Risperdal Consta Drug Information

Schizophrenia

RISPERDAL CONSTA (risperidone) is indicated for the treatment of schizophrenia.

Bipolar Disorder

RISPERDAL CONSTA is indicated as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder .

Clinical Trials Experience Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials -

Schizophrenia Table 4 lists the adverse reactions reported in 2% or more of RISPERDAL CONSTA-treated patients with schizophrenia in one 12-week double-blind, placebo-controlled trial. Table 4. Adverse Reactions in ≥2% of RISPERDAL CONSTA-Treated Patients with Schizophrenia in a 12-Week Double-Blind, Placebo-Controlled Trial Percentage of Patients Reporting Event RISPERDAL CONSTA Placebo System/Organ Class 25 mg 50 mg Adverse Reaction (N=99) (N=103) (N=98) Eye disorders Vision blurred 2 3 0 Gastrointestinal disorders Constipation 5 7 1 Dry mouth 0 7 1 Dyspepsia 6 6 0 Nausea 3 4 5 Toothache 1 3 0 Salivary hypersecretion 4 1 0 General disorders and administration site conditions Fatigue Fatigue includes fatigue and asthenia. Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, muscle rigidity, and bradykinesia.

Akathisia includes akathisia and restlessness. Sedation includes sedation and somnolence. 3 9 0 Edema peripheral 2 3 1 Pain 4 1 0 Pyrexia 2 1 0 Infections and infestations Upper respiratory tract infection 2 0 1 Investigations Weight increased 5 4 2 Weight decreased 4 1 1 Musculoskeletal and connective tissue disorders Pain in extremity 6 2 1 Nervous system disorders Headache 15 21 12 Parkinsonism 8 15 9 Dizziness 7 11 6 Akathisia 4 11 6 Sedation 5 6 3 Tremor 0 3 0 Syncope 2 1 0 Hypoesthesia 2 0 0 Respiratory, thoracic and mediastinal disorders Cough 4 2 3 Sinus congestion 2 0 0 Skin and subcutaneous tissue disorders Acne 2 2 0 Dry skin 2 0 0 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Disorder Table 5 lists the treatment-emergent adverse reactions reported in 2% or more of RISPERDAL CONSTA-treated patients in the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of RISPERDAL CONSTA when administered as monotherapy for maintenance treatment in patients with Bipolar I Disorder. Table 5. Adverse Reactions in ≥2% of Patients with Bipolar I Disorder Treated with RISPERDAL CONSTA as Monotherapy in a 24-Month Double-Blind, Placebo-Controlled Trial Percentage of Patients Reporting Event System/Organ Class Adverse Reaction RISPERDAL CONSTA (N=154) Placebo (N=149) Investigations Weight increased 5 1 Nervous system disorders Dizziness 3 1 Vascular disorders Hypertension 3 1 Table 6 lists the treatment-emergent adverse reactions reported in 4% or more of patients in the 52-week double-blind, placebo-controlled treatment phase of a trial assessing the efficacy and safety of RISPERDAL CONSTA when administered as adjunctive maintenance treatment in patients with bipolar disorder.

Table 6. Adverse Reactions in ≥ 4% of Patients with Bipolar Disorder Treated with RISPERDAL CONSTA as Adjunctive Therapy in a 52-Week Double-Blind, Placebo-Controlled Trial Percentage of Patients Reporting Event System/Organ Class Adverse Reaction RISPERDAL CONSTA + Treatment as Usual Patients received double-blind RISPERDAL CONSTA or placebo in addition to continuing their treatment as usual, which included mood stabilizers, antidepressants, and/or anxiolytics. (N=72) Placebo + Treatment as Usual (N=67) General disorders and administration site conditions Gait abnormal 4 0 Infections and infestations Upper respiratory tract infection 6 3 Investigations Weight increased 7 1 Metabolism and nutrition disorders Decreased appetite 6 1 Increased appetite 4 0 Musculoskeletal and connective tissue disorders Arthralgia 4 3 Nervous system disorders Tremor 24 16 Parkinsonism Parkinsonism includes muscle rigidity, hypokinesia, cogwheel rigidity, and bradykinesia. Dyskinesia includes muscle twitching and dyskinesia. 15 6 Dyskinesia 6 3 Sedation Sedation includes sedation and somnolence. 7 1 Disturbance in attention 4 0 Reproductive system and breast disorders Amenorrhea 4 1 Respiratory, thoracic and mediastinal disorders Cough 4 1 Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone The following additional adverse reactions occurred in < 2% of the RISPERDAL CONSTA-treated patients in the above schizophrenia double-blind, placebo-controlled trial dataset, in < 2% of the RISPERDAL CONSTA-treated patients in the above double-blind, placebo-controlled period of the monotherapy bipolar disorder trial dataset, or in < 4% of the RISPERDAL CONSTA-treated patients in the above double-blind, placebo-controlled period of the adjunctive treatment bipolar disorder trial dataset. The following also includes additional adverse reactions reported at any frequency in RISPERDAL CONSTA-treated patients who participated in the open-label phases of the above bipolar disorder studies and in other studies, including double-blind, active controlled and open-label studies in schizophrenia and bipolar disorder.

