ERZOFRI EXTENDED-RELEASE- paliperidone palmitate_injection

Paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12. 3) 2) 2A Paliperidone is an antagonist at the central dopamine Type 2 (D 2 2A 2 2A 1 2 1 1 2. The overall exposures (AUC) of paliperidone following another once-a-month paliperidone palmitate extended-release injectable suspension (also referred to as "PP1M" in this section) administration was dose-proportional over a dose range of 39 mg to 234 mg, and peak plasma concentrations (C max Absorption After intramuscular injection, paliperidone palmitate is hydrolyzed to paliperidone and absorbed into the systemic circulation. Following a single intramuscular dose of ERZOFRI, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at a median T max Following multiple intramuscular injections of ERZOFRI (351 mg on day 1 and 156 mg on day 29 and every 28 days for a total of 6 consecutive injections) in patients, the geometric least square mean C max trough avg max-ss trough,ss tau-ss Following multiple intramuscular injections of another PP1M (234 mg on day 1 and 156 mg on day 8 and every 28 days for a total of 7 consecutive injections), the geometric least square mean C max trough avg max-ss trough,ss tau-ss Following intramuscular injection of a single dose of ERZOFRI 156 mg in the deltoid muscle, the geometric mean C max max inf inf Following intramuscular injection of single doses (39 mg to 234 mg) of another PP1M in the deltoid muscle, on average, a 28% higher C max Following administration of paliperidone palmitate, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1. Distribution Based on a population analysis of data from ERZOFRI clinical trials, the apparent volume of distribution of paliperidone is 2840 L. The plasma protein binding of racemic paliperidone is 74%. Elimination Metabolism Four metabolic pathways have been identified in vivo in vitro in vivo The median apparent half-life of paliperidone following ERZOFRI single-dose administration at 156 mg is approximately 27 days. Excretion In a study with oral immediate-release 14 14 Drug Interaction Studies No specific drug interaction studies have been performed with ERZOFRI. The information below is obtained from studies with oral paliperidone. Effects of other drugs on the exposures of paliperidone are summarized in Figure 1. After oral administration of 20 mg/day of paroxetine (a potent CYP2D6 inhibitor), an increase in mean C max Figure 1 max [see Drug Interactions (7. 1) Figure 1: Effects of Other Drugs on Paliperidone Pharmacokinetics Clinically meaningful pharmacokinetic interaction between paliperidone and valproate (including valproic acid and divalproex sodium) is not expected. Oral administration of divalproex sodium extended-release tablets (two 500 mg tablets once daily at steady-state) with oral paliperidone extended-release tablets resulted in an increase of approximately 50% in the C max After oral administration of paliperidone, the steady-state C max [see Drug Interactions (7. 2) In vitro in vivo In vitro [see Drug Interactions (7. 2) In vitro Paliperidone is a weak inhibitor of P-gp at high concentrations. No in vivo Figure 1 Specific Populations No pharmacokinetic studies have been performed with ERZOFRI in specific populations. The information is obtained from studies with oral paliperidone or is based on the population pharmacokinetic modeling of oral paliperidone and another PP1M. Exposures of paliperidone in specific populations (renal impairment, hepatic impairment and elderly) are summarized in Figure 2 [see Dosage and Administration (2. 4) Use in Specific Populations (8. 6) After oral administration of paliperidone in patients with moderate hepatic impairment, the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Paliperidone has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8. 7) After oral administration of paliperidone in elderly subjects, the C max [see Dosage and Administration (2. 5) Figure 2 Effects of Intrinsic Factors on Paliperidone Pharmacokinetics Based on in vitro Slower absorption was observed in females in a population pharmacokinetic analysis. At apparent steady-state with PP1M, the trough concentrations were similar between males and females. Lower C max Figure 2.

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.

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. 1 Each injection must be administered by a healthcare professional. 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. 1 Dosage recommendations: Indication Initial Dose Monthly Dosage Administered 4 weeks after the first injection. 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 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. 4 See Full Prescribing Information for important preparation and administration information. 7 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 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 Monthly Dosage Administered 4 weeks after the first injection. Maximum Monthly Dosage Schizophrenia 351 mg 39 mg to 234 mg The recommended monthly dosage for treatment of schizophrenia is 117 mg. 234 mg Schizoaffective disorder 351 mg 78 mg to 234 mg Adjust dose based on tolerability and/or efficacy using available strengths. 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) 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. 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. 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) 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. 3) 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) Clinical Pharmacology (12. 3) 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) Table 3 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 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. 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. Select Needle For Deltoid injection For Gluteal injection If the patient weighs less than 90 kg, use the 1-inch 23 blue Use the 1 ½-inch 22 gray If the patient weighs 90 kg or more, use the 1 ½-inch 22 gray 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. 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 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. Inject Inject the entire contents intramuscularly slowly, deep into the selected deltoid or gluteal muscle of the patient. 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.

