Risperidone precautions

List of precautions
Increased mortality in elderly patients with dementia-related psychosis Neuroleptic malignant syndrome Tardive dyskinesia Hyperglycemia Diabetes mellitus Orthostatic hypotension Seizures Dysphagia Hyperprolactinemia Potential for cognitive/motor impairment Priapism Thrombotic thrombocytopenic purpura Antiemetic effect Body temperature regulation Suicide Patients with concomitant illness Lab tests Carcinogenesis Mutagenesis Impairment of fertility Pregnancy Labor & delivery Nursing mothers Pediatric use Geriatric use
 * Overview (NMS)
 * Diagnostic evaluation (NMS)
 * Management (NMS)
 * Reintroduction of drug therapy (NMS)
 * Overview (TD)
 * Treatment (TD)
 * Prescribing Risperidone (TD)
 * Discontinuation (TD)
 * Overview (pediatrics)
 * Tardive dyskinesia (pediatrics)
 * Weight gain (pediatrics)
 * Somnolence (pediatrics)
 * Hyperprolactinemia/growth/sexual maturation (pediatrics)
 * Overview (geriatrics)
 * Concomitant use with furosemide in elderly patients with dementia-related psychosis

Increased mortality in elderly patients with dementia-related psychosis
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Risperidone is not approved for the treatment of dementia-related psychosis. Return to top

Overview (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. Return to top

Diagnostic evaluation (NMS)
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. Return to top

Management (NMS)
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. Return to top

Reintroduction of drug therapy (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. Return to top

Overview (TD)
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. Return to top

Treatment (TD)
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. Return to top

Prescribing Risperidone (TD)
Given these considerations, Risperidone (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. Return to top

Discontinuation (TD)
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. Return to top

Hyperglycemia
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. Return to top

Diabetes mellitus
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. Return to top

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. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either QD or 1 mg BID) in normal adults and 0.5 mg BID in the elderly and patients with renal or hepatic impairment. 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. Return to top

Seizures
During premarketing testing, 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. Return to top

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. Return to top

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. 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. Return to top

Potential for cognitive/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. Return to top

Priapism
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. Return to top

Thrombotic thrombocytopenic purpura
A single case of TTP was reported in a 28 year-old female patient receiving Risperidone in a large, open premarketing experience (approximately 1300 patients). She experienced jaundice, fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to Risperidone therapy is unknown. Return to top

Antiemetic 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. Return to top

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. Return to top

Suicide
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 of tablets, consistent with good patient management, in order to reduce the risk of overdose. Return to top

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 m2), 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. Return to top

Lab tests
No specific laboratory tests are recommended. Return to top

Carcinogenesis
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis or 0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5–6 fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown. Return to top

Mutagenesis
No evidence of mutagenic potential for risperidone was found in the Ames reverse mutation test, mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo micronucleus test in mice, the sex-linked recessive lethal test in Drosophila, or the chromosomal aberration test in human lymphocytes or Chinese hamster cells. Return to top

Impairment of fertility
Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times the maximum recommended human dose (MRHD) on a mg/m2 basis. The effect appeared to be in females, since impaired mating behavior was not noted in the Segment I study in which males only were treated. In a subchronic study in Beagle dogs in which risperidone was administered at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the MRHD on a mg/m2 basis. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. No no-effect doses were noted in either rat or dog. Return to top

Pregnancy
Pregnancy Category C The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-Dawley and Wistar rats (0.63–10 mg/kg or 0.4 to 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) and in one Segment II study in New Zealand rabbits (0.31–5 mg/kg or 0.4 to 6 times the MRHD on a mg/m2 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/m2 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 0.16–5 mg/kg or 0.1 to 3 times the MRHD on a mg/m2 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/m2 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/m2 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 Risperdal® 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. Return to top

Labor & delivery
The effect of Risperidone on labor and delivery in humans is unknown. Return to top

Nursing 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. Return to top

Overview (pediatrics)
The safety and effectiveness of Risperidone in pediatric patients with schizophrenia or bipolar mania have not been established. The efficacy and safety of Risperidone in the treatment of irritability associated with autistic disorder were established in two 8-week, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years. Additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short- and long-term studies in more than 1200 pediatric patients with other psychiatric disorders who were of similar age and weight, and who received similar dosages of Risperdal® as patients treated for irritability associated with autistic disorder. The safety and effectiveness of Risperidone in pediatric patients with autistic disorder less than 5 years of age have not been established. Return to top

Tardive dyskinesia (pediatrics)
In clinical trials in 1885 children and adolescents with autistic disorder or other psychiatric disorders treated with risperidone, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of risperidone treatment. Return to top

Weight gain (pediatrics)
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. When treating patients with Risperidone, weight gain should be assessed against that expected with normal growth. Return to top

Somnolence (pediatrics)
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. Patients experiencing persistent somnolence may benefit from a change in dosing regimen. Return to top

Hyperprolactinemia/growth/sexual maturation (pediatrics)
Risperidone has been shown to elevate prolactin levels in children and adolescents as well as in adults. In double-blind, placebo-controlled studies of up to 8 weeks duration in children and adolescents (aged 5 to 17 years), 49% of patients who received risperidone had elevated prolactin levels compared to 2% of patients who received placebo. In clinical trials in 1885 children and adolescents with autistic disorder or other psychiatric disorders treated with risperidone, 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 notbeen fully evaluated. Return to top

Overview (geriatrics)
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. 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 BID followed by careful titration. 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. Return to top

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. Return to top