Risperidone Orally Disintegrating
Name: Risperidone Orally Disintegrating
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Contraindications
Risperidone is contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the resperidone 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.
Warnings and Precautions
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.
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.
Risperidone is not approved for the treatment of dementia-related psychosis [see BOXED WARNING].
Cerebrovascular Adverse Reactions, 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 WARNING and Warnings and Precautions (5.1).]
Neuroleptic Malignant Syndrome
Antipsychotic drugs including risperidone can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase (CPK), 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.
Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. 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, prescribe risperidone 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, consider drug discontinuation. However, some patients may require treatment with risperidone despite the presence of the syndrome.
Metabolic Changes
Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
Hyperglycemia and Diabetes Mellitus
Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with 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, including risperidone, 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, including risperidone, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including risperidone , should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including risperidone, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of resperidone.
Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 2.
| Placebo | Risperidone 1 to 8 mg/day | >8 to 16 mg/day | |
|---|---|---|---|
| Mean change from basline (mg/dL) | |||
| n=555 | n=748 | n=164 | |
| Serum Glucose | -1.4 | 0.8 | 0.6 |
| Proportion of patients with shifts | |||
| Serum Glucose (<140 mg/dL to ≥200 mg/dL) | 0.6% (3/525) | 0.4% (3/702) | 0% (0/158) |
In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in glucose of +2.8 mg/dL at Week 24 (n=151) and +4.1 mg/dL at Week 48 (n=50).
Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 3.
| Placebo | Risperidone 0.5 to 6mg/day | |
|---|---|---|
| Mean change from basline (mgdL) | ||
| n=76 | n=135 | |
| Serum Glucose | -1.3 | 2.6 |
| Proportion of patients with shifts | ||
| Serum Glucose (>100mg/dL to ≥126 mg/dL) | 0% (0/64) | 0.8% (1/120) |
In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in fasting glucose of +5.2mg/dL at Week 24 (N=119).
Dyslipidemia
Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 4.
| Placebo | Risperidone | ||
|---|---|---|---|
| 1-8 mg/day | > 8-16 mg/day | ||
| Mean change from baseline (mg/dL) | |||
| Cholesterol | n=559 | n=742 | n=156 |
| Change from baseline | 0.6 | 6.9 | 1.8 |
| Triglycerides | n=183 | n=307 | n=123 |
| Change from baseline | -17.4 | -4.9 | -8.3 |
| Proportion of patients with shifts | |||
| Cholesterol (<200 mg/dL to ≥240 mg/dL) | 2.7% (10/368) | 4.3% (22/516) | 6.3% (6/96) |
| Triglycerides (<500 mg/dL to ≥500 mg/dL) | 1.1% (2/180) | 2.7% (8/301) | 2.5% (3/121) |
In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n=231) and + 5.5 mg/dL at Week 48 (n=86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n=52).
Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 5.
| Placebo | Risperidone 0.5 to 6 mg/day | |
|---|---|---|
| Mean change from baseline (mg/dL) | ||
| Cholesterol | n=74 | n=133 |
| Change from baseline | 0.3 | -0.3 |
| LDL | n=22 | n=22 |
| Change from baseline | 3.7 | 0.5 |
| HDL | n=22 | n=22 |
| Change from baseline | 1.6 | -1.9 |
| Triglycerides | n=77 | n=138 |
| Change from baseline | -9.0 | -2.6 |
| Proportion of patients with shifts | ||
| Cholesterol (170 mg/dL to ≥200 mg/dL) | 2.4% (1/42) | 3.8% (3/80) |
| LDL (110 mg/dL to ≥130 mg/dL) | 0% (0/16) | 0% (0/16) |
| HDL (≥40 mg/dL to < 40mg/dL) | 0% (0/19) | 10% (2/20) |
| Triglycerides (<150 mg/dL to ≥200 mg/dL) | 1.5% (1/65) | 7.1% (8/113) |
In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n=114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n=103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n=103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n=120).