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 en dash Schizophrenia Studies in Adults Percentage of Subjects Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension EPS Group Placebo 39 mg 78 mg 156 mg Parkinsonism group includes: Extrapyramidal disorder, hypertonia, musculoskeletal stiffness, parkinsonism, drooling, masked facies, muscle tightness, hypokinesia 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. 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. During the 15-month double-blind treatment, the incidence of any EPS was similar to that of the placebo group (8. 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. 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. 8; 39 mg: 10. 7; 78 mg: 10. 2; 156 mg: 11. 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 Gastrointestinal disorders General disorders and administration site conditions Immune system disorders Infections and infestations: Musculoskeletal and connective tissue disorders Nervous system disorders Psychiatric disorders: Reproductive system and breast disorders Respiratory, thoracic and mediastinal disorders: Skin and subcutaneous tissue disorders: Vascular disorders: 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).">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 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. at 1-800-548-9765 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 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 :. Discontinuation of Treatment Due to Adverse Events : 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. During the double-blind, placebo-controlled period of that study, the percentages of subjects who discontinued due to adverse events were 5. 8% in PP1M- and placebo-treated subjects, respectively. Dose-Related Adverse Reactions : 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: 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 Placebo Placebo group is pooled from all studies and included either deltoid or gluteal injection depending on study design. 39 mg 78 mg 156 mg 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) 234/156 mg 234/234 mg 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: Ear and labyrinth disorders: Eye disorders: Gastrointestinal disorders: Immune system disorders: Investigations: Metabolism and nutrition disorders: Musculoskeletal and connective tissue disorders: Nervous system disorders: Psychiatric disorders: Reproductive system and breast disorders: Respiratory, thoracic and mediastinal disorders: Skin and subcutaneous tissue disorders: 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 en dash Schizophrenia Studies in Adults Percentage of Subjects Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension Scale Placebo 39 mg 78 mg 156 mg 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 en dash Schizophrenia Studies in Adults Percentage of Subjects Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension EPS Group Placebo 39 mg 78 mg 156 mg Parkinsonism group includes: Extrapyramidal disorder, hypertonia, musculoskeletal stiffness, parkinsonism, drooling, masked facies, muscle tightness, hypokinesia 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. 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. During the 15-month double-blind treatment, the incidence of any EPS was similar to that of the placebo group (8. 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. 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. 8; 39 mg: 10. 7; 78 mg: 10. 2; 156 mg: 11. 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 Gastrointestinal disorders General disorders and administration site conditions Immune system disorders Infections and infestations: Musculoskeletal and connective tissue disorders Nervous system disorders Psychiatric disorders: Reproductive system and breast disorders Respiratory, thoracic and mediastinal disorders: Skin and subcutaneous tissue disorders: Vascular disorders: 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).

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. 2) Known hypersensitivity to paliperidone, risperidone, or to any excipients in ERZOFRI.

