Invega Drug Information

(paliperidone palmitate) is indicated for the treatment of: Schizophrenia in adults. Schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants. INVEGA SUSTENNA is an atypical antipsychotic indicated for Treatment of schizophrenia in adults.

Treatment of schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Patient Exposure The data described in this section are derived from a clinical trial database consisting of a total of 3817 subjects (approximately 1705 patient-years exposure) with schizophrenia who received at least one dose of INVEGA SUSTENNA in the recommended dose range of 39 mg to 234 mg and a total of 510 subjects with schizophrenia who received placebo. Among the 3817 INVEGA SUSTENNA-treated subjects, 1293 received INVEGA SUSTENNA in four fixed-dose, double-blind, placebo-controlled trials (one 9-week and three 13-week studies), 849 received INVEGA SUSTENNA 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 INVEGA SUSTENNA during the double-blind placebo-controlled phase of this study ), and 1675 received INVEGA SUSTENNA in five non-placebo controlled trials (three noninferiority active-comparator trials, one long-term open-label pharmacokinetic and safety study, and an injection site cross-over trial). One of the 13-week studies included a 234 mg INVEGA SUSTENNA initiation dose followed by treatment with either 39 mg, 156 mg, or 234 mg every 4 weeks.

The safety of INVEGA SUSTENNA was also evaluated in a 15-month, long-term study comparing INVEGA SUSTENNA to selected oral antipsychotic therapies in adult subjects with schizophrenia. A total of 226 subjects received INVEGA SUSTENNA during the 15-month, open-label period of this study; 218 subjects received selected oral antipsychotic therapies. The safety of INVEGA SUSTENNA was similar to that seen in previous double-blind, placebo-controlled clinical trials in adult subjects with schizophrenia.

The safety of INVEGA SUSTENNA was also evaluated in a long-term study in adult subjects with schizoaffective disorder. A total of 667 subjects received INVEGA SUSTENNA during the initial 25-week open-label period of this study (median exposure 147 days); 164 subjects continued to receive INVEGA SUSTENNA during the 15-month double-blind placebo-controlled period of this study (median exposure 446 days). Adverse reactions that occurred more frequently in the INVEGA SUSTENNA 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 INVEGA SUSTENNA 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 INVEGA SUSTENNA- 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 INVEGA SUSTENNA- 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 INVEGA SUSTENNA, only akathisia increased with dose. Hyperprolactinemia also exhibited a dose relationship, but did not occur at ≥ 2% incidence in INVEGA SUSTENNA-treated subjects from the four fixed-dose studies. Adverse Reactions Occurring at an Incidence of 2% or More in INVEGA SUSTENNA-Treated Patients: Table 10 lists the adverse reactions reported in 2% or more of INVEGA SUSTENNA-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 10: Incidences of Adverse Reactions 2% or More of INVEGA SUSTENNA-Treated Patients (and Greater than Placebo) with Schizophrenia in Four Fixed-Dose, Double-Blind, Placebo-Controlled Trials INVEGA SUSTENNA 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. 234/156 mg 234/234 mg Adverse Reactions (N=510) (N=130) (N=302) (N=312) (N=160) (N=165) (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 INVEGA SUSTENNA 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 INVEGA SUSTENNA 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 INVEGA SUSTENNA 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: the Simpson-Angus global score which broadly evaluates parkinsonism, the Barnes Akathisia Rating Scale global clinical rating score which evaluates akathisia, the Abnormal Involuntary Movement Scale scores which evaluates dyskinesia, and use of anticholinergic medications to treat EPS (Table 11), and incidence of spontaneous reports of EPS (Table 12). Table 11: Extrapyramidal Symptoms (EPS) Assessed by Incidence of Rating Scales and Use of Anticholinergic Medication – Schizophrenia Studies in Adults Percentage of Subjects INVEGA SUSTENNA Scale Placebo (N=262) 39 mg (N=130) 78 mg (N=223) 156 mg (N=228) Parkinsonism For parkinsonism, percent of subjects with Simpson-Angus Total score > 0.3 at endpoint (Total score defined as total sum of items score divided by the number of items) 9 12 10 6 Akathisia For Akathisia, percent of subjects with Barnes Akathisia Rating Scale global score ≥ 2 at endpoint 5 5 6 5 Dyskinesia For Dyskinesia, percent of subjects with a score ≥ 3 on any of the first 7 items or a score ≥ 2 on two or more of any of the first 7 items of the Abnormal Involuntary Movement Scale at endpoint 3 4 6 4 Use of Anticholinergic Medications Percent of subjects who received anticholinergic medications to treat EPS 12 10 12 11 Table 12: Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term – Schizophrenia Studies in Adults Percentage of Subjects INVEGA SUSTENNA EPS Group Placebo (N=262) 39 mg (N=130) 78 mg (N=223) 156 mg (N=228) Parkinsonism group includes: Extrapyramidal disorder, hypertonia, musculoskeletal stiffness, parkinsonism, drooling, masked facies, muscle tightness, hypokinesia Hyperkinesia group includes: Akathisia, restless legs syndrome, restlessness Dyskinesia group includes: Dyskinesia, choreoathetosis, muscle twitching, myoclonus, tardive dyskinesia Dystonia group includes: Dystonia, muscle spasms Overall percentage of subjects with EPS-related adverse events 10 12 11 11 Parkinsonism 5 6 6 4 Hyperkinesia 2 2 2 4 Tremor 3 2 2 3 Dyskinesia 1 2 3 1 Dystonia 0 1 1 2 The results across all phases of the maintenance trial in subjects with schizophrenia exhibited comparable findings. In the 9-week, fixed-dose, double-blind, placebo-controlled trial, the proportions of parkinsonism and akathisia assessed by incidence of rating scales were higher in the INVEGA SUSTENNA 156 mg group (18% and 11%, respectively) than in the INVEGA SUSTENNA 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 INVEGA SUSTENNA 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 INVEGA SUSTENNA 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 INVEGA SUSTENNA 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 (INVEGA SUSTENNA versus placebo) were hyperkinesia (3.7% vs. 2.9%), parkinsonism (3.0% vs. 1.8%), and tremor (1.2% vs. 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 Local Injection Site Reactions In the pooled data from the two 13-week, fixed-dose, double-blind, placebo-controlled trials 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 INVEGA SUSTENNA and placebo groups.

