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.

Switching from Oral Antipsychotics

Previous oral antipsychotics can be gradually discontinued at the time of initiation of treatment with ERZOFRI. The recommended initial dosage of ERZOFRI is 351 mg on treatment Day 1, administered in the deltoid muscle [see Dosage and Administration (2.1)]. See Table 3 for subsequent monthly dosage recommendations for ERZOFRI in patients switching from oral extended-release paliperidone tablets.

Switching from Long-Acting Injectable Antipsychotics

When switching patients currently at steady-state on a long-acting injectable antipsychotic, initiate ERZOFRI therapy in place of the next scheduled injection.

Continue ERZOFRI at monthly intervals. The initial dosing regimen as described in Section 2.1 is not required. See Table 1 for recommended monthly dosing. Based on previous clinical response and tolerability, some patients may benefit from lower or higher doses within the available strengths (39 mg, 78 mg, 117 mg, 156 mg, and 234 mg).

If ERZOFRI is discontinued, its pharmacokinetic characteristics must be considered. As recommended with other antipsychotic medications, the need for continuing existing extrapyramidal symptoms (EPS) medication should be re-evaluated periodically.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials. Hyperglycemia and diabetes have been reported in trial subjects treated with another once-a-month paliperidone palmitate extended-release injectable suspension (also referred to as "PP1M" in this section). Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Pooled data from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies of another PP1M in subjects with schizophrenia are presented in Table 4.

In a long-term open-label pharmacokinetic and safety study in subjects with schizophrenia in which the highest maintenance dose available (234 mg) was evaluated, another PP1M was associated with a mean change in glucose of -0.4 mg/dL at Week 29 (n=109) and +6.8 mg/dL at Week 53 (n=100).

During the initial 25-week open-label period of a long-term study in subjects with schizoaffective disorder, another PP1M was associated with mean change in glucose of +5.3 mg/dL (n=518). At the endpoint of the subsequent 15-month double-blind period of the study, the PP1M was associated with a mean change in glucose of +0.3 mg/dL (n=131) compared with a mean change of +4.0 mg/dL in the placebo group (n=120).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies of another PP1M in subjects with schizophrenia are presented in Table 5.

In a long-term open-label pharmacokinetic and safety study in subjects with schizophrenia in which the highest maintenance dose available (234 mg) was evaluated, the mean changes from baseline in lipid values are presented in Table 6.

The mean changes from baseline in lipid values during the initial 25-week open-label period and at the endpoint of the subsequent 15-month double-blind period in a long-term study of another PP1M in subjects with schizoaffective disorder are presented in Table 7.

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies of anotherPP1M in subjects with schizophrenia are presented in Table 8.

In a long-term open-label pharmacokinetic and safety study in which the highest maintenance dose available (234 mg) was evaluated, another PP1Mwas associated with a mean change in weight of +2.4 kg at Week 29 (n=134) and +4.3 kg at Week 53 (n=113).

During the initial 25-week open-label period of a long-term study in subjects with schizoaffective disorder, another PP1M was associated with a mean change in weight of +2.2 kg and 18.4% of subjects had an increase in body weight of ≥ 7% (n=653). At the endpoint of the subsequent 15-month double-blind period of the study, the PP1M was associated with a mean change in weight of -0.2 kg and 13.0% of subjects had an increase in body weight of ≥ 7% (n=161); the placebo group had a mean change in weight of -0.8 kg and 6.0% of subjects had an increase in body weight of ≥ 7% (n=168).

Schizophrenia

In a long-term maintenance trial of another once-a-month paliperidone palmitate extended-release injectable suspension (PP1M) in schizophrenia patients (Study 5) [see Clinical Studies (14.1)], elevations of prolactin to above the reference range (> 18 ng/mL in males and > 30 ng/mL in females) relative to open-label baseline at any time during the double- blind phase were noted in a higher percentage of the patients in the PP1M group than those in the placebo group in males (51.9% versus 29.0%) and in females (50.5% versus 42.9%). During the double-blind phase, 4 females (4.2%) in the PP1M group experienced potentially prolactin-related adverse reactions (amenorrhea N=2; galactorrhea N=1; menstruation irregular N=1), while 2 females (2.2%) in the placebo group experienced potentially prolactin-related adverse reactions (amenorrhea N=1; breast pain N=1). One male (0.9%) in the PP1M group experienced erectile dysfunction and 1 male (0.9%) in placebo group experienced gynecomastia.

