WARNINGS
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. RISPERDAL ® CONSTA ® (risperidone) is not approved for the treatment of dementia-related psychosis (see Boxed Warning).
Neuroleptic 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 creatine 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.
Tardive 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, RISPERDAL® CONSTA® 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 RISPERDAL® CONSTA®, drug discontinuation should be considered. However, some patients may require treatment with RISPERDAL® CONSTA® despite the presence of the syndrome.
Cerebrovascular 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 73-97) in trials of oral 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 oral risperidone compared to patients treated with placebo. RISPERDAL® CONSTA® is not approved for the treatment of patients with dementia-related psychosis. (See also Boxed Warning, WARNINGS: Increased Mortality in Elderly Patients with Dementia-Related Psychosis.)
Hyperglycemia 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 RISPERDAL®. 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.
PRECAUTIONS
General
Administration
RISPERDAL® CONSTA® should be injected into the gluteal muscle, and care must be taken to avoid inadvertent injection into a blood vessel. (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS — Postintroduction Reports [retinal artery occlusion].)
Orthostatic Hypotension
RISPERDAL® CONSTA® (risperidone) may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.8% (12/1499 patients) of patients treated with RISPERDAL® CONSTA® in multiple-dose studies. Patients should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position).
RISPERDAL® CONSTA® should be used with particular caution in (1) 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, and (2) in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of oral RISPERDAL® and antihypertensive medication.
Seizures
During premarketing testing, seizures occurred in 0.3% (5/1499 patients) of patients treated with RISPERDAL® CONSTA®. Therefore, RISPERDAL® CONSTA® 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. RISPERDAL® CONSTA® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. (See also Boxed Warning, WARNINGS: Increased Mortality in Elderly Patients with Dementia-Related Psychosis.)
Osteodystrophy and Tumors in Animals
RISPERDAL® CONSTA® produced osteodystrophy in male and female rats in a 1-year toxicity study and a 2-year carcinogenicity study at a dose of 40 mg/kg administered IM every 2 weeks.
RISPERDAL® CONSTA® produced renal tubular tumors (adenoma, adenocarcinoma) and adrenomedullary pheochromocytomas in male rats in the 2-year carcinogenicity study at 40 mg/kg administered IM every 2 weeks. In addition, RISPERDAL® CONSTA® produced an increase in a marker of cellular proliferation in renal tissue in males in the 1-year toxicity study and in renal tumor-bearing males in the 2-year carcinogenicity study at 40 mg/kg administered IM every 2 weeks. (Cellular proliferation was not measured at the low dose or in females in either study.)
The effect dose for osteodystrophy and the tumor findings is 8 times the IM maximum recommended human dose (MRHD) (50 mg) on a mg/m2 basis and is associated with a plasma exposure (AUC) 2 times the expected plasma exposure (AUC) at the IM MRHD. The no-effect dose for these findings was 5 mg/kg (equal to the IM MRHD on a mg/m2 basis). Plasma exposure (AUC) at the no-effect dose was one third the expected plasma exposure (AUC) at the IM MRHD.
Neither the renal or adrenal tumors, nor osteodystrophy, were seen in studies of orally administered risperidone. Osteodystrophy was not observed in dogs at doses up to 14 times (based on AUC) the IM MRHD in a 1-year toxicity study.
The renal tubular and adrenomedullary tumors in male rats and other tumor findings are described in more detail under PRECAUTIONS, Carcinogenicity, Mutagenesis, Impairment of Fertility.
The relevance of these findings to human risk is unknown.
Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperdone 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 resperidone carcinogenicity studies conducted in mice and rats (see PRECAUTIONS – Carcinogenesis, Mutagenesis, Impairment of Fertility ). 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.
Potential for Cognitive and Motor Impairment
Somnolence was reported by 5% of patients treated with RISPERDAL® CONSTA® in multiple-dose trials. 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 treatment with RISPERDAL® CONSTA® does not affect them adversely.
