2DOSAGE AND ADMINISTRATION
2.1Schizophrenia
Adults
Usual Initial Dose
Risperidone can be administered once or twice daily. Initial dosing is generally 2 mg/day. Dose increases should then occur at intervals not less than 24 hours, in increments of 1 to 2 mg/day, as tolerated, to a recommended dose of 4 to 8 mg/day. In some patients, slower titration may be appropriate. Efficacy has been demonstrated in a range of 4 to 16 mg/day [see Clinical Studies (14.1)]. However, doses above 6 mg/day for twice daily dosing were not demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal symptoms and other adverse effects, and are generally not recommended. In a single study supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of doses above 16 mg/day has not been evaluated in clinical trials.
Maintenance Therapy
While it is unknown how long a patient with schizophrenia should remain on risperidone, the effectiveness of risperidone 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a controlled trial in patients who had been clinically stable for at least 4 weeks and were then followed for a period of 1 to 2 years[see Clinical Studies (14.1)]. Patients should be periodically reassessed to determine the need for maintenance treatment with an appropriate dose.
Adolescents
Due to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with schizophrenia. Dosage and administration information for pediatric patients with schizophrenia, 13 to 17 years of age, is approved for Janssen Pharmaceuticals Corporation’s risperidone drug product.
Reinitiation of Treatment in Patients Previously Discontinued
Although there are no data to specifically address reinitiation of treatment, it is recommended that after an interval off risperidone, the initial titration schedule should be followed.
Switching From Other Antipsychotics
There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to risperidone, or treating patients with concomitant antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some schizophrenic patients, more gradual discontinuation may be most appropriate for others. The period of overlapping antipsychotic administration should be minimized. When switching schizophrenic patients from depot antipsychotics, initiate risperidone therapy in place of the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated periodically.
2.2Bipolar Mania
Usual Dose
Adults
Risperidone should be administered on a once-daily schedule, starting with 2 mg to 3 mg per day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible dosage range of 1 to 6 mg per day [see Clinical Studies (14.2, 14.3)]. Risperidone doses higher than 6 mg per day were not studied.
Pediatrics
Due to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with bipolar mania, 10 to 17 years of age. Dosage and administration information for the treatment of pediatric patients with bipolar disorder is approved for Janssen Pharmaceuticals Corporation’s risperidone drug products.
Maintenance Therapy
There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during treatment of an acute manic episode with risperidone. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of risperidone in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to use risperidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.
2.3Irritability Associated with Autistic Disorder – Pediatrics (Children and Adolescents)
Due to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with irritability associated with autistic disorder. Dosage and administration information for the treatment of pediatric patients with irritability associated with autistic disorder, 5 to 16 years of age, is approved for Janssen Pharmaceuticals Corporation’s risperidone drug products.
2.4Dosage in Special Populations
The recommended initial dose is 0.5 mg twice daily in patients who are elderly or debilitated, patients with severe renal or hepatic impairment, and patients either predisposed to hypotension or for whom hypotension would pose a risk. Dosage increases in these patients should be in increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily should generally occur at intervals of at least 1 week. In some patients, slower titration may be medically appropriate.
Elderly or debilitated patients, and patients with renal impairment, may have less ability to eliminate risperidone than normal adults. Patients with impaired hepatic function may have increases in the free fraction of risperidone, possibly resulting in an enhanced effect [see Clinical Pharmacology (12.3)]. Patients with a predisposition to hypotensive reactions or for whom such reactions would pose a particular risk likewise need to be titrated cautiously and carefully monitored [see Warnings and Precautions (5.2, 5.7, 5.16)]. If a once-daily dosing regimen in the elderly or debilitated patient is being considered, it is recommended that the patient be titrated on a twice-daily regimen for 2 to 3 days at the target dose. Subsequent switches to a once-daily dosing regimen can be done thereafter.
2.5Co-Administration of Risperidone Oral Solution with Certain Other Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin, phenobarbital) with risperidone oral solution would be expected to cause decreases in the plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead to decreased efficacy of risperidone oral solution treatment. The dose of risperidone oral solution needs to be titrated accordingly for patients receiving these enzyme inducers, especially during initiation or discontinuation of therapy with these inducers [see Drug Interactions (7.11)].
Fluoxetine and paroxetine have been shown to increase the plasma concentration of risperidone 2.5 to 2.8 fold and 3 to 9 fold, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. The dose of risperidone oral solution needs to be titrated accordingly when fluoxetine or paroxetine is co-administered [see Drug Interactions (7.10)].
2.6Administration of Risperidone Oral Solution
Risperidone oral solution can be administered directly from the calibrated syringe, or can be mixed with a beverage prior to administration. Risperidone oral solution is compatible in the following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with either cola or tea.