Blood and lymphatic system disorders: anemia, neutropenia Cardiac disorders: tachycardia, atrioventricular block first degree, palpitations, sinus bradycardia, bundle branch block left, bradycardia, sinus tachycardia, bundle branch block right Ear and labyrinth disorders: ear pain, vertigo Endocrine disorders: hyperprolactinemia Eye disorders: conjunctivitis, visual acuity reduced Gastrointestinal disorders: diarrhea, vomiting, abdominal pain upper, abdominal pain, stomach discomfort, gastritis General disorders and administration site conditions: injection site pain, chest discomfort, chest pain, influenza like illness, sluggishness, malaise, induration, injection site induration, injection site swelling, injection site reaction, face edema Immune system disorders: hypersensitivity Infections and infestations: nasopharyngitis, influenza, bronchitis, urinary tract infection, rhinitis, respiratory tract infection, ear infection, pneumonia, lower respiratory tract infection, pharyngitis, sinusitis, viral infection, infection, localized infection, cystitis, gastroenteritis, subcutaneous abscess Injury and poisoning: fall, procedural pain Investigations: blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, gamma-glutamyl transferase increased, blood glucose increased, hepatic enzyme increased, aspartate aminotransferase increased, electrocardiogram QT prolonged, glucose urine present Metabolism and nutritional disorders: anorexia, hyperglycemia Musculoskeletal, connective tissue and bone disorders: posture abnormal, myalgia, back pain, buttock pain, muscular weakness, neck pain, musculoskeletal chest pain Nervous system disorders: coordination abnormal, dystonia, tardive dyskinesia, drooling, paresthesia, dizziness postural, convulsion, akinesia, hypokinesia, dysarthria Psychiatric disorders: insomnia, agitation, anxiety, sleep disorder, depression, initial insomnia, libido decreased, nervousness Renal and urinary disorders: urinary incontinence Reproductive system and breast disorders: galactorrhea, oligomenorrhea, erectile dysfunction, sexual dysfunction, ejaculation disorder, gynecomastia, breast discomfort, menstruation irregular, menstruation delayed, menstrual disorder, ejaculation delayed Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, dyspnea, rhinorrhea Skin and subcutaneous tissue disorders: rash, eczema, pruritus generalized, pruritus Vascular disorders: hypotension, orthostatic hypotension Additional Adverse Reactions Reported with Oral RISPERDAL The following is a list of additional adverse reactions that have been reported during the clinical trial evaluation of oral RISPERDAL, regardless of frequency of occurrence: Blood and Lymphatic Disorders: granulocytopenia Cardiac Disorders: atrioventricular block Ear and Labyrinth Disorders: tinnitus Eye Disorders: ocular hyperemia, eye discharge, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma Gastrointestinal Disorders: abdominal pain upper, dysphagia, fecaloma, abdominal discomfort, fecal incontinence, lip swelling, cheilitis, aptyalism General Disorders: thirst, feeling abnormal, gait disturbance, pitting edema, edema, chills, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness Immune System Disorders: drug hypersensitivity Infections and Infestations: tonsillitis, eye infection, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic Investigations: body temperature increased, heart rate increased, eosinophil count increased, white blood cell count decreased, hemoglobin decreased, blood creatine phosphokinase increased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased Metabolism and Nutrition Disorders: polydipsia Musculoskeletal, Connective Tissue, and Bone Disorders: joint swelling, joint stiffness, rhabdomyolysis, torticollis Nervous System Disorders: hypertonia, balance disorder, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypokinesia, parkinsonian rest tremor, transient ischemic attack, cerebrovascular accident, masked facies, speech disorder, loss of consciousness, muscle contractions involuntary, akinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation Psychiatric Disorders: blunted affect, confusional state, middle insomnia, listlessness, anorgasmia Renal and Urinary Disorders: enuresis, dysuria, pollakiuria Reproductive System and Breast Disorders: vaginal discharge, retrograde ejaculation, ejaculation disorder, ejaculation failure, breast enlargement Respiratory, Thoracic, and Mediastinal Disorders: epistaxis, wheezing, pneumonia aspiration, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, skin disorder, rash erythematous, rash papular, hyperkeratosis, dandruff, seborrheic dermatitis, rash generalized, rash maculopapular Vascular Disorders: flushing Discontinuations Due to Adverse Reactions Schizophrenia Approximately 11% (22/202) of RISPERDAL CONSTA-treated patients in the 12-week double-blind, placebo-controlled schizophrenia trial discontinued treatment due to an adverse event, compared with 13% (13/98) who received placebo. The adverse reactions associated with discontinuation in two or more RISPERDAL CONSTA-treated patients were: agitation (3%), depression (2%), anxiety (1%), and akathisia (1%). Bipolar Disorder In the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of RISPERDAL CONSTA when administered as monotherapy for maintenance treatment in patients with bipolar I disorder, 1 (0.6%) of 154 RISPERDAL CONSTA-treated patients discontinued due to an adverse reaction (hyperglycemia). In the 52-week double-blind phase of the placebo-controlled trial in which RISPERDAL CONSTA was administered as adjunctive therapy to patients with bipolar disorder in addition to continuing with their treatment as usual, approximately 4% (3/72) of RISPERDAL CONSTA-treated patients discontinued treatment due to an adverse event, compared with 1.5% (1/67) of placebo-treated patients. Adverse reactions associated with discontinuation in RISPERDAL CONSTA-treated patients were: hypokinesia (one patient) and tardive dyskinesia (one patient). Dose Dependency of Adverse Reactions in Clinical Trials Extrapyramidal Symptoms Two methods were used to measure extrapyramidal symptoms (EPS) in the 12-week double-blind, placebo-controlled trial comparing three doses of RISPERDAL CONSTA (25 mg, 50 mg, and 75 mg) with placebo in patients with schizophrenia, including: the incidence of spontaneous reports of EPS symptoms; and the change from baseline to endpoint on the total score (sum of the subscale scores for parkinsonism, dystonia, and dyskinesia) of the Extrapyramidal Symptom Rating Scale (ESRS). As shown in Table 1, the overall incidence of EPS-related adverse reactions (akathisia, dystonia, parkinsonism, and tremor) in patients treated with 25 mg RISPERDAL CONSTA was comparable to that of patients treated with placebo; the incidence of EPS-related adverse reactions was higher in patients treated with 50 mg RISPERDAL CONSTA. The median change from baseline to endpoint in total ESRS score showed no worsening in patients treated with RISPERDAL CONSTA compared with patients treated with placebo: 0 (placebo group); -1 (25-mg group, significantly less than the placebo group); and 0 (50-mg group). Dystonia Class Effect: 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.