Prior to the double-blind phase (during the 33-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline were 14.9 (22.3) ng/mL in males (N=490) and 35.2 (39.6) ng/mL in females (N=358). At the end of the open-label phase, mean (SD) prolactin values were 24.7 (22.5) ng/mL in males (N=470) and 59.5 (38.1) ng/mL in females (N=333). During the open-label phases 49.2% of females and 47.7% of males experienced elevations of prolactin above the reference range relative to baseline, and a higher proportion of females experienced potentially prolactin-related adverse reactions compared to males (5.3% versus 1.8%). Amenorrhea (2.5%) in females and no single potentially prolactin-related adverse reaction in males were observed with a rate greater than 2%.

Schizoaffective Disorder

In a long-term maintenance trial of another PP1M in patients with schizoaffective disorder (Study SCA-3004) see Clinical Studies (14.2), elevations of prolactin to above the reference range (> 13.13 ng/mL in males and > 26.72 ng/mL in females) relative to open-label baseline at any time during the 15-month double-blind phase were noted in a higher percentage of patients in the PP1M group than those in the placebo group in males (55.6% versus 23.2%) and in females (44.3% versus 25.0%). During the 15-month double-blind phase, 11 females (13.9%) in the PP1M group had 14 potentially prolactin-related adverse reactions (hyperprolactinemia N=3; blood prolactin increased N=4; libido decreased N=1; amenorrhea N=3; galactorrhea N=3), while 5 females (5.8%) in the placebo group had 6 potentially prolactin-related adverse reactions (hyperprolactinemia N=2; blood prolactin increased N=1; amenorrhea N=2; galactorrhea N=1). Six males (7.1%) in the PP1M group experienced 6 potentially prolactin-related adverse reactions (hyperprolactinemia N=4; libido decreased N=1; erectile dysfunction N=1), while 1 male (1.2%) in the placebo group experienced adverse reaction of blood prolactin increased.

Prior to the 15-month double-blind phase (during the 25-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline were 14.6 (14.0) ng/mL in males (N=352) and 39.1 (44.6) ng/mL in females (N=302). At the end of the open-label phase, mean (SD) prolactin values were 32.8 (17.2) ng/mL in males (N=275) and 72.4 (46.5) ng/mL in females (N=239). During the open-label phase, 48.9% of females and 53.3% of males experienced elevations of prolactin above the reference range relative to baseline, and a higher proportion of females experienced potentially prolactin-related adverse reactions compared to males (10.0% versus 9.0%). Amenorrhea (5.8%) and galactorrhea (2.9%) in females and libido decrease (2.8%) and erectile dysfunction (2.5%) in males were observed with a rate greater than 2%.

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

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension

The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, or 4) which were not considered to have significant clinical implications.

Cardiac disorders: atrioventricular block first degree, bradycardia, bundle branch block, palpitations, postural orthostatic tachycardia syndrome, tachycardia

Ear and labyrinth disorders: vertigo

Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurred

Gastrointestinal disorders: constipation, dyspepsia, flatulence, salivary hypersecretion

Immune system disorders: hypersensitivity

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, electrocardiogram abnormal

Metabolism and nutrition disorders: decreased appetite, hyperinsulinemia, increased appetite

Musculoskeletal and connective tissue disorders: arthralgia, joint stiffness, muscle rigidity, muscle spasms, muscle tightness, muscle twitching, nuchal rigidity

Nervous system disorders: bradykinesia, cerebrovascular accident, cogwheel rigidity, convulsion, dizziness postural, drooling, dysarthria, dyskinesia, dystonia, hypertonia, lethargy, oromandibular dystonia, parkinsonism, psychomotor hyperactivity, syncope

Psychiatric disorders: insomnia, libido decreased, restlessness

Reproductive system and breast disorders: amenorrhea, breast discharge, breast enlargement/breast swelling, breast tenderness/breast pain, ejaculation disorder, erectile dysfunction, galactorrhea, gynecomastia, menstrual disorder, menstruation delayed, menstruation irregular, sexual dysfunction

Respiratory, thoracic and mediastinal disorders: nasal congestion

Skin and subcutaneous tissue disorders: drug eruption, pruritus, pruritus generalized, rash, urticaria

Demographic Differences

An examination of population subgroups in the double-blind placebo-controlled trials did not reveal any evidence of differences in safety on the basis of age, gender, or race alone; however, there were few subjects 65 years of age and older.