Pregnancy: 8. 1 Moderate or severe renal impairment 2. 5 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ERZOFRI, during pregnancy. Healthcare providers are encouraged to advise patients to register by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth. org/clinical- and-research-programs/pregnancyregistry/ Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations (see Data (see Clinical Considerations [see Clinical Pharmacology (12. 3) The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. In animal reproduction studies, there were no treatment related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate during the period of organogenesis at doses up to 10 times the maximum recommended human dose (MRHD) of 234 mg paliperidone palmitate based on mg/m 2 2 see Animal data Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including paliperidone palmitate, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates exhibiting extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. A retrospective cohort study from a Medicaid database of 9,258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR= 1. 26, 95% CI 1. 56) and of cardiac malformations (RR=1. 26, 95% CI 0. 81) in a subgroup of 1,566 women exposed to the parent compound of paliperidone, risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal Data There were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate extended-release injectable suspension during the period of organogenesis at doses up to 250 mg/kg, which is 10 times MRHD of 234 mg paliperidone palmitate as a monthly maintenance dose based on body surface area (BSA). In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg based on BSA. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone. Cleft palate was observed in the offspring of pregnant mice treated with risperidone at 3 to 4 times the MRHD of 16 mg based on BSA; maternal toxicity occurred at 4 times the MHRD. There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to 6 times the MRHD of 16 mg risperidone based on BSA. When the offspring of pregnant rats, treated with risperidone at 0. 6 times the MRHD based on BSA, reached adulthood, learning was impaired. Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0. 2 times the MRHD; the postnatal development and growth of the offspring were delayed. In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on BSA; it is not known whether these deaths were due to a direct effect on the fetuses or pups or, to effects on the dams (see RISPERDAL registered Risk Summary Limited data from published literature report the presence of paliperidone in human breast milk. There is no information on the effects on the breastfed infant or the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidone's parent compound, risperidone (see Clinical Considerations [see Clinical Pharmacology (12. 3) Clinical Considerations Infants exposed to ERZOFRI through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements). Infertility Females Based on the pharmacologic action of paliperidone (D 2 [see Warnings and Precautions (5. 10) Safety and effectiveness of ERZOFRI in pediatric patients have not been established. Juvenile Animal Toxicity Data In a study in which juvenile rats were treated with oral paliperidone from Days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0. 63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents dosed at a 12 mg/day oral dose. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2. 5 mg/kg/day), which produced plasma levels of paliperidone 2-3 times those in adolescents. Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0. 25, or 5 mg/kg/day. Decreased bone length and density were seen with a no-effect dose of 0. 31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone, which were similar to those in children and adolescents receiving the MRHD of oral risperidone. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period. The long-term effects of ERZOFRI on growth and sexual maturation have not been fully evaluated in pediatric patients. Clinical studies of ERZOFRI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Paliperidone palmitate is substantially excreted by the kidney and clearance is decreased in patients with renal impairment [see Clinical Pharmacology (12. 3) [see Dosage and Administration (2. 4) Use of ERZOFRI is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min). Dose reduction is recommended for patients with mild renal impairment (creatinine clearance >= 50 mL/min to < 80 mL/min) [see Dosage and Administration (2. 4) Clinical Pharmacology (12. 3) ERZOFRI 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) Patients with Parkinson's Disease or Dementia with Lewy Bodies can experience increased sensitivity to ERZOFRI. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

Drugs that may cause orthostatic hypotension: 7. 1 Strong CYP3A4 and P-glycoprotein (P-gp) inducers 2. 3 Because paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12. 3) 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. 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. Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of ERZOFRI is required when administered with valproate [see Clinical Pharmacology (12. 3) [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 in vivo [see Clinical Pharmacology (12.