Changes in ECG The electrocardiograms of 202 schizophrenic patients treated with 25 mg or 50 mg RISPERDAL CONSTA and 98 schizophrenic patients treated with placebo in the 12-week double-blind, placebo-controlled trial were evaluated. Compared with placebo, there were no statistically significant differences in QTc intervals (using Fridericia's and linear correction factors) during treatment with RISPERDAL CONSTA. The electrocardiograms of 227 patients with Bipolar I Disorder were evaluated in the 24-month double-blind, placebo-controlled period. There were no clinically relevant differences in QTc intervals (using Fridericia's and linear correction factors) during treatment with RISPERDAL CONSTA compared to placebo.

The electrocardiograms of 85 patients with bipolar disorder were evaluated in the 52-week double-blind, placebo-controlled trial. There were no statistically significant differences in QTc intervals (using Fridericia's and linear correction factors) during treatment with RISPERDAL CONSTA 25 mg, 37.5 mg, or 50 mg when administered as adjunctive treatment in addition to continuing treatment as usual compared to placebo. Pain Assessment and Local Injection Site Reactions The mean intensity of injection pain reported by patients with schizophrenia 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: 16.7 to 12.6; 25 mg: 12.0 to 9.0; 50 mg: 18.2 to 11.8). After the sixth injection (Week 10), investigator ratings indicated that 1% of patients treated with 25 mg or 50 mg RISPERDAL CONSTA experienced redness, swelling, or induration at the injection site.