5WARNINGS AND PRECAUTIONS
5.1Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Risperidone is not approved for the treatment of dementia-related psychosis (see BOXED WARNING).
5.2Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73 to 97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. Risperidone is not approved for the treatment of patients with dementia-related psychosis. [See also Boxed Warnings and Warnings and Precautions (5.1)].
5.3Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
5.4Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, risperidone should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with risperidone, drug discontinuation should be considered. However, some patients may require treatment with risperidone despite the presence of the syndrome.
5.5Hyperglycemia and Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including risperidone. 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 treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
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.
5.6Hyperprolactinemia
As with other drugs that antagonize dopamine D
2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Non-Clinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.
5.7Orthostatic Hypotension
Risperidone may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of risperidone -treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment [see Dosage and Administration (2.1, 2.4)]. Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. A dose reduction should be considered if hypotension occurs. Risperidone should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia. Clinically significant hypotension has been observed with concomitant use of risperidone and antihypertensive medication.
5.8Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including risperidone. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of risperidone should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm
3) should discontinue risperidone and have their WBC followed until recovery.
5.9Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event associated with risperidone treatment, especially when ascertained by direct questioning of patients. This adverse event is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (risperidone 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of risperidone 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse event. Since risperidone has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that risperidone therapy does not affect them adversely.
5.10Seizures
During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of risperidone-treated patients, two in association with hyponatremia. Risperidone should be used cautiously in patients with a history of seizures.
5.11Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia. Risperidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. [See also Boxed Warning and Warnings and Precautions (5.1)]
5.12Priapism
Rare cases of priapism have been reported. While the relationship of the events to risperidone use has not been established, other drugs with alpha-adrenergic blocking effects have been reported to induce priapism, and it is possible that risperidone may share this capacity. Severe priapism may require surgical intervention.
5.13Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone use. Caution is advised when prescribing for patients who will be exposed to temperature extremes.
5.14Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal obstruction, Reye’s syndrome, and brain tumor.
5.15Suicide
The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania, including children and adolescent patients, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for risperidone should be written for the smallest quantity, consistent with good patient management, in order to reduce the risk of overdose.
5.16Use in Patients with Concomitant Illness
Clinical experience with risperidone in patients with certain concomitant systemic illnesses is limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive antipsychotics, including risperidone, are reported to have an increased sensitivity to antipsychotic medications. Manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.
Caution is advisable in using risperidone in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Risperidone has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product's premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m
2, and an increase in the free fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose should be used in such patients [see Dosage and Administration (2.4)].
5.17Monitoring: Laboratory Tests
No specific laboratory tests are recommended.
6ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
- Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)]
- Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2)]
- Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
- Tardive dyskinesia [see Warnings and Precautions (5.4)]
- Hyperglycemia and diabetes mellitus [see Warnings and Precautions (5.5)]
- Hyperprolactinemia [see Warnings and Precautions (5.6)]
- Orthostatic hypotension [see Warnings and Precautions (5.7)]
- Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.8)]
- Potential for cognitive and motor impairment [see Warnings and Precautions (5.9)]
- Seizures [see Warnings and Precautions (5.10)]
- Dysphagia [see Warnings and Precautions (5.11)]
- Priapism [see Warnings and Precautions (5.12)]
- Disruption of body temperature regulation [see Warnings and Precautions (5.13)]
- Antiemetic effect [see Warnings and Precautions (5.14)]
- Suicide [see Warnings and Precautions (5.15)]
- Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies [see Warnings and Precautions (5.16)]
- Diseases or conditions that could affect metabolism or hemodynamic responses [see Warnings and Precautions (5.16)]
The most common adverse reactions in clinical trials (≥ 10%) were somnolence, appetite increased, fatigue, rhinitis, upper respiratory tract infection, vomiting, coughing, urinary incontinence, saliva increased, constipation, fever, Parkinsonism, dystonia, abdominal pain, anxiety, nausea, dizziness, dry mouth, tremor, rash, akathisia, and dyspepsia.
The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in > 1% of adults and/or > 2% of pediatrics) were somnolence, nausea, abdominal pain, dizziness, vomiting, agitation, and akathisia [see Adverse Reactions (6.5)].
The data described in this section are derived from a clinical trial database consisting of 9712 adult and pediatric patients exposed to one or more doses of risperidone for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatric and elderly patients with dementia. Of these 9712 patients, 2626 were patients who received risperidone while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with risperidone varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 3 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs.
Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using WHOART terminology.
Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of risperidone (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for risperidone often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The majority of all adverse reactions were mild to moderate in severity.
6.1Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Schizophrenia
Adult Patients with Schizophrenia
Table 1 lists the adverse reactions reported in 1% or more of risperidone -treated adult patients with schizophrenia in three 4 to 8-week, double-blind, placebo-controlled trials.