= 25% increase (if the baseline score was > 40) or a 10-point increase (if the baseline score was <= 40) in total PANSS score on two consecutive assessments, deliberate self-injury, violent behavior, suicidal/homicidal ideation, or a score of >= 5 (if the maximum baseline score was <= 3) or >= 6 (if the maximum baseline score was 4) on two consecutive assessments of the specific PANSS items. The primary efficacy variable was time to relapse. A pre-planned interim analysis showed a statistically significantly longer time to relapse in patients treated with PP1M compared to placebo, and the study was stopped early because maintenance of efficacy was demonstrated. Thirty-four percent (34%) of subjects in the placebo group and 10% of subjects in the PP1M group experienced a relapse event. There was a statistically significant difference between the treatment groups in favor of PP1M. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 3. The time to relapse for subjects in the placebo group was statistically significantly shorter than for the PP1M group. An examination of population subgroups did not reveal any clinically significant differences in responsiveness on the basis of gender, age, or race. Figure 3: Kaplan-Meier Plot of Cumulative Proportion of Subjects with Relapse Over Time (Schizophrenia Study 5) * median time to relapse for placebo group is 163 days Figure 3 Long-Term Comparative Monotherapy Treatment versus Oral Antipsychotic Therapy (Study 6: SCH-3006) The efficacy of another PP1M in delaying time to treatment failure compared with selected oral antipsychotic medications was established in a long-term, randomized, flexible-dose study in subjects with schizophrenia and a history of incarceration. Subjects were screened for up to 14 days followed by a 15-month treatment phase during which they were observed for treatment failure. The primary endpoint was time to first treatment failure. Treatment failure was defined as one of the following: arrest and/or incarceration; psychiatric hospitalization; discontinuation of antipsychotic treatment because of safety or tolerability; treatment supplementation with another antipsychotic because of inadequate efficacy; need for increase in level of psychiatric services to prevent an imminent psychiatric hospitalization; discontinuation of antipsychotic treatment because of inadequate efficacy; or suicide. Treatment failure was determined by an Event Monitoring Board (EMB) that was blinded to treatment assignment. A total of 444 subjects were randomly assigned to either PP1M (N = 226; median dose 156 mg) or one of up to seven pre-specified, flexibly-dosed, commonly prescribed oral antipsychotic medications (N = 218; aripiprazole, haloperidol, olanzapine, paliperidone, perphenazine, quetiapine, or risperidone). The selection of the oral antipsychotic medication was determined to be appropriate for the patient by the investigator. A statistically significantly longer time to first treatment failure was seen for PP1M compared with oral antipsychotic medications. The median time to treatment failure was 416 days and 226 days for PP1M and antipsychotic medications, respectively. A Kaplan-Meier plot of time to first treatment failure is shown in Figure 4. The frequencies of first treatment failure events by type are shown in Table 14. The time to first arrest and/or incarceration or psychiatric hospitalization was also statistically significantly longer for the PP1M group compared to the oral antipsychotic group. Figure 4: Kaplan-Meier Plot of Time to First Treatment Failure in a Long-Term, Randomized, Flexible-Dose Study in Subjects with Schizophrenia and a History of Incarceration (Schizophrenia Study 6) * Median time to first treatment failure: 416 days with once-a-month paliperidone palmitate extended-release injectable suspension; 226 days with oral antipsychotics Table 14: Components of Composite Endpoint in a Long-Term, Randomized, Flexible-Dose Study in Subjects with Schizophrenia and a History of Incarceration (Schizophrenia Study 6) Event Type Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension Oral Antipsychotics Hazard Ratio Hazard ratio of once-a-month paliperidone palmitate extended-release injectable suspension to Oral Antipsychotics based on Cox regression model for time-to-event analysis. Note that the hazard ratio did not appear constant throughout the trial. First Treatment Failures 90 (39. 8%) 117 (53. 70 First Treatment Failure Component Events Arrest and/or incarceration 48 (21. 4%) Psychiatric hospitalization 18 (8. 9%) Discontinuation of antipsychotic treatment because of safety or tolerability 15 (6. 7%) Treatment supplementation with another antipsychotic because of inadequate efficacy 5 (2. 8%) Need for increase in level of psychiatric services to prevent an imminent psychiatric hospitalization 3 (1. 8%) Discontinuation of antipsychotic treatment because of inadequate efficacy 1 (0. 1%) Suicide 0 0 Arrest and/or Incarceration or Psychiatric Hospitalization Events, regardless of whether they were first events Analysis results, which incorporated relevant events collected after discontinuation for those who discontinued, were consistent with the results from the pre-specified analysis of this secondary endpoint. 70 Figure 4 The efficacy of ERZOFRI for the treatment of schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants is based upon an adequate and well-controlled study of another PP1M. The results of the adequate and well-controlled study is presented below. Maintenance Treatment en dash Monotherapy and as Adjunct to Mood Stabilizer or Antidepressant (SAff Study 1: SCA-3004) The efficacy of PP1M in maintaining symptom control in schizoaffective disorder was established in a long-term double-blind, placebo-controlled, flexible-dose randomized-withdrawal study designed to delay relapse in adult subjects who met DSM-IV criteria for schizoaffective disorder, as confirmed by the Structured Clinical Interview for DSM-IV Disorders. The population included subjects with schizoaffective bipolar and depressive types. Subjects received PP1M either as monotherapy or as an adjunct to stable doses of antidepressant or mood stabilizers. This study included a 13-week, open-label, flexible-dose (PP1M 78 mg, 117 mg, 156 mg, or 234 mg) lead-in period which enrolled a total of 667 subjects who had 1) acute exacerbation of psychotic symptoms; 2) score >=4 on >=3 PANSS items of delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, tension, and poor impulse control; and 3) prominent mood symptoms >=16 on the Young Mania Rating Scale (YMRS) and/or the Hamilton Rating Scale for Depression, 21-item version (HAM-D-21). Subjects were 19 to 66 years old (mean 39. 5 years) and 53. 5% were male. The mean scores at open-label enrollment of PANSS total was 85. 8 (range 42 to 128), HAM-D- 21 was 20. 4 (range 3 to 43), YMRS was 18. 6 (range 0 to 50), and CGI-S-SCA was 4. 