: Incidences of Adverse Reactions 2% or More of a Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension-Treated Patients (and Greater than Placebo) with Schizophrenia in Four Fixed-Dose, Double-Blind, Placebo-Controlled Trials Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension System Organ Class Adverse Reactions Placebo Placebo group is pooled from all studies and included either deltoid or gluteal injection depending on study design. (N=510) 39 mg (N=130) 78 mg (N=302) 156 mg (N=312) 234/39 mg Initial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection. [see Clinical Studies (14.1) ] (N=160) 234/156 mg (N=165) 234/234 mg (N=163) Percentages are rounded to whole numbers. Table includes adverse reactions that were reported in 2% or more of subjects in any of the once-a-month paliperidone palmitate extended-release injectable suspension dose groups and which occurred at greater incidence than in the placebo group. Total percentage of subjects with adverse reactions 70 75 68 69 63 60 63 Gastrointestinal disorders Abdominal discomfort/abdominal pain upper 2 2 4 4 1 2 4 Diarrhea 2 0 3 2 1 2 2 Dry mouth 1 3 1 0 1 1 1 Nausea 3 4 4 3 2 2 2 Toothache 1 1 1 3 1 2 3 Vomiting 4 5 4 2 3 2 2 General disorders and administration site conditions Asthenia 0 2 1 <1 0 1 1 Fatigue 1 1 2 2 1 2 1 Injection site reactions 2 0 4 6 9 7 10 Infections and infestations Nasopharyngitis 2 0 2 2 4 2 2 Upper respiratory tract infection 2 2 2 2 1 2 4 Urinary tract infection 1 0 1 <1 1 1 2 Investigations Weight increased 1 4 4 1 1 1 2 Musculoskeletal and connective tissue disorders Back pain 2 2 1 3 1 1 1 Musculoskeletal stiffness 1 1 <1 <1 1 1 2 Myalgia 1 2 1 <1 1 0 2 Pain in extremity 1 0 2 2 2 3 0 Nervous system disorders Akathisia 3 2 2 3 1 5 6 Dizziness 1 6 2 4 1 4 2 Extrapyramidal disorder 1 5 2 3 1 0 0 Headache 12 11 11 15 11 7 6 Somnolence/sedation 3 5 7 4 1 5 5 Psychiatric disorders Agitation 7 10 5 9 8 5 4 Anxiety 7 8 5 3 5 6 6 Nightmare <1 2 0 0 0 0 0 Respiratory, thoracic and mediastinal disorders Cough 1 2 3 1 0 1 1 Vascular disorders Hypertension 1 2 1 1 1 1 0 Adverse reactions for which the once-a-month paliperidone palmitate extended-release injectable suspension incidence was equal to or less than placebo are not listed in the table, but included the following: dyspepsia, psychotic disorder, schizophrenia, and tremor. The following terms were combined: somnolence/sedation, breast tenderness/breast pain, abdominal discomfort/abdominal pain upper/stomach discomfort, and tachycardia/sinus tachycardia/heart rate increased. All injection site reaction-related adverse reactions were collapsed and are grouped under "Injection site reactions". Other Adverse Reactions Observed During the Clinical Trial Evaluation of Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, or 4) which were not considered to have significant clinical implications. Cardiac disorders: atrioventricular block first degree, bradycardia, bundle branch block, palpitations, postural orthostatic tachycardia syndrome, tachycardia Ear and labyrinth disorders: vertigo Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurred Gastrointestinal disorders: constipation, dyspepsia, flatulence, salivary hypersecretion Immune system disorders: hypersensitivity Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, electrocardiogram abnormal Metabolism and nutrition disorders: decreased appetite, hyperinsulinemia, increased appetite Musculoskeletal and connective tissue disorders: arthralgia, joint stiffness, muscle rigidity, muscle spasms, muscle tightness, muscle twitching, nuchal rigidity Nervous system disorders: bradykinesia, cerebrovascular accident, cogwheel rigidity, convulsion, dizziness postural, drooling, dysarthria, dyskinesia, dystonia, hypertonia, lethargy, oromandibular dystonia, parkinsonism, psychomotor hyperactivity, syncope Psychiatric disorders: insomnia, libido decreased, restlessness Reproductive system and breast disorders: amenorrhea, breast discharge, breast enlargement/breast swelling, breast tenderness/breast pain, ejaculation disorder, erectile dysfunction, galactorrhea, gynecomastia, menstrual disorder, menstruation delayed, menstruation irregular, sexual dysfunction Respiratory, thoracic and mediastinal disorders: nasal congestion Skin and subcutaneous tissue disorders: drug eruption, pruritus, pruritus generalized, rash, urticaria Demographic Differences An examination of population subgroups in the double-blind placebo-controlled trials did not reveal any evidence of differences in safety on the basis of age, gender, or race alone; however, there were few subjects 65 years of age and older. Extrapyramidal Symptoms (EPS) Pooled data from the two double-blind, placebo-controlled, 13-week, fixed-dose trials in adult subjects with schizophrenia provided information regarding EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score which broadly evaluates parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score