Priapism
No cases of priapism have been reported in patients treated with RISPERDAL® CONSTA®. However, rare cases of priapism have been reported in patients treated with oral RISPERDAL®. While the relationship of these events to oral RISPERDAL® use has not been established, other drugs with alpha-adrenergic blocking effects have been reported to induce priapism, and it is possible that RISPERDAL® may share this capacity. Severe priapism may require surgical intervention.
Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient receiving oral RISPERDAL® in a large, open premarketing experience (approximately 1300 patients). She experienced jaundice, fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to RISPERDAL® therapy is unknown.
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.
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 RISPERDAL® use. Caution is advised when prescribing RISPERDAL® CONSTA® for patients who will be exposed to temperature extremes.
Suicide
The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high-risk patients should accompany drug therapy. RISPERDAL® CONSTA® is to be administered by a health care professional (see DOSAGE and ADMINISTRATION ); therefore, suicide due to an overdose is unlikely.
Use in Patients with Concomitant Illness
Clinical experience with RISPERDAL® CONSTA® in patients with certain concomitant systemic illnesses is limited. Patients with Parkinson's Disease or Dementia with Lewy Bodies who receive antipsychotics, including RISPERDAL® CONSTA®, 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 when using RISPERDAL® CONSTA® in patients with diseases or conditions that could affect metabolism or hemodynamic responses.RISPERDAL® CONSTA® 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) treated with oral RISPERDAL®; an increase in the free fraction of risperidone is also seen in patients with severe hepatic impairment. Patients with renal or hepatic impairment should be carefully titrated on oral RISPERDAL® before treatment with RISPERDAL® CONSTA® is initiated at a dose of 25 mg. A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose adjustment, such as in patients with renal or hepatic impairment. (see DOSAGE AND ADMINISTRATION - Dosage in Special Populations ).
Information for Patients
Physicians are advised to discuss the following issues with patients for whom they prescribe RISPERDAL® CONSTA®.
Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension and instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position).
Interference With Cognitive and Motor Performance
Because RISPERDAL® CONSTA® 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 treatment with RISPERDAL® CONSTA® does not affect them adversely.
Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy and for at least 12 weeks after the last injection of RISPERDAL® CONSTA®.
Nursing
Patients should be advised not to breast-feed an infant during treatment and for at least 12 weeks after the last injection of RISPERDAL® CONSTA®.
Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.
Alcohol
Patients should be advised to avoid alcohol during treatment with RISPERDAL® CONSTA®.
Laboratory Tests
No specific laboratory tests are recommended.
Drug Interactions
The interactions of RISPERDAL® CONSTA® and other drugs have not been systematically evaluated. Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® CONSTA® is administered in combination with other centrally-acting drugs or alcohol.
Because of its potential for inducing hypotension, RISPERDAL® CONSTA® may enhance the hypotensive effects of other therapeutic agents with this potential.
RISPERDAL® CONSTA® may antagonize the effects of levodopa and dopamine agonists.
Amytriptyline did not affect the pharmacokinetics of risperidone or the active moiety. Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of the active moiety, whereas ranitidine increased the AUC of the active moiety by 20%.
Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.
Carbamazepine and Other CYP 3A4 Enzyme Inducers
In a drug interaction study in schizophrenic patients, 11 subjects received oral risperidone titrated to 6 mg/day for 3 weeks, followed by concurrent administration of carbamazepine for an additional 3 weeks. During co-administration, the plasma concentrations of risperidone and its pharmacologically active metabolite, 9-hydroxyrisperidone, were decreased by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. Co-administration of other known CYP 3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of RISPERDAL® CONSTA® treatment. At the initiation of therapy with carbamazepine or other known CYP 3A4 hepatic enzyme inducers, patients should be closely monitored during the first 4-8 weeks, since the dose of RISPERDAL® CONSTA® may need to be adjusted. A dose increase, or additional oral RISPERDAL®, may need to be considered. On discontinuation of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of RISPERDAL® CONSTA® should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose of RISPERDAL® CONSTA® between 2 to 4 weeks before the planned discontinuation of carbamazepine or other CYP 3A4 enzyme inducers to adjust for the expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg RISPERDAL® CONSTA® and discontinuing from carbamazepine or other CYP 3A4 enzyme inducers, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates lowering the RISPERDAL® CONSTA® dose to 12.5 mg or necessitates interruption of RISPERDAL® CONSTA® treatment. (See also DOSAGE AND ADMINISTRATION ). The efficacy of the 12.5 mg dose has not been investigated in clinical trials.