In a separate study to observe local-site tolerability in which RISPERDAL CONSTA was administered into the deltoid muscle every 2 weeks over a period of 8 weeks, no patient discontinued treatment due to local injection site pain or reaction. Clinician ratings indicated that only mild redness, swelling, or induration at the injection site was observed in subjects treated with 37.5 mg or 50 mg RISPERDAL CONSTA at 2 hours after deltoid injection. All ratings returned to baseline at the predose assessment of the next injection 2 weeks later.

No moderate or severe reactions were observed in any subject.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of risperidone; because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic reaction, angioedema, atrial fibrillation, blood cholesterol increased, blood triglycerides increased, catatonia, diabetes mellitus, diabetic ketoacidosis in patients with impaired glucose metabolism, drug withdrawal syndrome neonatal, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication. In addition, the following adverse reactions have been observed during postapproval use of RISPERDAL CONSTA: cerebrovascular disorders, including cerebrovascular accidents, and diabetes mellitus aggravated. Retinal artery occlusion after injection of RISPERDAL CONSTA has been reported during postmarketing surveillance.

This has been reported in the presence of abnormal arteriovenous anastomosis. Serious injection site reactions including abscess, cellulitis, cyst, hematoma, necrosis, nodule, and ulcer have been reported with RISPERDAL CONSTA during postmarketing surveillance. Isolated cases required surgical intervention.

Very rarely, cases of anaphylactic reaction after injection with RISPERDAL CONSTA have been reported during postmarketing experience in patients who have previously tolerated oral risperidone. Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.

Centrally-Acting Drugs and Alcohol Given the primary

CNS effects of risperidone, caution should be used when RISPERDAL CONSTA is administered in combination with other centrally-acting drugs or alcohol.

Drugs with Hypotensive Effects

Because of its potential for inducing hypotension, RISPERDAL CONSTA may enhance the hypotensive effects of other therapeutic agents with this potential.

Levodopa and Dopamine Agonists

RISPERDAL CONSTA may antagonize the effects of levodopa and dopamine agonists.

Amitriptyline Amitriptyline did not affect the pharmacokinetics of risperidone or of risperidone

and 9-hydroxyrisperidone combined following concomitant administration with oral RISPERDAL.

Cimetidine and Ranitidine Cimetidine and ranitidine increased the bioavailability of oral risperidone

by 64% and 26%, respectively. However, cimetidine did not affect the AUC of risperidone and 9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9-hydroxyrisperidone combined by 20%.

Methylphenidate

Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS). Monitor for symptoms of EPS with concomitant use of RISPERDAL CONSTA and methylphenidate .

Clozapine Chronic administration of clozapine with risperidone may decrease the clearance of

risperidone.

Lithium Repeated doses of oral

RISPERDAL (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C max ) of lithium (N=13).

Valproate Repeated doses of oral

RISPERDAL (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (N=21). However, there was a 20% increase in valproate peak plasma concentration (C max ) after concomitant administration of oral RISPERDAL. 7.10 Digoxin Oral RISPERDAL (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. 7.11 Topiramate Oral RISPERDAL administered at doses from 1–6 mg/day concomitantly with topiramate 400 mg/day resulted in a 23% decrease in risperidone C max and a 33% decrease in risperidone AUC 0–12 hour at steady state. Minimal reductions in the exposure to risperidone and 9-hydroxyrisperidone combined, and no change for 9-hydroxyrisperidone were observed. This interaction is unlikely to be of clinical significance.

There was no clinically relevant effect of oral RISPERDAL on the pharmacokinetics of topiramate. 7.12 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is polymorphic in the population and that can be inhibited by a variety of psychotropic and other drugs . Drug interactions that reduce the metabolism of risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a modest number of poor metabolizers (n≅70 patients) does not suggest that poor and extensive metabolizers have different rates of adverse effects. No comparison of effectiveness in the two groups has been made.

In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism. Fluoxetine and Paroxetine Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), CYP 2D6 inhibitors, have been shown to increase the plasma concentration of risperidone 2.5–2.8 fold and 3–9 fold respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone.

Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dose of RISPERDAL CONSTA. When initiation of fluoxetine or paroxetine is considered, patients may be placed on a lower dose of RISPERDAL CONSTA between 2 to 4 weeks before the planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma concentrations of risperidone. When fluoxetine or paroxetine is initiated in patients receiving the recommended dose of 25 mg RISPERDAL CONSTA, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates lowering the RISPERDAL CONSTA dose to 12.5 mg or necessitates interruption of RISPERDAL CONSTA treatment. When RISPERDAL CONSTA is initiated in patients already receiving fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered.