which evaluates akathisia, (3) the Abnormal Involuntary Movement Scale scores which evaluates dyskinesia, and (4) use of anticholinergic medications to treat EPS (Table 10), and (5) incidence of spontaneous reports of EPS (Table 11). Table 10: Extrapyramidal Symptoms (EPS) Assessed by Incidence of Rating Scales and Use of Anticholinergic Medication – Schizophrenia Studies in Adults Percentage of Subjects Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension Scale Placebo (N=262) 39 mg (N=130) 78 mg (N=223) 156 mg (N=228) Parkinsonism For parkinsonism, percent of subjects with Simpson-Angus Total score > 0.3 at endpoint (Total score defined as total sum of items score divided by the number of items) 9 12 10 6 Akathisia For Akathisia, percent of subjects with Barnes Akathisia Rating Scale global score ≥ 2 at endpoint 5 5 6 5 Dyskinesia For Dyskinesia, percent of subjects with a score ≥ 3 on any of the first 7 items or a score ≥ 2 on two or more of any of the first 7 items of the Abnormal Involuntary Movement Scale at endpoint 3 4 6 4 Use of Anticholinergic Medications Percent of subjects who received anticholinergic medications to treat EPS 12 10 12 11 Table 11: Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term – Schizophrenia Studies in Adults Percentage of Subjects Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension EPS Group Placebo (N=262) 39 mg (N=130) 78 mg (N=223) 156 mg (N=228) Parkinsonism group includes: Extrapyramidal disorder, hypertonia, musculoskeletal stiffness, parkinsonism, drooling, masked facies, muscle tightness, hypokinesia Hyperkinesia group includes: Akathisia, restless legs syndrome, restlessness Dyskinesia group includes: Dyskinesia, choreoathetosis, muscle twitching, myoclonus, tardive dyskinesia Dystonia group includes: Dystonia, muscle spasms Overall percentage of subjects with EPS-related adverse events 10 12 11 11 Parkinsonism 5 6 6 4 Hyperkinesia 2 2 2 4 Tremor 3 2 2 3 Dyskinesia 1 2 3 1 Dystonia 0 1 1 2 The results across all phases of the maintenance trial in subjects with schizophrenia exhibited comparable findings. In the 9-week, fixed-dose, double-blind, placebo-controlled trial, the proportions of parkinsonism and akathisia assessed by incidence of rating scales were higher in the PP1M 156 mg group (18% and 11%, respectively) than in the PP1M 78 mg group (9% and 5%, respectively) and placebo group (7% and 4%, respectively). In the 13-week study in subjects with schizophrenia involving 234 mg initiation dosing, the incidence of any EPS was similar to that of the placebo group (8%), but exhibited a dose-related pattern with 6%, 10%, and 11% in the PP1M 234/39 mg, 234/156 mg, and 234/234 mg groups, respectively. Hyperkinesia was the most frequent category of EPS-related adverse events in this study, and was reported at a similar rate between the placebo (4.9%) and PP1M 234/156 mg (4.8%) and 234/234 mg (5.5%) groups, but at a lower rate in the 234/39 mg group (1.3%). In the long-term study in subjects with schizoaffective disorder, EPS reported during the 25-week open-label PP1M treatment included hyperkinesia (12.3%), parkinsonism (8.7%), tremor (3.4%), dyskinesia (2.5%), and dystonia (2.1%). During the 15-month double-blind treatment, the incidence of any EPS was similar to that of the placebo group (8.5% and 7.1% respectively). The most commonly reported treatment-emergent EPS-related adverse events (> 2%) in any treatment group in the double-blind phase of the study (PP1M versus placebo) were hyperkinesia (3.7% versus 2.9%), parkinsonism (3.0% versus 1.8%), and tremor (1.2% versus 2.4%). Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Pain Assessment and Injection Site Reactions In the pooled data from the two 13-week, fixed-dose, double-blind, placebo-controlled trials of another PP1M in subjects with schizophrenia, the mean intensity of injection pain reported by subjects using a visual analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from the first to the last injection (placebo: 10.9 to 9.8; 39 mg: 10.3 to 7.7; 78 mg: 10.0 to 9.2; 156 mg: 11.1 to 8.8). The results from both the 9-week, fixed-dose, double-blind, placebo-controlled trial and the double-blind phase of the maintenance trial exhibited comparable findings. In the 13-week study involving 234 mg initiation dosing in subjects with schizophrenia, occurrences of induration, redness, or swelling, as assessed by blinded study personnel, were infrequent, generally mild, decreased over time, and similar in incidence between the PP1M and placebo groups. Investigator ratings of injection pain were similar for the placebo and PP1M groups. Investigator evaluations of the injection site after the first injection for redness, swelling, induration, and pain were rated as absent for 69-100% of subjects in both the PP1M and placebo groups. At Day 92, investigators rated absence of redness, swelling, induration, and pain in 95-100% of