Table 1. Adverse Reactions in ≥1% of Risperidone -Treated Adult Patients with Schizophrenia in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
|
Body System Adverse reaction
| Risperidone 2 to 8 mg per day (N=366)
| Risperidone >8 to 16 mg per day
| Placebo (N=225)
|
Body as a whole - general disorders |
|
|
|
Back pain
| 3
| 2
| <1 |
Fatigue
| 3
| 1
| 0
|
Chest pain
| 3
| 1
| 2
|
Fever
| 2
| 1
| 1
|
Asthenia
| 1
| 1
| <1 |
Syncope
| <1 | 1
| <1 |
Edema
| <1 | 1
| 0
|
Cardiovascular disorders, general |
|
|
|
Hypotension postural
| 2
| <1 | 0
|
Hypotension
| <1 | 1
| 0
|
Central and peripheral nervous system disorders |
|
|
|
Parkinsonism*
| 12
| 17
| 6
|
Dizziness
| 10
| 4
| 2
|
Dystonia*
| 5
| 5
| 2
|
Akathisia*
| 5
| 5
| 2
|
Dyskinesia
| 1
| 1
| <1 |
Gastrointestinal system disorders |
|
|
|
Dyspepsia
| 10
| 7
| 6
|
Nausea
| 9
| 4
| 4
|
Constipation
| 8
| 9
| 7
|
Abdominal pain
| 4
| 3
| 0
|
Mouth dry
| 4
| <1 | <1 |
Saliva increased
| 3
| 1
| <1 |
Diarrhea
| 2
| <1 | 1
|
Hearing and vestibular disorders
|
|
|
|
Earache
| 1
| 1
| 0
|
Heart rate and rhythm disorders |
|
|
|
Tachycardia
| 2
| 5
| 0
|
Arrhythmia
| 0
| 1
| 0
|
Metabolic and nutritional disorders |
|
|
|
Weight increase
| 1
| <1 | 0
|
Creatine phosphokinase increased
| <1
| 2
| <1 |
Musculoskeletal system disorders |
|
|
|
Arthralgia
| 2
| 3
| <1 |
Myalgia
| 1 | 0
| 0
|
Platelet, bleeding and clotting disorders |
|
|
|
Epistaxis
| <1 | 2
| 0
|
Psychiatric disorders
|
|
|
|
Anxiety
| 16
| 12
| 11
|
Somnolence
| 14
| 5
| 4
|
Anorexia
| 2
| 0
| <1 |
Red blood cell disorders |
|
|
|
Anemia
| <1 | 1
| 0
|
Reproductive disorders, male |
|
|
|
Ejaculation failure
| <1 | 1
| 0
|
Respiratory system disorders |
|
|
|
Rhinitis
| 7
| 11
| 6
|
Coughing
| 3
| 3
| 3
|
Upper respiratory tract infection
| 2
| 3
| <1 |
Dyspnea
| 2
| 2
| 0
|
Skin and appendages disorder |
|
|
|
Rash
| 2
| 4
| 2
|
Seborrhea
| <1 | 2
| 0
|
Urinary system disorders |
|
|
|
Urinary tract infection
| <1 | 3
| 0
|
Vision disorders |
|
|
|
Vision abnormal
| 3
| 1
| <1 |
* Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradycardia. Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions involuntary, tetany, laryngismus, tongue paralysis, and torticollis. Akathisia includes hyperkinesia and akathisia.
Pediatric Patients with Schizophrenia
Table 2 lists the adverse reactions reported in 5% or more of risperidone -treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.
Table 2. Adverse Reactions in ≥5% of Risperidone -Treated Pediatric Patients with Schizophrenia in a Double-Blind Trial
Percentage of Patients Reporting Event Risperidone
|
Body System Adverse Reaction
| 1 to 3 mg per day (N=55)
| 4 to 6 mg per day (N=51)
| Placebo (N=54)
|
Central and peripheral nervous system disorders |
|
|
|
Parkinsonism*
| 13
| 16
| 6
|
Tremor
| 11
| 10
| 6
|
Dystonia*
| 9
| 18
| 7
|
Dizziness
| 7
| 14
| 2
|
Akathisia*
| 7
| 10
| 6
|
Gastrointestinal system disorders |
|
|
|
Saliva increased
| 0
| 10
| 2
|
Psychiatric disorders |
|
|
|
Somnolence
| 24
| 12
| 4
|
Anxiety
| 7
| 6
| 0
|
* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions involuntary, tetany, laryngismus, tongue paralysis, and torticollis. Akathisia includes hyperkinesia and akathisia.
6.2Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Mania
Adult Patients with Bipolar Mania
Table 3 lists the adverse reactions reported in 1% or more of risperidone -treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.