The efficacy of the 12.5 mg dose has not been investigated in clinical trials. . The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied. Erythromycin There were no significant interactions between oral RISPERDAL and erythromycin. 7.13 Carbamazepine and Other CYP 3A4 Enzyme Inducers Carbamazepine co-administration with oral RISPERDAL decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. Co-administration of other known CYP 3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of RISPERDAL CONSTA treatment.

At the initiation of therapy with carbamazepine or other known hepatic enzyme inducers, patients should be closely monitored during the first 4–8 weeks, since the dose of RISPERDAL CONSTA may need to be adjusted. A dose increase, or additional oral RISPERDAL, may need to be considered. On discontinuation of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of RISPERDAL CONSTA should be re-evaluated and, if necessary, decreased.

Patients may be placed on a lower dose of RISPERDAL CONSTA between 2 to 4 weeks before the planned discontinuation of carbamazepine or other CYP 3A4 enzyme inducers to adjust for the expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg RISPERDAL CONSTA and discontinuing from carbamazepine or other CYP 3A4 enzyme inducers, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates lowering the RISPERDAL CONSTA dose to 12.5 mg or necessitates interruption of RISPERDAL CONSTA treatment. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. 7.14 Drugs Metabolized by CYP 2D6 In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, RISPERDAL CONSTA is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway.

In drug interaction studies, oral RISPERDAL did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including RISPERDAL CONSTA, 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 risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ). There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including RISPERDAL CONSTA, during pregnancy (see Clinical Considerations ). Risperidone has been detected in plasma in adult subjects up to 8 weeks after a single-dose administration of RISPERDAL CONSTA . The clinical significance of RISPERDAL CONSTA administered before pregnancy or anytime during pregnancy is not known. Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human dose (MRHD) with maternal toxicity observed at 4-times the MRHD based on mg/m 2 body surface area.

Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the MRHD based on mg/m 2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the MRHD based on mg/m 2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the MRHD and offspring mortality increased at doses 0.1 to 3 times the MRHD based on mg/m 2 body surface area.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, 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.

Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, 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 RISPERDAL CONSTA, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for 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 demonstrated placental passage of risperidone.

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 major of 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 risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal Data Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area; maternal toxicity occurred at 4 times the MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2 body surface area.

Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the MRHD based on mg/m 2 body surface area; postnatal development and growth of the offspring were also delayed. Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the MRHD of 16 mg/day 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; a no-effect dose could not be determined.

The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the MRHD based on mg/m 2 body surface area. In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered.

Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the MRHD based on mg/m 2 and the only dose tested in the study.

Pediatric Use Safety and effectiveness of RISPERDAL CONSTA in pediatric patients have not been established. However, juvenile animal toxicology studies have been conducted with oral risperidone. Juvenile Animal Studies Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day, which are 1.2, 3.4 and 13.5 times the MRHD of 6 mg/day for children, based on mg/m 2 body surface area.

Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUC of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) that were similar to those in children and adolescents receiving the MRHD of 6 mg/day. In addition, sexual maturation was delayed 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.

Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the MRHD of 6 mg/day for children, based on mg/m 2 body surface area. This dose produced plasma AUC of risperidone plus paliperidone about half the exposure observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the MRHD and produced plasma AUC of risperidone plus paliperidone that were about two thirds of those observed in humans at the MRHD of 6 mg/day for children.

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

Known hypersensitivity to risperidone, paliperidone, or to any excipients in RISPERDAL CONSTA.

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

RISPERDAL CONSTA. Because RISPERDAL CONSTA is to be administered by health care professionals, the potential for overdosage by patients is low. In premarketing experience with oral RISPERDAL, there were eight reports of acute RISPERDAL overdosage, with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms.

One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure. Postmarketing experience with oral RISPERDAL includes reports of acute overdose, with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms.

Other adverse reactions reported since market introduction related to oral RISPERDAL overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of oral RISPERDAL and paroxetine.

Management of Overdosage

In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT prolonging effects that might be additive to those of risperidone.

Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of risperidone, resulting in problematic hypotension. There is no specific antidote to risperidone. Therefore, appropriate supportive measures should be instituted.

The possibility of multiple drug involvement should be considered. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.