Weight Gain
Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8-week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 6.
| Placebo (n=597) | Risperidone | ||
|---|---|---|---|
| 1 to 8 mg/day (n=769) | >8 to 16 mg/day (n=158) | ||
| Weight (kg) | |||
| Change from baseline | -0.3 | 0.7 | 2.2 |
| Weight Gain | |||
| ≥7% increase from baseline | 2.9% | 8.7% | 20.9% |
In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in weight of +4.3kg at Week 24 (N=395) and +5.3kg at Week 48 (N=203).
Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7% gain in body weight from 9 placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), autistic disorder (5 to 17 years of age), or other psychiatric disorders (5 to 17 years of age) are presented in Table 7.
| Placebo (n=375) | Risperidone 0.5-6 mg/day (n=448) | |
|---|---|---|
| Weight (kg) | ||
| Change from baseline | 0.6 | 2.0 |
| Weight Gain | ||
| ≥7% increase from baseline | 6.9% | 32.6% |
In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in weight of +5.5 kg at Week 24 (n=748) and +8.0 kg at Week 48 (n=242).
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 7.5kg after 12 months of risperidone treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5kg per year adjusted for age, based on Center 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 (1.90kg in the risperdidone 0.5 to 2 to 5 mg group, 1.44kg in the risperidone 3 to 6 mg group, and 0.65kg 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.
Hyperprolactinemia
As with other drugs that antagonize dopamine D2 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 Nonclinical 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.
Orthostatic 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.
Falls
Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including risperidone, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropinia 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/mm3) should discontinue risperidone and have their WBC followed until recovery.
Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse reaction 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 reaction. 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.
Seizures
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.
Dysphagia
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 BOXED WARNING and Warning and Precautions (5.1)].
Priapism
Priapism has been reported during postmarketing surveillance. Severe priapism may require surgical intervention.
Body 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.
Patients with Phenylketonuria
Inform patients that Risperidone Orally Disintegrating tablets contains phenylalanine. Phenylalanine is a component of aspartame. Each 4mg Risperidone Orally Disintegrating tablet contains 6.72 mg phenylalanine, each 3 mg Risperidone Orally Disintegrating tablet contains 5.04 mg phenylalanine each 2 mg Risperidone Orally Disintegrating tablet contains 3.36 mg phenylalanine, each 1mg Risperidone Orally Disintegrating tablet contains 1.68 mg phenylalanine, and each 0.5 mg Risperidone Orally Disintegrating tablet contains 0.84 mg phenylalanine, and each 0.25 mg Risperidone Orally Disintegrating tablet contains 0.42 mg phenylalanine.
Risperidone Orally Disintegrating Description
Risperidone Orally Disintegrating Tablets, USP contains risperidone, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is:
Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 N HCI.
Risperidone Orally Disintegrating Tablets, USP are available in 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg strengths and are white in color. Risperidone Orally Disintegrating Tablets, USP contain the following inactive ingredients: aspartame, croscarmellose sodium, crospovidone, magnesium stearate, maltodextrin, mannitol, methacrylic acid polymer with divinylbenzene, modified food starch, silicon dioxide, sorbitol, talc, tartaric acid, and natural grapefruit flavor.
Clinical Studies
Schizophrenia
AdultsShort-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:
- 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.
- 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.
- 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.
- 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.
PediatricsThe efficacy of risperidone in the treatment of schizophrenia in adolescents aged 13 to 17 years was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at time of enrollment. In the first trial (study #1), patients were randomized into one of three treatment groups: risperidone 1 to 3 mg/day (n = 55, mean modal dose = 2.6 mg), risperidone 4 to 6 mg/day (n = 51, mean modal dose = 5.3 mg), or placebo (n = 54).
In the second trial (study #2), patients were randomized to either risperidone 0.15 to 0.6 mg/day (n = 132, mean modal dose = 0.5 mg) or risperidone 1.5 to 6 mg/day (n = 125, mean modal dose = 4 mg). In all cases, study medication was initiated at 0.5 mg/day (with the exception of the 0.15 to 0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to the target dosage range by approximately Day 7. Subsequently, dosage was increased to the maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable in all studies was the mean change from baseline in total PANSS score.