Table 3. Adverse Reactions in ≥1% of Risperidone -Treated Adult Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy Trials
Percentage of Patients Reporting Event
|
Body System Adverse Reaction
| Risperidone 1 to 6 mg per day (N=448)
| Placebo (N=424)
|
Body as a whole - general disorders |
|
|
Fatigue
| 2
| <1
|
Fever | 1
| <1 |
Asthenia | 1
| <1 |
Edema | 1
| <1 |
Central and peripheral nervous system disorders |
|
|
Parkinsonism*
| 20
| 6
|
Dystonia*
| 11
| 3
|
Akathisia*
| 9
| 3
|
Tremor
| 6
| 4
|
Dizziness | 5
| 5
|
Gastrointestinal system disorders |
|
|
Nausea
| 5
| 2
|
Dyspepsia
| 4
| 2
|
Saliva increased
| 3
| <1 |
Diarrhea
| 3
| 2
|
Mouth dry | 1
| 1
|
Heart rate and rhythm disorders |
|
|
Tachycardia | 1
| <1 |
Liver and biliary system disorders |
|
|
SGOT increased | 1
| <1 |
Musculoskeletal disorders |
|
|
Myalgia
| 2
| 2
|
Psychiatric disorders |
|
|
Somnolence
| 12
| 4
|
Anxiety | 2
| 2
|
Reproductive disorders, female |
|
|
Lactation nonpuerperal
| 1
| 0
|
Respiratory disorders |
|
|
Rhinitis
| 2
| 2
|
Skin and appendages disorders |
|
|
Acne
| 1
| 0
|
Vision disorders |
|
|
Vision abnormal | 2
| <1 |
* Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradycardia. Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions involuntary, tetany, laryngismus, tongue paralysis, and torticollis. Akathisia includes hyperkinesia and akathisia.
Table 4 lists the adverse reactions reported in 2% or more of risperidone -treated adult patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy trials.
Table 4. Adverse Reactions in ≥2% of Risperidone -Treated Adult Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Adjuvant Therapy Trials
Percentage of Patients Reporting Event
|
Body System Adverse Reaction
| Risperidone + Mood Stabilizer (N=127)
| Placebo + Mood Stabilizer (N=126)
|
Body as a whole – general disorders
|
|
|
Chest pain
| 2
| 2
|
Fatigue | 2
| 2
|
Central and peripheral nervous system disorders |
|
|
Parkinsonism*
| 9
| 4
|
Dizziness
| 8
| 2
|
Dystonia*
| 6
| 3
|
Akathisia*
| 6
| 0
|
Tremor | 5
| 2
|
Gastrointestinal system disorders |
|
|
Nausea
| 6
| 5
|
Diarrhea
| 6
| 4
|
Saliva increased
| 4
| 0
|
Abdominal pain | 2
| 0
|
Heart rate and rhythm disorders
|
|
|
Palpitation | 2
| 0
|
Metabolic and nutritional disorders
|
|
|
Weight increase | 2
| 2
|
Psychiatric disorders
|
|
|
Somnolence | 12
| 5
|
Anxiety
| 4
| 2
|
Respiratory disorders |
|
|
Pharyngitis
| 5
| 2
|
Coughing | 3
| 1
|
Skin and appendages disorders
|
|
|
Rash
| 2
| 2
|
Urinary system disorders |
|
|
Urinary incontinence
| 2
| 1
|
Urinary tract infection | 2
| 1
|
* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions involuntary, tetany, laryngismus, tongue paralysis, and torticollis. Akathisia includes hyperkinesia and akathisia.
Pediatric Patients with Bipolar Mania
Table 5 lists the adverse reactions reported in 5% or more of risperidone -treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.
Table 5. Adverse Reactions in ≥5% of Risperidone-Treated Pediatric Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
|
Body System Adverse Reaction
| Risperidone 0.5 to 2.5 mg per day (N=50)
| Risperidone 3 to 6 mg per day (N=61)
| Placebo (N=58)
|
Body as a whole - general disorders
|
|
|
|
Fatigue
| 18
| 30
| 3
|
Central and peripheral nervous system disorders
|
|
|
|
Dizziness
| 16
| 13
| 5
|
Dystonia*
| 8
| 13
| 2
|
Parkinsonism*
| 2
| 7
| 2
|
Akathisia* | 0
| 7
| 2
|
Gastrointestinal system disorders |
|
|
|
Abdominal pain
| 18
| 15
| 5
|
Dyspepsia
| 16
| 5
| 3
|
Nausea
| 16
| 13
| 7
|
Vomiting
| 12
| 10
| 7
|
Diarrhea | 8
| 7
| 2
|
Heart rate and rhythm disorders |
|
|
|
Tachycardia
| 0
| 5
| 2
|
Psychiatric disorders |
|
|
|
Somnolence
| 42
| 56
| 19
|
Appetite increased
| 4
| 7
| 2
|
Anxiety | 0
| 8
| 3
|
Reproductive disorders, female |
|
|
|
Lactation nonpuerperal
| 2
| 5
| 0
|
Respiratory system disorders |
|
|
|
Rhinitis
| 14
| 13
| 10
|
Dyspnea
| 2
| 5
| 0
|
Skin and appendages disorders
|
|
|
|
Rash
| 0
| 7
| 2
|
Urinary system disorders |
|
|
|
Urinary incontinence
| 0
| 5
| 0
|
Vision disorders
|
|
|
|
Vision abnormal | 4
| 7
| 0
|
* Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions involuntary, tetany, laryngismus, tongue paralysis, and torticollis. Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradykinesia. Akathisia includes hyperkinesia and akathisia.