Fluoxetine and Paroxetine
Fluoxetine (20 mg QD) and paroxetine (20 mg QD), CYP 2D6 inhibitors, have been shown to increase the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dose of RISPERDAL® CONSTA®. When initiation of fluoxetine or paroxetine is considered, patients may be placed on a lower dose of RISPERDAL® CONSTA® between 2 to 4 weeks before the planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma concentrations of risperidone. When fluoxetine or paroxetine is initiated in patients receiving the recommended dose of 25 mg RISPERDAL® CONSTA®, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates lowering the RISPERDAL® CONSTA® dose to 12.5 mg or necessitates interruption of RISPERDAL® CONSTA® treatment. When RISPERDAL® CONSTA® is initiated in patients already receiving fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. (See also DOSAGE AND ADMINISTRATION ).The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.
Lithium
Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or peak plasma concentrations (Cmax) of lithium (n=13).
Valproate
Repeated oral doses of risperidone (4 mg QD) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma concentration (Cmax) after concomitant administration of risperidone.
Digoxin
RISPERDAL® (0.25 mg BID) did not show a clinically relevant effect on the pharmacokinetics of digoxin.
Drugs that Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is polymorphic in the population and that can be inhibited by a variety of psychotropic and other drugs (see CLINICAL PHARMACOLOGY ). Drug interactions that reduce the metabolism of risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a modest number of poor metabolizers (n≅70 patients) does not suggest that poor and extensive metabolizers have different rates of adverse effects. No comparison of effectiveness in the two groups has been made.
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
There were no significant interactions between risperidone and erythromycin (see CLINICAL PHARMACOLOGY ).
Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, RISPERDAL® CONSTA® is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, oral risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis - Oral
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 oral maximum recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis, or 0.2, 0.75, and 3 times the oral MRHD (mice) or 0.4, 1.5, and 6 times the oral MRHD (rats) on a mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There was a significant increase in pituitary gland adenomas in female mice at doses 0.75 and 3 times the oral MRHD on a mg/m2 basis. There was a significant increase in endocrine pancreatic adenomas in male rats at doses 1.5 and 6 times the oral MRHD on a mg/m2 basis. Mammary gland adenocarcinomas were significantly increased in female mice at all doses tested (0.2, 0.75, and 3 times the oral MRHD on a mg/m2 basis), in female rats at all doses tested (0.4, 1.5, and 6 times the oral MRHD on a mg/m2 basis), and in male rats at a dose 6 times the oral MRHD on a mg/m2 basis.
Carcinogenesis - IM
RISPERDAL® CONSTA® was evaluated in a 24-month carcinogenicity study in which SPF Wistar rats were treated every 2 weeks with IM injections of either 5 mg/kg or 40 mg/kg of risperidone. These doses are 1 and 8 times the MRHD (50 mg) on a mg/m2 basis. A control group received injections of 0.9% NaCl, and a vehicle control group was injected with placebo microspheres. There was a significant increase in pituitary gland adenomas, endocrine pancreas adenomas, and adrenomedullary pheochromocytomas at 8 times the IM MRHD on a mg/m2 basis. The incidence of mammary gland adenocarcinomas was significantly increased in female rats at both doses (1 and 8 times the IM MRHD on a mg/m2 basis). A significant increase in renal tubular tumors (adenoma, adenocarcinomas) was observed in male rats at 8 times the IM MRHD on a mg/m2 basis. Plasma exposures (AUC) in rats were 0.3 and 2 times (at 5 and 40 mg/kg, respectively) the expected plasma exposure (AUC) at the IM MRHD.