Results of the studies demonstrated efficacy of risperidone in all dose groups from 1 to 6 mg/day compared to placebo, as measured by significant reduction of total PANSS score. The efficacy on the primary parameter in the 1 to 3 mg/day group was comparable to the 4 to 6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5 to 6 mg/day group in study #2. In study #2, the efficacy in the 1.5 to 6 mg/day group was statistically significantly greater than that in the 0.15 to 0.6 mg/day group. Doses higher than 3 mg/day did not reveal any trend towards greater efficacy.
Bipolar Mania - Monotherapy
AdultsThe 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.
The efficacy of risperidone in the treatment of mania in children or adolescents with Bipolar I disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled, multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a manic or mixed episode of bipolar I disorder. Patients were randomized into one of three treatment groups: risperidone 0.5 to 2.5 mg/day (n = 50, mean modal dose = 1.9 mg), risperidone 3 to 6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases, study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7, with further increases in dosage to the maximum tolerated dose within the targeted dose range by Day 10. The primary rating instrument used for assessing efficacy in this study was the mean change from baseline in the total YMRS score.
Results of this study demonstrated efficacy of risperidone in both dose groups compared with placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary parameter in the 3 to 6 mg/day dose group was comparable to the 0.5 to 2.5 mg/day dose group. Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy.
Bipolar Mania – Adjunctive Therapy with Lithium or Valproate
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.
Irritability Associated with Autistic Disorder
Short-Term Efficacy
The efficacy of risperidone in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in children and adolescents (aged 5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects were under 12 years of age and most weighed over 20 kg (16 to 104.3 kg).
Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured the emotional and behavioral symptoms of autism, including aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.
The results of these trials are as follows:
(1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or risperidone0.5 to 3.5 mg/day on a weight-adjusted basis. Risperidone, starting at 0.25 mg/day or 0.5 mg/day depending on baseline weight (<20 kg and ≥20 kg, respectively) and titrated to clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day), significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with placebo.
(2) In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged 5 to 12 years, risperidone 0.02 to 0.06 mg/kg/day given once or twice daily, starting at 0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day, equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared with placebo.
A third trial was a 6-week, multicenter, randomized, double blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects (N=96) 5 to 17 years of age with autistic disorder (defined by DSM-IV criteria) and associated irritability and related behavioral symptoms. Approximately 77% of patients were younger than 12 years of age (mean age = 9), and 88% were male. Most patients (73%) weighed less than 45kg (mean weight = 40 kg). Approximately 90% of patients were antipsychotic-naïve before entering the study.
There were two weight-based, fixed doses of risperidone (high-dose and low-dose). The high dose was 1.25 mg per day for patients weighing 20 to <45 kg, and it was 1.75 mg per day for patients weighing ≥45 kg. The low dose was 0.125 mg per day for patients weighing 20 to <45 kg, and it was 0.175 mg per day for patients weighing ≥45 kg. The dose was administered once daily in the morning, or in the evening if sedation occurred.
The primary efficacy endpoint was the mean change in the Aberrant Behavior Checklist – Irritability subscale (ABC-I) score from baseline to the end of Week 6. The study demonstrated the efficacy of high-dose risperidone, as measured by the mean change in ABC-I score. It did not demonstrate efficacy for low-dose risperidone.The mean baseline ABC-I scores were 29 in the placebo group (n=35), 27 in the risperidone low-dose group (n=30), and 28 in the risperidone high dose group. (n=31). The mean changes in ABC-I scores were -3.5, -7.4, and -12.4 in the placebo, low-dose, and high-dose group respectively. The results in the high-dose group were statistically significant (p<0.001) but not in the low-dose group (p=0.164).
Long-Term Efficacy
Following completion of the first 8-week double-blind study, 63 patients entered an open-label study extension where they were treated with risperidone for 4 or 6 months (depending on whether they received risperidone or placebo in the double-blind study). During this open-label treatment period, patients were maintained on a mean modal dose of risperidone of 1.8 to 2.1 mg/day (equivalent to 0.05 to 0.07 mg/kg/day).