6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Autistic Disorder
Table 6 lists the adverse reactions reported in 5% or more of risperidone -treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials.
Table 6. Adverse Reactions in ≥5% of Risperidone -Treated Pediatric Patients Treated for Irritability Associated with Autistic Disorder in Double-Blind, Placebo-Controlled Trials
Percentage Patients Reporting Event
|
Body System Adverse Reaction
| Risperidone 0.5 to 4.0 mg per day (N=76)
| Placebo (N=80)
|
Body as a whole - general disorders | 42
| 13
|
Fatigue
| 20
| 19
|
Fever
|
|
|
Central and peripheral nervous system disorders
|
|
|
Dystonia*
| 12
| 6
|
Tremor
| 12
| 1
|
Dizziness
| 9
| 3
|
Parkinsonism*
| 8
| 0
|
Automatism
| 7
| 1
|
Dyskinesia
| 7
| 0
|
Gastrointestinal system disorders
|
|
|
Vomiting
| 25
| 21
|
Saliva increased
| 22
| 6
|
Constipation
| 21
| 8
|
Mouth dry
| 13
| 6
|
Nausea
| 8
| 8
|
Heart rate and rhythm disorders |
|
|
Tachycardia
| 7
| 0
|
Metabolic and nutritional disorders
|
|
|
Weight increase
| 5
| 0
|
Psychiatric disorders |
|
|
Somnolence
| 67
| 23
|
Appetite increased
| 49
| 19
|
Anxiety
| 16
| 15
|
Anorexia
| 8
| 8
|
Confusion
| 5
| 0
|
Respiratory system disorders |
|
|
Rhinitis
| 36
| 23
|
Upper respiratory tract infection
| 34
| 15
|
Coughing
| 24
| 18
|
Skin and appendages disorders
|
|
|
Rash | 11
| 8
|
Urinary system disorders |
|
|
Urinary incontinence
| 22
| 20
|
*Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions involuntary, tetany, laryngismus, tongue paralysis, and torticollis. Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradycardia.
6.4 Other Adverse Reactions Observed During the Premarketing Evaluation of Risperidone
The following adverse reactions occurred in < 1% of the adult patients and in < 5% of the pediatric patients treated with risperidone in the above double-blind, placebo-controlled clinical trial data sets. In addition, the following also includes adverse reactions reported in risperidone -treated patients who participated in other studies, including double-blind, active-controlled and open-label studies in schizophrenia and bipolar mania studies in pediatric patients with psychiatric disorders other than schizophrenia, bipolar mania, or autistic disorder, and studies in elderly patients with dementia.