Extrapyramidal Symptoms (EPS)

Pooled data from the two double-blind, placebo-controlled, 13-week, fixed-dose trials in adult subjects with schizophrenia provided information regarding EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score which broadly evaluates parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score which evaluates akathisia, (3) the Abnormal Involuntary Movement Scale scores which evaluates dyskinesia, and (4) use of anticholinergic medications to treat EPS (Table 10), and (5) incidence of spontaneous reports of EPS (Table 11).

The results across all phases of the maintenance trial in subjects with schizophrenia exhibited comparable findings. In the 9-week, fixed-dose, double-blind, placebo-controlled trial, the proportions of parkinsonism and akathisia assessed by incidence of rating scales were higher in the PP1M 156 mg group (18% and 11%, respectively) than in the PP1M 78 mg group (9% and 5%, respectively) and placebo group (7% and 4%, respectively).

In the 13-week study in subjects with schizophrenia involving 234 mg initiation dosing, the incidence of any EPS was similar to that of the placebo group (8%), but exhibited a dose-related pattern with 6%, 10%, and 11% in the PP1M 234/39 mg, 234/156 mg, and 234/234 mg groups, respectively. Hyperkinesia was the most frequent category of EPS-related adverse events in this study, and was reported at a similar rate between the placebo (4.9%) and PP1M 234/156 mg (4.8%) and 234/234 mg (5.5%) groups, but at a lower rate in the 234/39 mg group (1.3%).

In the long-term study in subjects with schizoaffective disorder, EPS reported during the 25-week open-label PP1M treatment included hyperkinesia (12.3%), parkinsonism (8.7%), tremor (3.4%), dyskinesia (2.5%), and dystonia (2.1%). During the 15-month double-blind treatment, the incidence of any EPS was similar to that of the placebo group (8.5% and 7.1% respectively). The most commonly reported treatment-emergent EPS-related adverse events (> 2%) in any treatment group in the double-blind phase of the study (PP1M versus placebo) were hyperkinesia (3.7% versus 2.9%), parkinsonism (3.0% versus 1.8%), and tremor (1.2% versus 2.4%).

Dystonia

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Pain Assessment and Injection Site Reactions

In the pooled data from the two 13-week, fixed-dose, double-blind, placebo-controlled trials of another PP1M in subjects with schizophrenia, the mean intensity of injection pain reported by subjects using a visual analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from the first to the last injection (placebo: 10.9 to 9.8; 39 mg: 10.3 to 7.7; 78 mg: 10.0 to 9.2; 156 mg: 11.1 to 8.8). The results from both the 9-week, fixed-dose, double-blind, placebo-controlled trial and the double-blind phase of the maintenance trial exhibited comparable findings.

In the 13-week study involving 234 mg initiation dosing in subjects with schizophrenia, occurrences of induration, redness, or swelling, as assessed by blinded study personnel, were infrequent, generally mild, decreased over time, and similar in incidence between the PP1M and placebo groups. Investigator ratings of injection pain were similar for the placebo and PP1M groups. Investigator evaluations of the injection site after the first injection for redness, swelling, induration, and pain were rated as absent for 69-100% of subjects in both the PP1M and placebo groups. At Day 92, investigators rated absence of redness, swelling, induration, and pain in 95-100% of subjects in both the PP1M and placebo groups.

ERZOFRI was evaluated in 281 patients with schizophrenia or schizoaffective disorder in an open-label randomized parallel arm study. The percentage of patients in the open-label study reporting injection site-related adverse reactions at the first injection for patients treated with ERZOFRI (all reported as injection site pain) was similar to the percentage of patients treated with another PP1M.

Additional Adverse Reactions Reported in Clinical Trials with Oral Paliperidone

The following is a list of additional adverse reactions that have been reported in clinical trials with oral paliperidone:

Cardiac disorders: bundle branch block left, sinus arrhythmia

Gastrointestinal disorders: abdominal pain, small intestinal obstruction

General disorders and administration site conditions: edema, edema peripheral

Immune system disorders: anaphylactic reaction

Infections and infestations: rhinitis

Musculoskeletal and connective tissue disorders: musculoskeletal pain, torticollis, trismus

Nervous system disorders: grand mal convulsion, parkinsonian gait, transient ischemic attack

Psychiatric disorders: sleep disorder

Reproductive system and breast disorders: breast engorgement

Respiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, pneumonia aspiration

Skin and subcutaneous tissue disorders: rash papular

Vascular disorders: hypotension, ischemia

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/m2 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/m2 BSA. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone (see Animal data).