4 (range 2 to 6). After the 13-week open-label flexible-dose PP1M treatment, 432 subjects met stabilization criteria (PANSS total score <=70, YMRS <=12, and HAM-D-21 <=12) and continued into the 12-week open-label fixed-dose stabilization period. A total of 334 subjects who met stabilization criteria for 12 consecutive weeks were randomized (1:1) to continue the same dose of PP1M or to placebo in the 15-month, double- blind, maintenance period. For the 164 subjects who were randomized to PP1M, dose distribution was 78 mg (4. 9%), 117 mg (9. 8%), 156 mg (47. 0%), and 234 mg (38. Relapse was defined as the first occurrence of one or more of the following: 1) psychiatric hospitalization; 2) intervention employed to avert hospitalization; 3) clinically significant self-injury, suicidal or homicidal ideation or violent behavior; 4) a score of >=6 (if the score was <=4 at randomization) of any of the individual PANSS items: delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, or poor impulse control; 5) on two consecutive assessments within 7 days: >= 25% increase (if the score at randomization was > 45) or >= 10-point increase (if the score at randomization was <= 45) in total PANSS score; a score of >= 5 (if the score was <= 3 at randomization) of any of the individual PANSS items: delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, or poor impulse control; an increase of >= 2 points (if the score was 1 [not ill] to 3 [mildly ill] at randomization) or increase of >= 1 point (if the score was >= 4 [moderately ill or worse] at randomization) in CGI-S-SCA overall score. There was a statistically significant difference in time to relapse between the treatment groups in favor of PP1M. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 5. Figure 5: Kaplan-Meier Plot of Cumulative Proportion of Subjects with Relapse Over Time (SAff Study 1) Table 15 summarizes the number of subjects with relapse in the overall population, by subgroup (monotherapy versus adjunctive therapy), and by symptom type at the first occurrence of relapse. Table 15: Summary of Relapse Rates (SAff Study 1). Number (Percent) of Subjects Who Relapsed Placebo Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension N=170 N=164 All Subjects 57 (33. 2%) Monotherapy subset N=73 N=78 Adjunct to Antidepressants or Mood Stabilizer subset N=97 N=86 Psychotic Symptoms 8 subjects experienced a relapse without psychotic symptoms. 8%) Mood Symptoms 16 subjects experienced a relapse without any mood symptoms. Any Mood Symptoms 48 (28. 0%) Manic 16 (9. 0%) Depressive 23 (13. 9%) Mixed 9 (5. 0%) Figure 5.">OVERDOSAGE
Human Experience While experience with paliperidone overdose is limited, among the few cases of overdose reported in premarketing trials with oral paliperidone, the highest estimated ingestion was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone''s known pharmacological effects, i. , drowsiness and sedation, tachycardia and hypotension, and QT prolongation. Torsades de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose with oral paliperidone. Paliperidone is the major active metabolite of risperidone. Refer to the OVERDOSAGE section of the risperidone prescribing information for overdose experience with risperidone. Management of Overdosage There is no specific antidote to paliperidone. Provide supportive care, including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. Consider the pharmacokinetic profile of ERZOFRI and the half-life of paliperidone when assessing treatment needs and recovery. Consider contacting the Poison Help Line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations.
NONCLINICAL TOXICOLOGY
Carcinogenesis The carcinogenic potential of intramuscularly injected paliperidone palmitate was assessed in rats. There was an increase in mammary gland adenocarcinomas in female rats at 16, 47, and 94 mg/kg monthly injections, which are 0. 6, 2, and 4 times, respectively, the MRHD of 234 mg of another once-a-month paliperidone palmitate extended-release injectable suspension based on body surface area (BSA). A no-effect dose was not established. Male rats showed an increase in mammary gland adenomas, fibroadenomas, and carcinomas at 2 and 4 times the MRHD based on BSA. A carcinogenicity study in mice has not been conducted with paliperidone palmitate. Carcinogenicity studies with risperidone, which is extensively converted to paliperidone in rats, mice, and humans, were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at daily doses of 0. 5, and 10 mg/kg for 18 months to mice and for 25 months to rats. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The no-effect dose for these tumors was less than or equal to the MRHD of risperidone based on BSA (see risperidone prescribing information). An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D 2 [see Warnings and Precautions (5. 7) Mutagenesis Paliperidone palmitate was not genotoxic in the in vitro in vitro in vivo Impairment of Fertility No fertility studies were conducted with paliperidone palmitate. Paliperidone did not affect fertility in treated female rats at oral doses of up to 2. 5 mg/kg/day which is 2 times the MRHD based on BSA. However, pre- and post-implantation loss was increased, and the number of live embryos was slightly decreased, at 2. 5 mg/kg, a dose that also caused slight maternal toxicity. These parameters were not affected at a dose of 0. 63 mg/kg, which is half of the MRHD based on BSA. Paliperidone did not affect fertility of treated male rats at oral doses of up to 2 times the MRHD of 12 mg/day based on BSA. However, studies to assess sperm count and sperm viability were not conducted with paliperidone. In a subchronic study in Beagle dogs with risperidone, which is extensively converted to paliperidone in dogs and humans, all doses tested (0. 31 mg/kg - 5. 0 mg/kg) resulted in decreases in serum testosterone and in sperm motility and concentration (0. 6 to 10 times the MRHD of 16 mg/day for risperidone, based on BSA). Serum testosterone and sperm parameters partially recovered, and remained decreased after the last observation at two months after treatment was discontinued.