Body as a Whole, General Disorders: edema peripheral, pain, influenza-like symptoms, leg pain, malaise, allergy, crying abnormal, allergic reaction, rigors, allergy aggravated, anaphylactoid reaction, hypothermia
Central Nervous System Disorders: gait abnormal, speech disorder, coma, ataxia, dysphonia, stupor, cramps legs, vertigo, hypoesthesia, tardive dyskinesia, neuroleptic malignant syndrome
Endocrine Disorders: hyperprolactinemia, gynecomastia
Gastrointestinal System Disorders: dysphagia, flatulence
Heart Rate and Rhythm Disorders: AV block, bundle branch block
Liver and Biliary Disorders: SGPT increased, hepatic enzymes increased
Metabolic and Nutritional Disorders: thirst, hyperglycemia, xerophthalmia, generalized edema, diabetes mellitus aggravated, diabetic coma
Musculoskeletal Disorders: muscle weakness, rhabdomyolysis
Platelet, Bleeding, and Clotting Disorders: purpura
Psychiatric Disorders: insomnia, agitation, emotional lability, apathy, nervousness, concentration impaired, impotence, decreased libido
Reproductive Disorders, Female: amenorrhea, menstrual disorder, leukorrhea
Reproductive Disorders, Male: ejaculation disorder, abnormal sexual function, priapism
Resistance Mechanism Disorders: otitis media, viral infection
Respiratory Disorders: respiratory disorder
Skin and Appendages Disorders: skin ulceration, skin discoloration, rash erythematous, skin exfoliation, rash maculopapular, erythema multiforme
Urinary Disorders: micturition frequency
Vascular Disorders: cerebrovascular disorder
Vision Disorders: conjunctivitis
White Cell Disorders: leucopenia, granulocytopenia
6.5 Discontinuations Due to Adverse Reactions
Schizophrenia - Adults
Approximately 7% (39/564) of risperidone -treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse event, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more risperidone -treated patients were:
Table 7. Adverse Reactions Associated With Discontinuation in 2 or More Risperidone-Treated Adult Patients in Schizophrenia Trials
Risperidone
|
Adverse reaction
| 2 to 8 mg/day (N=366)
| > 8 to 16 mg/day (N=198)
|
| Placebo (N=225)
|
Dizziness
| 1.4%
| 1.0%
|
| 0%
|
Nausea
| 1.4%
| 0%
|
| 0%
|
Agitation | 1.1%
| 1.0%
|
| 0%
|
Parkinsonism
| 0.8%
| 0%
|
| 0%
|
Somnolence
| 0.8%
| 0.5%
|
| 0%
|
Dystonia
| 0.5%
| 0%
|
| 0%
|
Abdominal pain
| 0.5%
| 0%
|
| 0%
|
Hypotension postural
| 0.3%
| 0.5%
|
| 0%
|
Tachycardia
| 0.3%
| 0.5%
|
| 0%
|
Akathisia
| 0%
| 1.0%
|
| 0%
|
Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated patients in a double-blind, placebo- and active-controlled trial.
Schizophrenia - Pediatrics
Approximately 7% (7/106), of risperidone -treated patients discontinued treatment due to an adverse event in a double-blind, placebo-controlled trial, compared with 4% (2/54) placebo-treated patients. The adverse reactions associated with discontinuation for at least one risperidone -treated patient were somnolence (2%), dizziness (2%), anorexia (1%), anxiety (1%), ataxia (1%), hypotension (1%), and palpitation (1%).
Bipolar Mania - Adults
In double-blind, placebo-controlled trials with risperidone as monotherapy, approximately 6% (25/448) of risperidone -treated patients discontinued treatment due to an adverse event, compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions associated with discontinuation in risperidone -treated patients were:
Table 8. Adverse Reactions Associated With Discontinuation in 2 or More Risperidone-Treated Adult Patients in Bipolar Mania Clinical Trials
Risperidone
|
Adverse reactions
| 1 to 6mg/day (N=448)
| Placebo (N=424)
|
Parkinsonism
| 0.4%
| 0%
|
Somnolence
| 0.2%
| 0%
|
Dizziness
| 0.2%
| 0%
|
Dystonia
| 0.2%
| 0%
|
SGOT increased | 0.2%
| 0.2%
|
SGPT increased | 0.2%
| 0.2%
|
Bipolar Mania - Pediatrics
In a double-blind, placebo-controlled trial 12% (13/111) of risperidone -treated patients discontinued due to an adverse event, compared with 7% (4/58) of placebo-treated patients. The adverse reactions associated with discontinuation in more than one risperidone -treated pediatric patient were somnolence (5%), nausea (3%), abdominal pain (2%), and vomiting (2%).
Autistic Disorder - Pediatrics
Due to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with irritability associated with autistic disorder. Information on discontinuations due to adverse reactions for pediatric patients with irritability associated with autistic disorder, 5 to 16 years of age, is approved for Janssen Pharmaceuticals Corporation’s risperidone drug product.
6.6Dose Dependency of Adverse Reactions in Clinical Trials
Extrapyramidal Symptoms
Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with risperidone treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of risperidone (2, 6, 10, and 16 mg/day), including (1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS:
Dose Groups
| Placebo
| Risperidone
2 mg | Risperidone
6 mg | Risperidone
10 mg | Risperidone
16 mg |
Pakinsonism
| 1.2
| 0.9
| 1.8
| 2.4
| 2.6
|
EPS Incidence
| 11% | 15% | 16% | 20% | 31%
|
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day):
Dose Groups
| Risperidone 1 mg
| Risperidone 4 mg | Risperidone 8 mg | Risperidone
12 mg | Risperidone
16 mg |
Pakinsonism
| 0.6
| 1.7
| 2.4
| 2.9
| 4.1
|
EPS Incidence
| 7% | 11% | 17% | 18% | 20% |
Other Adverse Reactions
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p < 0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness, palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function abnormal, fatigue, and skin discoloration.