Patients who maintained their positive response to risperidone (response was defined as ≥25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very much improved’) during the 4 to 6 month open-label treatment phase for about 140 days, on average, were randomized to receive risperidone or placebo during an 8-week, double-blind withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients who completed the withdrawal study (n=32), undertaken by an independent Data Safety Monitoring Board, demonstrated a significantly lower relapse rate in the risperidone group compared with the placebo group. Based on the interim analysis results, the study was terminated due to demonstration of a statistically significant effect on relapse prevention. Relapse was defined as ≥25% worsening on the most recent assessment of the ABC-I subscale (in relation to baseline of the randomized withdrawal phase).
How Supplied/Storage and Handling
How Supplied
Risperidone Orally Disintegrating Tablets, USP 0.25 mg, are white, round, flat-faced beveled edge tablets debossed “212” on one side and “P on the other side.
Risperidone Orally Disintegrating Tablets, USP 0.5 mg, are white, round, flat-faced beveled edge tablets debossed “311” on one side and “P on the other side.
Risperidone Orally Disintegrating Tablets, USP 1 mg, are white, round, flat-faced beveled edge tablets deboseed “315” on one side and “P” on the other side.
Risperidone Orally Disintegrating Tablets, USP 2 mg, are white, round, flat-faced beveled edge tablets debossed “401” on one side and “P” on the other side.
Risperidone Orally Disintegrating Tablets, USP 3 mg, are white, round, flat-faced beveled edge tablets debossed “402” on one side and “P” on the other side.
Risperidone Orally Disintegrating Tablets, USP 4 mg, are white, round, flat-faced beveled edge tablets debossed “403” on one side and “P” on the other side.
Risperidone Orally Disintegrating Tablets, USP 0.25 mg are packaged in cartons of 30 tablets with 5 blister packs of 6 (3 x 2) tablets.
Risperidone Orally Disintegrating Tablets, USP 0.5 mg and 1 mg are packaged in cartons of 28 tablets with 7 blister packs of 4 (2x2) tablets, and on cartons of 30 tablets with 5 blister packs of 6 (3x2) tablets.
Risperidone Orally Disintegrating Tablets, USP 2 mg, 3 mg and 4 mg are packaged in cartons of 28 tablets with 7 blister packs of 4 (2 x 2) tablets.
| 0.25 mg | Cartons of 30 tablets with 5 blister packs of 6 (3 x 2) tablets | NDC 49884-212-55 |
| 0.5 mg | Cartons of 28 tablets with 7 blister packs of 4 (2 x 2) tablets Cartons of 30 tablets with 5 blister packs of 6 (3 x 2) tablets | NDC 49884-311-91 NDC 49884-311-55 |
| 1 mg | Cartons of 28 tablets with 7 blister packs of 4 (2 x 2) tablets Cartons of 30 tablets with 5 blister packs of 6 (3 x 2) tablets | NDC 49884-315-91 NDC 49884-315-55 |
| 2 mg | Cartons of 28 tablets with 7 blister packs of 4 (2 x 2) tablets | NDC 49884-401-91 |
| 3 mg | Cartons of 28 tablets with 7 blister packs of 4 (2 x 2) tablets | NDC 49884-402-91 |
| 4 mg | Cartons of 28 tablets with 7 blister packs of 4 (2 x 2) tablets | NDC 49884-403-91 |
Storage and Handling
Risperidone Orally Disintegrating Tablets, USP should be stored at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Protect from light and moisture.
Keep out of reach of children.
PRINCIPAL DISPLAY PANEL – CARTON 1 MG/28 TABLETS
Carton 1 mg (28 Tablets)
PRINCIPAL DISPLAY PANEL – CARTON 1 MG/30 TABLETS
Carton 1 mg (30 Tablets)
PRINCIPAL DISPLAY PANEL – BLISTER 0.5 MG - 6 COUNT
Blister 0.5mg (6 blisters)
PRINCIPAL DISPLAY PANEL – BLISTER 4 MG
Blister 4 mg
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| Labeler - Par Pharmaceutical, Inc. (092733690) |
| Registrant - Par Pharmaceutical Inc. (092733690) |