CLINICAL STUDIES
The efficacy of ERZOFRI for the treatment of schizophrenia in adults 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). The results of these adequate and well-controlled studies of another PP1M are presented below. Short-Term Monotherapy (Studies 1, 2, 3, 4) The efficacy of another PP1M in the acute treatment of schizophrenia was evaluated in four short-term (one 9-week and three 13-week) double-blind, randomized, placebo-controlled, fixed-dose studies of acutely relapsed adult inpatients who met DSM-IV criteria for schizophrenia. The fixed doses of PP1M in these studies were given on days 1, 8, and 36 in the 9-week study, and additionally on Day 64 of the 13-week studies, i. , at a weekly interval for the initial two doses and then every 4 weeks for maintenance. Efficacy was evaluated using the total score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210. In Study 1 (PSY-3007), a 13-week study (n=636) comparing three fixed doses of PP1M (initial deltoid injection of 234 mg followed by 3 gluteal or deltoid doses of either 39 mg/4 weeks, 156 mg/4 weeks or 234 mg/4 weeks) to placebo, all three doses of PP1M were superior to placebo in improving the PANSS total score. In Study 2 (PSY-3003), another 13-week study (n=349) comparing three fixed doses of PP1M (78 mg/4 weeks, 156 mg/4 weeks, and 234 mg/4 weeks) to placebo, only 156 mg/4 weeks of PP1M was superior to placebo in improving the PANSS total score. In Study 3 (PSY-3004), a third 13-week study (n=513) comparing three fixed doses of PP1M (39 mg/4 weeks, 78 mg/4 weeks, and 156 mg/4 weeks) to placebo, all three doses of PP1M were superior to placebo in improving the PANSS total score. In Study 4 (SCH-201), the 9-week study (n=197) comparing two fixed doses of PP1M (78 mg/4 weeks and 156 mg/4 weeks) to placebo, both doses of PP1M were superior to placebo in improving PANSS total score. A summary of the mean baseline PANSS scores along with the mean changes from baseline in the four short-term acute schizophrenia studies are provided in Table 13. Table 13: Schizophrenia Short-term Studies Study Number Treatment Group Primary Efficacy Measure: PANSS Total Score Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline. SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. Study 1 Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (39 mg/4 weeks) p<0. 05 (Doses statistically significantly superior to placebo). 10) Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (156 mg/4 weeks) 86. 78) Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (234 mg/4 weeks) 88. 85) Placebo 86. 69) -- Study 2 Because an insufficient number of subjects received the 234 mg/4 weeks dose, results from this group are not included. Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (78 mg/4 weeks) 89. 77) Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (156 mg/4 weeks) 90. 68) Placebo 92. 15) -- Study 3 Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (39 mg/4 weeks) 90. 73) Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (78 mg/4 weeks) 91. 07) Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (156 mg/4 weeks) 90. 43) Placebo 90. 21) -- Study 4 Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (78 mg/4 weeks) 88. 57) Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (156 mg/4 weeks) 85. 58) Placebo 87. 45) -- Maintenance Monotherapy Treatment (Study 5: PSY-3001) The efficacy of another PP1M in maintaining symptomatic control in schizophrenia was established in a longer-term double-blind, placebo-controlled, flexible-dose study involving adult subjects who met DSM-IV criteria for schizophrenia. This study included a minimum 12-week, fixed-dose stabilization phase, and a randomized, placebo-controlled phase to observe for relapse. During the double-blind phase, patients were randomized to either the same dose of PP1M they received during the stabilization phase, i. , 39 mg, 78 mg, or 156 mg administered every 4 weeks, or to placebo. A total of 410 stabilized patients were randomized to either PP1M or to placebo until they experienced a relapse of schizophrenia symptoms. Relapse was pre-defined as time to first emergence of one or more of the following: psychiatric hospitalization, >= 25% increase (if the baseline score was > 40) or a 10-point increase (if the baseline score was <= 40) in total PANSS score on two consecutive assessments, deliberate self-injury, violent behavior, suicidal/homicidal ideation, or a score of >= 5 (if the maximum baseline score was <= 3) or >= 6 (if the maximum baseline score was 4) on two consecutive assessments of the specific PANSS items. The primary efficacy variable was time to relapse. A pre-planned interim analysis showed a statistically significantly longer time to relapse in patients treated with PP1M compared to placebo, and the study was stopped early because maintenance of efficacy was demonstrated. Thirty-four percent (34%) of subjects in the placebo group and 10% of subjects in the PP1M group experienced a relapse event. There was a statistically significant difference between the treatment groups in favor of PP1M. