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Indications
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 )
Contraindications
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 )
Warnings and precautions
Cerebrovascular Adverse Reactions, in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities). ( 5.2 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of drug and close monitoring. ( 5.3 ) QT Prolongation: Avoid use with drugs that also increase QT interval and in patients with risk factors for prolonged QT interval.
( 5.4 ) Tardive Dyskinesia: Discontinue drug if clinically appropriate. ( 5.5 ) Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. ( 5.6 ) Orthostatic Hypotension and Syncope: Use with caution in patients with known cardiovascular or cerebrovascular disease and patients predisposed to hypotension. ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with history of clinically significant low white blood cell count (WBC) or history of leukopenia or neutropenia.
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Consider discontinuing ERZOFRI if clinically significant decline in WBC in the absence of other causative factors. ( 5.9 ) Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. ( 5.10 ) Potential for Cognitive and Motor Impairment: Use caution when operating machinery. ( 5.11 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold.
( 5.12 )
5.1Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.
Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.
ERZOFRI is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2) ] .
5.2Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis
In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. No studies have been conducted with oral paliperidone, 1-month or 3-month paliperidone palmitate extended-release injectable suspensions, or ERZOFRI, in elderly patients with dementia.
ERZOFRI is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1) ] .
a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
If NMS is suspected, immediately discontinue ERZOFRI and provide symptomatic treatment and monitoring.
5.4QT Prolongation
Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval.
Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of Torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.
The effects of oral paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter QT study in adults with schizophrenia and schizoaffective disorder, and in three placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia. In the QT study (n=141) of oral paliperidone, the 8 mg dose of immediate-release oral paliperidone (n=50) showed a mean placebo-subtracted increase from baseline in QTcLD (QT interval corrected for heart rate using the population specified linear derived method) of 12.3 msec (90% CI: 8.9; 15.6) on Day 8 at 1.5 hours post-dose.
The mean steady-state peak plasma concentration for this 8 mg oral dose of immediate release paliperidone (C max ss = 113 ng/mL) was more than 2-fold the exposure observed with the maximum recommended 234 mg maintenance dose of another once-a-month paliperidone extended-release injectable suspension administered in the deltoid muscle (predicted median C max-ss = 50 ng/mL). In this same study, a 4 mg dose of the immediate-release oral formulation of paliperidone, for which C max-ss = 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on Day 2 at 1.5 hours post-dose.
In the three fixed-dose efficacy studies of oral paliperidone extended release in subjects with schizophrenia, electrocardiogram (ECG) measurements taken at various time points showed only one subject in the oral paliperidone 12 mg group had a change exceeding 60 msec at one time- point on Day 6 (increase of 62 msec). In the four fixed-dose efficacy studies of another once-a-month paliperidone palmitate extended-release injectable suspension in subjects with schizophrenia and in the long-term study in subjects with schizoaffective disorder, no subject experienced a change in QTcLD exceeding 60 msec and no subject had a QTcLD value of > 500 msec at any time point.
In the maintenance study in subjects with schizophrenia, no subject had a QTcLD change > 60 msec, and one subject had a QTcLD value of 507 msec (Bazett's QT corrected interval [QTcB] value of 483 msec); this latter subject also had a heart rate of 45 beats per minute.
5.5Tardive Dyskinesia
Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase with the duration of treatment and the cumulative dose. The syndrome can develop after
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Interactions
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 )
7.1Drugs 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.
7.2Drugs 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) ]
Pregnancy and breastfeeding
8.1Pregnancy 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 ) .
Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not established a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ) . There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including ERZOFRI, during pregnancy (see Clinical Considerations ). Paliperidone has been detected in plasma in adult subjects up to 176 days after a single-dose administration of ERZOFRI [see Clinical Pharmacology (12.3) ] , and the clinical significance of ERZOFRI administered before pregnancy or anytime during pregnancy is not known.
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. In the U.S. 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 body surface area (BSA).
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 of paliperidone based on mg/m 2 BSA. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone ( 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 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88-1.81) 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 0.5 to 1.2 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 ® prescribing information).
Adverse reactions
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.
6.1Clinical 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 uppe
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