Clinical Considerations

Data

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). 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 on the breastfed infant is not known. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ERZOFRI and any potential adverse effects on the breastfed child from ERZOFRI or from the mother's underlying condition.

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

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 0.31, 1.25, 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.

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 Tmax of 16 to 28 days. The release of the drug starts as early as day 1 and lasts for as long as 176 days.

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 Cmax, trough plasma concentrations (Ctrough) and average plasma concentrations (Cavg) were 43.7 ng/mL, 28.5 ng/mL and 30.3 ng/mL, respectively, during the initial regimen period; at steady state, Cmax-ss, Ctrough,ss and AUCtau-ss were 42.6 ng/mL, 28.3 ng/mL and 909 ng*hr/mL, respectively.

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 Cmax, Ctrough and Cavg were 58.7 ng/mL, 30.1 ng/mL and 37.8 ng/mL, respectively, during the initial regimen period; at steady state, Cmax-ss, Ctrough,ss and AUCtau-ss of another once-a-month paliperidone palmitate extended-release injectable suspension for paliperidone were 43.8 ng/mL, 30.4 ng/mL and 953 ng*hr/mL, respectively.

Following intramuscular injection of a single dose of ERZOFRI 156 mg in the deltoid muscle, the geometric mean Cmax was approximately 43% higher compared with injections of 156 mg in the gluteal muscle. Following intramuscular injection of a single dose of ERZOFRI 351 mg in the deltoid muscle, the geometric mean Cmax was approximately 21% higher compared with injections of 351 mg in the gluteal muscle. Over the dose range of 39 mg to 234 mg, the AUCinf after a single dose injection in the deltoid muscle was comparable to the AUCinf after a single dose injection in the gluteal muscle.

Following intramuscular injection of single doses (39 mg to 234 mg) of another PP1M in the deltoid muscle, on average, a 28% higher Cmax was observed compared with injection in the gluteal muscle. The mean steady-state peak:trough ratio for PP1M dose of 156 mg was 1.8 following gluteal administration and 2.2 following deltoid administration.

Following administration of paliperidone palmitate, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6 to 1.8.

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

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 Cmax and AUC values at steady-state was observed (see Figure 1). Higher doses of paroxetine have not been studied. The clinical relevance is unknown. After oral administration, a decrease in mean Cmax and AUC values at steady state is expected when patients are treated with carbamazepine, a strong inducer of both CYP3A4 and P-gp [see Drug Interactions (7.1)]. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone.

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 Cmax and AUC of paliperidone.

After oral administration of paliperidone, the steady-state Cmax and AUC of divalproex sodium extended-release tablets were not affected in 13 patients stabilized on divalproex sodium extended- release tablets. In a clinical study, subjects on stable doses of divalproex sodium extended-release tablets had comparable valproate average plasma concentrations when oral paliperidone extended- release tablets 3-15 mg/day was added to their existing divalproex sodium extended-release tablets treatment [see Drug Interactions (7.2)].

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; they contribute to only a small fraction of total body clearance. In vitro studies demonstrated that paliperidone is a substrate of P-glycoprotein (P-gp) [see Drug Interactions (7.2)].

In vitro studies in human liver microsomes demonstrated that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.

Paliperidone is a weak inhibitor of P-gp at high concentrations. No in vivo data are available, and the clinical relevance is unknown.

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) and 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 Cmax and AUC increased 1.2-fold compared to young subjects. However, there may be age-related decreases in creatinine clearance [see Dosage and Administration (2.4) and Use in Specific Populations (8.5)].

Figure 2 Effects of Intrinsic Factors on Paliperidone Pharmacokinetics

Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone.

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 Cmax was observed in overweight and obese subjects. At apparent steady-state PP1M, the trough concentrations were similar among normal, overweight, and obese subjects.

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 0.63, 2.5, 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 D2 antagonism and hyperprolactinemia. The relevance of these tumor findings in rodents to human risk is unclear [see Warnings and Precautions (5.7)].

Mutagenesis

Paliperidone palmitate was not genotoxic in the in vitro Ames bacterial reverse mutation test or the mouse lymphoma assay. Paliperidone was not genotoxic in the in vitro Ames bacterial reverse mutation test, the mouse lymphoma assay, or the in vivo rat bone marrow micronucleus test.

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.

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.e., 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.

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.e., 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)

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

Maintenance Treatment – 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 (38.4%). The primary efficacy variable was time to relapse. 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.