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 3. The time to relapse for subjects in the placebo group was statistically significantly shorter than for the PP1M group. An examination of population subgroups did not reveal any clinically significant differences in responsiveness on the basis of gender, age, or race. Figure 3: Kaplan-Meier Plot of Cumulative Proportion of Subjects with Relapse Over Time (Schizophrenia Study 5) * median time to relapse for placebo group is 163 days Figure 3 Long-Term Comparative Monotherapy Treatment versus Oral Antipsychotic Therapy (Study 6: SCH-3006) The efficacy of another PP1M in delaying time to treatment failure compared with selected oral antipsychotic medications was established in a long-term, randomized, flexible-dose study in subjects with schizophrenia and a history of incarceration. Subjects were screened for up to 14 days followed by a 15-month treatment phase during which they were observed for treatment failure. The primary endpoint was time to first treatment failure. Treatment failure was defined as one of the following: arrest and/or incarceration; psychiatric hospitalization; discontinuation of antipsychotic treatment because of safety or tolerability; treatment supplementation with another antipsychotic because of inadequate efficacy; need for increase in level of psychiatric services to prevent an imminent psychiatric hospitalization; discontinuation of antipsychotic treatment because of inadequate efficacy; or suicide. Treatment failure was determined by an Event Monitoring Board (EMB) that was blinded to treatment assignment. A total of 444 subjects were randomly assigned to either PP1M (N = 226; median dose 156 mg) or one of up to seven pre-specified, flexibly-dosed, commonly prescribed oral antipsychotic medications (N = 218; aripiprazole, haloperidol, olanzapine, paliperidone, perphenazine, quetiapine, or risperidone). The selection of the oral antipsychotic medication was determined to be appropriate for the patient by the investigator. A statistically significantly longer time to first treatment failure was seen for PP1M compared with oral antipsychotic medications. The median time to treatment failure was 416 days and 226 days for PP1M and antipsychotic medications, respectively. A Kaplan-Meier plot of time to first treatment failure is shown in Figure 4. The frequencies of first treatment failure events by type are shown in Table 14. The time to first arrest and/or incarceration or psychiatric hospitalization was also statistically significantly longer for the PP1M group compared to the oral antipsychotic group. Figure 4: Kaplan-Meier Plot of Time to First Treatment Failure in a Long-Term, Randomized, Flexible-Dose Study in Subjects with Schizophrenia and a History of Incarceration (Schizophrenia Study 6) * Median time to first treatment failure: 416 days with once-a-month paliperidone palmitate extended-release injectable suspension; 226 days with oral antipsychotics Table 14: Components of Composite Endpoint in a Long-Term, Randomized, Flexible-Dose Study in Subjects with Schizophrenia and a History of Incarceration (Schizophrenia Study 6) Event Type Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension Oral Antipsychotics Hazard Ratio Hazard ratio of once-a-month paliperidone palmitate extended-release injectable suspension to Oral Antipsychotics based on Cox regression model for time-to-event analysis. Note that the hazard ratio did not appear constant throughout the trial. First Treatment Failures 90 (39. 8%) 117 (53. 70 First Treatment Failure Component Events Arrest and/or incarceration 48 (21. 4%) Psychiatric hospitalization 18 (8. 9%) Discontinuation of antipsychotic treatment because of safety or tolerability 15 (6. 7%) Treatment supplementation with another antipsychotic because of inadequate efficacy 5 (2. 8%) Need for increase in level of psychiatric services to prevent an imminent psychiatric hospitalization 3 (1. 8%) Discontinuation of antipsychotic treatment because of inadequate efficacy 1 (0. 