subjects in both the PP1M and placebo groups. ERZOFRI was evaluated in 281 patients with schizophrenia or schizoaffective disorder in an open-label randomized parallel arm study. The percentage of patients in the open-label study reporting injection site-related adverse reactions at the first injection for patients treated with ERZOFRI (all reported as injection site pain) was similar to the percentage of patients treated with another PP1M. Additional Adverse Reactions Reported in Clinical Trials with Oral Paliperidone The following is a list of additional adverse reactions that have been reported in clinical trials with oral paliperidone: Cardiac disorders : bundle branch block left, sinus arrhythmia Gastrointestinal disorders : abdominal pain, small intestinal obstruction General disorders and administration site conditions : edema, edema peripheral Immune system disorders : anaphylactic reaction Infections and infestations: rhinitis Musculoskeletal and connective tissue disorders : musculoskeletal pain, torticollis, trismus Nervous system disorders : grand mal convulsion, parkinsonian gait, transient ischemic attack Psychiatric disorders: sleep disorder Reproductive system and breast disorders : breast engorgement Respiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, pneumonia aspiration Skin and subcutaneous tissue disorders: rash papular Vascular disorders: hypotension, ischemia 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of paliperidone; because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: angioedema, catatonia, ileus, somnambulism, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary retention. Cases of anaphylactic reaction after injection with another once-a-month paliperidone palmitate extended-release injectable suspension product have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral paliperidone. Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with oral risperidone and risperidone long-acting injection can be found in the Adverse Reactions (6) sections of the package inserts for those products.

Drugs that may cause orthostatic hypotension: An additive effect may occur when co-administered with ERZOFRI. ( 7.1 ) Strong CYP3A4 and P-glycoprotein (P-gp) inducers : Avoid using a strong inducer of CYP3A4 and/or P-gp during a dosing interval for ERZOFRI. If concomitant use is necessary, consider using paliperidone extended-release tablets. ( 2.5 , 7.1 , 12.3 ) 7.1 Drugs Having Clinically Important Interactions with ERZOFRI Because paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3) ] , results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential. Table 12 presents clinically significant drug interactions with ERZOFRI. Table 12: Clinically Important Drug Interactions with ERZOFRI Centrally Acting Drugs and Alcohol Clinical Rationale: Given the primary CNS effects of paliperidone, concomitant use of centrally acting drugs and alcohol may modulate the CNS effects of ERZOFRI. Clinical Recommendation: ERZOFRI should be used with caution in combination with other centrally acting drugs and alcohol [see Adverse Reactions (6.1 , 6.2) ] . Drugs with Potential for Inducing Orthostatic Hypotension Clinical Rationale: Because ERZOFRI has the potential for inducing orthostatic hypotension, an additive effect may occur when ERZOFRI is administered with other therapeutic agents that have this potential [see Warnings and Precautions (5.7) ] . Clinical Recommendation: Monitor orthostatic vital signs in patients who are vulnerable to hypotension [see Warnings and Precautions (5.7) ] . Strong Inducers of CYP3A4 and P-gp Clinical Rationale: The concomitant use of paliperidone and strong inducers of CYP3A4 and P-gp may decrease the exposure of paliperidone [see Clinical Pharmacology (12.3) ] . Clinical Recommendation: Avoid using CYP3A4 and/or P-gp inducers with ERZOFRI during the 1-month dosing interval, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets [see Dosage and Administration (2.5) ] . Levodopa and Other Dopamine Agonists Clinical Rationale: Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Clinical Recommendation: Monitor and manage patient as clinically appropriate. 7.2 Drugs Having No Clinically Important Interactions with ERZOFRI Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of ERZOFRI is required when administered with valproate [see Clinical Pharmacology (12.3) ]. Additionally, no dosage adjustment is necessary for valproate when co-administered with ERZOFRI [See Clinical Pharmacology (12.3) ]. Pharmacokinetic interaction between lithium and ERZOFRI is also unlikely. Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism; however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone. Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or inducers of these isozymes is unlikely. [see Clinical Pharmacology (12.3) ]

Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not mix with any other product or diluent.