Investigator ratings of injection pain were similar for the placebo and INVEGA SUSTENNA 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 INVEGA SUSTENNA and placebo groups. At Day 92, investigators rated absence of redness, swelling, induration, and pain in 95–100% of subjects in both the INVEGA SUSTENNA and placebo groups.

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

Postmarketing Experience

The following adverse reactions have been identified during postapproval 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 INVEGA SUSTENNA 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 sections of the package inserts for those products.

Drugs Having Clinically Important Interactions with

INVEGA SUSTENNA Because paliperidone palmitate is hydrolyzed to paliperidone , results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential. Table 13. Clinically Important Drug Interactions with INVEGA SUSTENNA Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Centrally Acting Drugs and Alcohol Given the primary CNS effects of paliperidone, concomitant use of centrally acting drugs and alcohol may modulate the CNS effects of INVEGA SUSTENNA. INVEGA SUSTENNA should be used with caution in combination with other centrally acting drugs and alcohol . Drugs with Potential for Inducing Orthostatic Hypotension Because INVEGA SUSTENNA has the potential for inducing orthostatic hypotension, an additive effect may occur when INVEGA SUSTENNA is administered with other therapeutic agents that have this potential . Monitor orthostatic vital signs in patients who are vulnerable to hypotension . Strong Inducers of CYP3A4 and P-gp (e.g., carbamazepine, rifampin, or St. John's Wort) The concomitant use of paliperidone and strong inducers of CYP3A4 and P-gp may decrease the exposure of paliperidone . Avoid using CYP3A4 and/or P-gp inducers with INVEGA SUSTENNA during the 1-month dosing interval, if possible.

If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets . Levodopa and Other Dopamine Agonists Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Monitor and manage patient as clinically appropriate.

Drugs Having No Clinically Important Interactions with

INVEGA SUSTENNA Clinically meaningful pharmacokinetic interaction between INVEGA SUSTENNA and valproate (including valproic acid and divalproex sodium) is not expected. Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of INVEGA SUSTENNA is required when administered with valproate. Additionally, no dosage adjustment is necessary for valproate when co-administered with INVEGA SUSTENNA. Pharmacokinetic interaction between lithium and INVEGA SUSTENNA 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.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including INVEGA SUSTENNA, during pregnancy. Healthcare providers are encouraged to register patients 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 INVEGA SUSTENNA, during pregnancy (see Clinical Considerations ). Paliperidone has been detected in plasma in adult subjects up to 126 days after a single-dose administration of INVEGA SUSTENNA , and the clinical significance of INVEGA SUSTENNA 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 2–4% and 15–20%, 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 based on mg/m 2 body surface area.

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 body surface area. 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 INVEGA SUSTENNA, 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 9258 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 1566 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 based on mg/m 2 body surface area. 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 mg/m 2 body surface area. 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 mg/m 2 body surface area; 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/day risperidone based on mg/m 2 body surface area. When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/m 2 body surface area, 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 was delayed.

In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on mg/m 2 body surface area; 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 package insert).

Pediatric Use Safety and effectiveness of INVEGA SUSTENNA in patients < 18 years of age have not been established. Juvenile Animal Studies 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 12 mg/day. 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 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 INVEGA SUSTENNA on growth and sexual maturation have not been fully evaluated in children and adolescents.

is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the INVEGA SUSTENNA formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone palmitate is converted to paliperidone, which is a metabolite of risperidone.

Known hypersensitivity to paliperidone, risperidone, or to any excipients in INVEGA SUSTENNA.

Human Experience No cases of overdose were reported in premarketing studies with

INVEGA SUSTENNA. Because INVEGA SUSTENNA is to be administered by healthcare professionals, the potential for overdosage by patients is low. 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.e., 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.

Overdose experience reported with risperidone can be found in the OVERDOSAGE section of the risperidone package insert.

Management of Overdosage Contact a Certified Poison Control Center for the most

up to date information on the management of INVEGA SUSTENNA overdosage (1-800-222-1222 or www.poison.org). 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.

There is no specific antidote to paliperidone. Consider the prolonged-release characteristics of INVEGA SUSTENNA and the long apparent half-life of paliperidone when assessing treatment needs and recovery.