1%) Suicide 0 0 Arrest and/or Incarceration or Psychiatric Hospitalization Events, regardless of whether they were first events Analysis results, which incorporated relevant events collected after discontinuation for those who discontinued, were consistent with the results from the pre-specified analysis of this secondary endpoint. 70 Figure 4 The efficacy of ERZOFRI for the treatment of schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants is based upon an adequate and well-controlled study of another PP1M. The results of the adequate and well-controlled study is presented below. Maintenance Treatment en dash Monotherapy and as Adjunct to Mood Stabilizer or Antidepressant (SAff Study 1: SCA-3004) The efficacy of PP1M in maintaining symptom control in schizoaffective disorder was established in a long-term double-blind, placebo-controlled, flexible-dose randomized-withdrawal study designed to delay relapse in adult subjects who met DSM-IV criteria for schizoaffective disorder, as confirmed by the Structured Clinical Interview for DSM-IV Disorders. The population included subjects with schizoaffective bipolar and depressive types. Subjects received PP1M either as monotherapy or as an adjunct to stable doses of antidepressant or mood stabilizers. This study included a 13-week, open-label, flexible-dose (PP1M 78 mg, 117 mg, 156 mg, or 234 mg) lead-in period which enrolled a total of 667 subjects who had 1) acute exacerbation of psychotic symptoms; 2) score >=4 on >=3 PANSS items of delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, tension, and poor impulse control; and 3) prominent mood symptoms >=16 on the Young Mania Rating Scale (YMRS) and/or the Hamilton Rating Scale for Depression, 21-item version (HAM-D-21). Subjects were 19 to 66 years old (mean 39. 5 years) and 53. 5% were male. The mean scores at open-label enrollment of PANSS total was 85. 8 (range 42 to 128), HAM-D- 21 was 20. 4 (range 3 to 43), YMRS was 18. 6 (range 0 to 50), and CGI-S-SCA was 4. 4 (range 2 to 6). After the 13-week open-label flexible-dose PP1M treatment, 432 subjects met stabilization criteria (PANSS total score <=70, YMRS <=12, and HAM-D-21 <=12) and continued into the 12-week open-label fixed-dose stabilization period. A total of 334 subjects who met stabilization criteria for 12 consecutive weeks were randomized (1:1) to continue the same dose of PP1M or to placebo in the 15-month, double- blind, maintenance period. For the 164 subjects who were randomized to PP1M, dose distribution was 78 mg (4. 9%), 117 mg (9. 8%), 156 mg (47. 0%), and 234 mg (38. Relapse was defined as the first occurrence of one or more of the following: 1) psychiatric hospitalization; 2) intervention employed to avert hospitalization; 3) clinically significant self-injury, suicidal or homicidal ideation or violent behavior; 4) a score of >=6 (if the score was <=4 at randomization) of any of the individual PANSS items: delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, or poor impulse control; 5) on two consecutive assessments within 7 days: >= 25% increase (if the score at randomization was > 45) or >= 10-point increase (if the score at randomization was <= 45) in total PANSS score; a score of >= 5 (if the score was <= 3 at randomization) of any of the individual PANSS items: delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, or poor impulse control; an increase of >= 2 points (if the score was 1 [not ill] to 3 [mildly ill] at randomization) or increase of >= 1 point (if the score was >= 4 [moderately ill or worse] at randomization) in CGI-S-SCA overall score. There was a statistically significant difference in time to relapse between the treatment groups in favor of PP1M. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 5. Figure 5: Kaplan-Meier Plot of Cumulative Proportion of Subjects with Relapse Over Time (SAff Study 1) Table 15 summarizes the number of subjects with relapse in the overall population, by subgroup (monotherapy versus adjunctive therapy), and by symptom type at the first occurrence of relapse. Table 15: Summary of Relapse Rates (SAff Study 1). Number (Percent) of Subjects Who Relapsed Placebo Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension N=170 N=164 All Subjects 57 (33. 2%) Monotherapy subset N=73 N=78 Adjunct to Antidepressants or Mood Stabilizer subset N=97 N=86 Psychotic Symptoms 8 subjects experienced a relapse without psychotic symptoms. 8%) Mood Symptoms 16 subjects experienced a relapse without any mood symptoms. Any Mood Symptoms 48 (28. 0%) Manic 16 (9. 0%) Depressive 23 (13. 9%) Mixed 9 (5. 0%) Figure 5.

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