6.7Changes in Body Weight
The proportions of risperidone and placebo-treated adult patients with schizophrenia meeting a weight gain criterion of ≥ 7% of body weight were compared in a pool of 6- to 8-week, placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain for risperidone (18%) compared to placebo (9%). In a pool of placebo-controlled 3-week studies in adult patients with acute mania, the incidence of weight increase of ≥ 7% at endpoint was comparable in the risperidone (2.5%) and placebo (2.4%) groups, and was slightly higher in the active-control group (3.5%).
Changes in body weight were also evaluated in pediatric patients [see Use in Specific Populations (8.4)]
6.8Changes in ECG
Between-group comparisons for pooled placebo-controlled trials in adults revealed no statistically significant differences between risperidone and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all risperidone doses were pooled from randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of risperidone (8 to 16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4 to 6 beats per minute). In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean heart rate, similar among all treatment groups.
Due to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with schizophrenia, bipolar mania or autistic disorder. Information regarding changes in ECG during the treatment of pediatric patients with schizophrenia, 13 to 17 years of age, the treatment of pediatric patients with bipolar mania, 10 to 17 years of age, and the treatment of pediatric patients with irritability associated with autistic disorder, 5 to 16 years of age, is approved for Janssen Pharmaceuticals Corporation’s risperidone drug products.
6.9Postmarketing 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: anaphylactic reaction, angioedema, atrial fibrillation, diabetic ketoacidosis in patients with impaired glucose metabolism, intestinal obstruction, jaundice, mania, QT prolongation, and sleep apnea.
Other adverse events reported since market introduction, which were temporally related to risperidone but not necessarily causally related, include the following: pituitary adenoma, pulmonary embolism, precocious puberty, cardiopulmonary arrest, and sudden death.
8USE IN SPECIFIC POPULATIONS
8.1Pregnancy
Pregnancy Category C.
The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-Dawley and Wistar rats (0.63 to 10 mg/kg or 0.4 to 6 times the maximum recommended human dose [MRHD] on a mg/m
2 basis) and in one Segment II study in New Zealand rabbits (0.31 to 5 mg/kg or 0.4 to 6 times the MRHD on a mg/m
2 basis). The incidence of malformations was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the MRHD on a mg/m
2 basis. In three reproductive studies in rats (two Segment III and a multigenerational study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16 to 5 mg/kg or 0.1 to 3 times the MRHD on a mg/m
2 basis. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams.
There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m
2 basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams. These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m
2 basis.
Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled studies in pregnant women. However, there was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero. The causal relationship to risperidone therapy is unknown. Reversible extrapyramidal symptoms in the neonate were observed following postmarketing use of risperidone during the last trimester of pregnancy.
Risperidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
8.2Labor and Delivery
The effect of risperidone on labor and delivery in humans is unknown.
8.3Nursing Mothers
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving risperidone should not breast-feed.
8.4Pediatric Use
Safety and effectiveness of risperidone in children less than 13 years of age with schizophrenia have not been established.
Safety and effectiveness of risperidone in children less than 10 years of age with bipolar disorder have not been established.
The safety and effectiveness of risperidone in pediatric patients less than 5 years of age with autistic disorder have not been established.
Due to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with schizophrenia, bipolar mania or irritability associated with autistic disorder. Information on clinical trials and risperidone use for pediatric patients with schizophrenia, 13 to 17 years of age, bipolar mania, 10 to 17 years of age, and irritability associated with autistic disorder, 5 to 16 years of age, is approved for Janssen Pharmaceuticals Corporation’s risperidone drug products.
Tardive Dyskinesia
In clinical trials in 1885 children and adolescents treated with risperidone, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of risperidone treatment [see also Warnings and Precautions (5.4)].
Weight Gain
In a long-term, open-label extension study in adolescent patients with schizophrenia, weight increase was reported as a treatment-emergent adverse event in 14% of patients. In 103 adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of risperidone treatment. The majority of that increase was observed within the first 6 months. The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index.
In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric disorders), a mean increase of 7.5 kg after 12 months of risperidone treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year adjusted for age, based on Centers for Disease Control and Prevention normative data). The majority of that increase occurred within the first 6 months of exposure to risperidone. The average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index.
In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the risperidone groups than the placebo group, but not dose related (1.90 kg in the risperidone 0.5 to 2.5 mg group, 1.44 kg in the risperidone 3 to 6 mg group, and 0.65 kg in the placebo group). A similar trend was observed in the mean change from baseline in body mass index.
When treating pediatric patients with risperidone for any indication, weight gain should be assessed against that expected with normal growth. [See also Adverse Reactions (6.7)]
Somnolence
Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients with autistic disorder. Most cases were mild or moderate in severity. These events were most often of early onset with peak incidence occurring during the first two weeks of treatment, and transient with a median duration of 16 days. Somnolence was the most commonly observed adverse event in the clinical trial of bipolar disorder in children and adolescents, as well as in the schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these events were most often of early onset and transient in duration. [See also Adverse Reactions (6.1, 6.2, 6.3)] Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see Dosage and Administration (2.1, 2.2, 2.3)].