Dopamine D2 receptor antagonists have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the carcinogenicity studies of oral risperidone; however, measurements taken during subchronic toxicity studies showed that oral risperidone elevated serum prolactin levels 5- to 6-fold in mice and rats at the same doses used in the oral carcinogenicity studies. Serum prolactin levels increased in a dose-dependent manner up to 6- and 1.5-fold in male and female rats, respectively, at the end of the 24-month treatment with RISPERDAL® CONSTA® every 2 weeks. Increases in the incidence of pituitary gland, endocrine pancreas, and mammary gland neoplasms have been found in rodents after chronic administration of other antipsychotic drugs and may be prolactin-mediated.
The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown (see PRECAUTIONS - Hyperprolactinemia ).
Mutagenesis
No evidence of mutagenic potential for oral risperidone was found in the in vitro Ames reverse mutation test, in vitro mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo oral micronucleus test in mice, the sex-linked recessive lethal test in Drosophila, or the in vitro chromosomal aberration test in human lymphocytes or in Chinese hamster cells.
In addition, no evidence of mutagenic potential was found in the in vitro Ames reverse mutation test for RISPERDAL® CONSTA®.
Impairment of Fertility
Oral risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in three reproductive studies (two mating and fertility studies and a multigenerational study) at doses 0.1 to 3 times the oral maximum recommended human dose (MRHD) (16 mg/day) on a mg/m2 basis. The effect appeared to be in females, since impaired mating behavior was not noted in the mating and fertility study in which males only were treated. In a subchronic study in Beagle dogs in which oral 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 oral MRHD on a mg/m2 basis. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm values partially recovered, but remained decreased after treatment was discontinued. No no-effect doses were noted in either rat or dog.
No mating and fertility studies were conducted with RISPERDAL® CONSTA®.
Pregnancy
Pregnancy Category C
The teratogenic potential of oral risperidone was studied in three embryofetal development studies in Sprague-Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the oral maximum recommended human dose [MRHD] on a mg/m2 basis) and in one embryofetal development study in New Zealand rabbits (0.31-5 mg/kg or 0.4 to 6 times the oral 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 oral MRHD on a mg/m2 basis. In three reproductive studies in rats (two peri/post-natal development studies 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 oral 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 peri/post-natal development study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the oral 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 Days 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 oral MRHD on a mg/m2 basis.
No studies were conducted with RISPERDAL® CONSTA®.
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 oral RISPERDAL® therapy is unknown. Reversible extrapyramidal symptoms in the neonate were observed following postmarketing use of risperidone during the last trimester of pregnancy.
RISPERDAL® CONSTA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The effect of RISPERDAL® CONSTA® on labor and delivery in humans is unknown.
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 should not breast-feed during treatment with RISPERDAL® CONSTA® and for at least 12 weeks after the last injection.
Pediatric Use
RISPERDAL® CONSTA® has not been studied in children younger than 18 years old.
Geriatric Use
In an open-label study, 57 clinically stable, elderly patients (≥65 years old) with schizophrenia or schizoaffective disorder received RISPERDAL® CONSTA® every 2 weeks for up to 12 months. In general, no differences in the tolerability of RISPERDAL® CONSTA® were observed between otherwise healthy elderly and nonelderly patients. Therefore, dosing recommendations for otherwise healthy elderly patients are the same as for nonelderly patients. Because elderly patients exhibit a greater tendency to orthostatic hypotension than nonelderly patients, elderly patients should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). In addition, monitoring of orthostatic vital signs should be considered in elderly patients for whom orthostatic hypotension is of concern (see CLINICAL PHARMACOLOGY , PRECAUTIONS , and DOSAGE AND ADMINISTRATION ).
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 oral risperidone when compared to patients treated with oral risperidone alone or with oral 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 oral risperidone regardless of concomitant use with furosemide. RISPERDAL® CONSTA® is not approved for the treatment of patients with dementia-related psychosis. (See also Boxed Warning, WARNINGS: Increased Mortality in Elderly Patients with Dementia-Related Psychosis.)
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