Hyperprolactinemia, Growth, and Sexual Maturation
Risperidone has been shown to elevate prolactin levels in children and adolescents as well as in adults [see Warnings and Precautions (5.6)]. In double-blind, placebo-controlled studies of up to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of patients who received risperidone had elevated prolactin levels compared to 2% of patients who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged 10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia, 82 to 87% of patients who received risperidone had elevated levels of prolactin compared to 3 to 7% of patients on placebo. Increases were dose-dependent and generally greater in females than in males across indications.
In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of risperidone-treated patients and gynecomastia was reported in 2.3% of risperidone-treated patients.
The long-term effects of risperidone on growth and sexual maturation have not been fully evaluated.
8.5Geriatric Use
Clinical studies of risperidone in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.4, 2.5)]. While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful titration [see Warnings and Precautions (5.7)]. Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.4)].
Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis
In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone when compared to patients treated with risperidone alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. An increase of mortality in elderly patients with dementia-related psychosis was seen with the use of risperidone regardless of concomitant use with furosemide. Risperidone is not approved for the treatment of patients with dementia-related psychosis. [See Boxed Warning and Warnings and Precautions (5.1)]
14 CLINICAL STUDIES
14.1 Schizophrenia
Adults
Short-Term Efficacy
The efficacy of risperidone in the treatment of schizophrenia was established in four short-term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for schizophrenia.
Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative Symptoms (SANS) were employed.
The results of the trials follow:
(1) In a 6-week, placebo-controlled trial (n=160) involving titration of risperidone in doses up to 10 mg/day (twice-daily schedule), risperidone was generally superior to placebo on the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on the SANS.
(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of risperidone (2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all 4 risperidone groups were generally superior to placebo on the BPRS total score, BPRS psychosis cluster, and CGI severity score; the 3 highest risperidone dose groups were generally superior to placebo on the PANSS negative subscale. The most consistently positive responses on all measures were seen for the 6 mg dose group, and there was no suggestion of increased benefit from larger doses.
(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of risperidone (1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the four highest risperidone dose groups were generally superior to the 1 mg risperidone dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None of the dose groups were superior to the 1 mg group on the PANSS negative subscale. The most consistently positive responses were seen for the 4 mg dose group.
(4) In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of risperidone (4 and 8 mg/day on a once-daily schedule), both risperidone dose groups were generally superior to placebo on several PANSS measures, including a response measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg than for the 4 mg dose group.
Long-Term Efficacy
In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic medication were randomized to risperidone (2 to 8 mg/day) or to an active comparator, for 1 to 2 years of observation for relapse. Patients receiving risperidone experienced a significantly longer time to relapse over this time period compared to those receiving the active comparator.
Pediatrics
Due to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with schizophrenia. Clinical trial information for pediatric patients with schizophrenia, 13 to 17 years of age, is approved for Janssen Pharmaceuticals Corporation’s risperidone drug products.
14.2 Bipolar Mania - Monotherapy
Adults
The efficacy of risperidone in the treatment of acute manic or mixed episodes was established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the YMRS total score. The results of the trials follow:
- In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes, which involved a dose range of risperidone 1 to 6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 4.1 mg/day), risperidone was superior to placebo in the reduction of YMRS total score.
- In another 3-week placebo-controlled trial (n=286), which involved a dose range of 1 to 6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day), risperidone was superior to placebo in the reduction of YMRS total score.
Pediatrics
Due to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with bipolar mania. Clinical trial information for pediatric patients with bipolar mania, 10 to 17 years of age, is approved for Janssen Pharmaceuticals Corporation’s risperidone drug products.
14.3 Bipolar Mania – Combination Therapy
The efficacy of risperidone with concomitant lithium or valproate in the treatment of acute manic or mixed episodes was established in one controlled trial in adult patients who met the DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic features and with or without a rapid-cycling course.
- In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms were randomized to receive risperidone, placebo, or an active comparator, in combination with their original therapy. Risperidone, in a dose range of 1 to 6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of YMRS total score.
- In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium, valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms were randomized to receive risperidone or placebo, in combination with their original therapy. Risperidone, in a dose range of 1 to 6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine (in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for valproate, or 4 to 12 mcg/mL for carbamazepine, respectively) was not superior to lithium, valproate, or carbamazepine alone in the reduction of YMRS total score. A possible explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxyrisperidone.
14.4 Irritability Associated with Autistic Disorder
Due to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with irritability associated with autistic disorder. Clinical trial information for pediatric patients with irritability associated with autistic disorder,5 to 16 years of age, is approved for Janssen Pharmaceuticals Corporation’s risperidone drug products.