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ECG Changes Between-group comparisons for pooled placebo-controlled trials revealed no statistically significant differences between risperidone and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all RISPERDAL ® doses were pooled from randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of risperidone ( 8-16 mg/ day) were associated with a higher mean increase in heart rate compared to placebo ( 4-6 beats per minute) . Text Continues Below
Other Events Observed During the Premarketing Evaluation of RISPERDAL ® During its premarketing assessment, multiple doses of RISPERDAL ® were administered to 2607 patients in Phase 2 and 3 studies. The conditions and duration of exposure to RISPERDAL ® varied greatly, and included ( in overlapping categories) open-label and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and short-term or longer-term exposure. In most studies, untoward events associated with this exposure were obtained by spontaneous report and recorded by clinical nvestigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of ndividuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In two large studies, adverse events were also elicited utilizing the UKU ( direct questioning) side effect rating scale, and these events were not further categorized using standard terminology. ( Note: These events are marked with an asterisk in the listings that follow. ) In the listings that follow, spontaneously reported adverse events were classified using World Health Organization ( WHO) preferred terms. The frequencies presented, therefore, represent the proportion of the 2607 patients exposed to multiple doses of RISPERDAL ® who experienced an event of the type cited on at least one occasion while receiving RISPERDAL ® . All reported events are included, except those already listed in Table 1, those events for which a drug cause was remote, and those event terms which were so general as to be uninformative. It is important to emphasize that, although the events reported occurred during treatment with RISPERDAL ® , they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/ 100 patients ( only those not already listed in the tabulated results from placebo-controlled trials appear in this listing) ; infrequent adverse events are those occurring in 1/ 100 to 1/ 1000 patients; rare events are those occurring in fewer than 1/ 1000 patients. Psychiatric Disorders Frequent increased dream activity* , diminished sexual desire* , nervousness. Infrequent impaired concentration, depression, apathy, catatonic reaction, euphoria, increased libido, amnesia. Rare emotional lability, nightmares, delirium, withdrawal syndrome, yawning. Central and Peripheral Nervous System Disorders Frequent increased sleep duration* . Infrequent dysarthria, vertigo, stupor, paraesthesia, confusion. Rare aphasia, cholinergic syndrome, hypoesthesia, tongue paralysis, leg cramps, torticollis, hypotonia, coma, migraine, hyperreflexia, choreoathetosis. Gastrointestinal Disorders Frequent anorexia, reduced salivation* . Infrequent flatulence, diarrhea, increased appetite, stomatitis, melena, dysphagia, hemorrhoids, gastritis. Rare fecal incontinence, eructation, gastroesophageal reflux, gastroenteritis, esophagitis, tongue discoloration, cholelithiasis, tongue edema, diverticulitis, gingivitis, discolored feces, GI hemorrhage, hematemesis. Body as a Whole/ General Disorders Frequent fatigue. Infrequent edema, rigors, malaise, nfluenza-like symptoms. Rare pallor, enlarged abdomen, allergic reaction, ascites, sarcoidosis, flushing. Respiratory System Disorders Infrequent hyperventilation, bronchospasm, pneumonia, stridor. Rare asthma, increased sputum, aspiration. Skin and Appendage Disorders Frequent increased pigmentation* , photosensitivity* . Infrequent increased sweating, acne, decreased sweating, alopecia, hyperkeratosis, pruritus, skin exfoliation. Rare bullous eruption, skin ulceration, aggravated psoriasis, furunculosis, verruca, dermatitis lichenoid, hypertrichosis, genital pruritus, urticaria. Cardiovascular Disorders Infrequent palpitation, hypertension, hypotension, AV block, myocardial infarction. Rare ventricular tachycardia, angina pectoris, premature atrial contractions, T wave inversions, ventricular extrasystoles, ST depression, myocarditis. Vision Disorders Infrequent abnormal accommodation, xerophthalmia. Rare diplopia, eye pain, blepharitis, photopsia, photophobia, abnormal lacrimation. Metabolic and Nutritional Disorders Infrequent hyponatremia, weight ncrease, creatinine phosphokinase increase, thirst, weight decrease, diabetes mellitus. Rare decreased serum iron, cachexia, dehydration, hypokalemia, hypoproteinemia, hyperphosphatemia, hypertriglyceridemia, hyperuricemia, hypoglycemia. Urinary System Disorders Frequent polyuria/ polydipsia* . Infrequent urinary incontinence, hematuria, dysuria. Rare urinary retention, cystitis, renal insufficiency. Musculo-Skeletal System Disorders Infrequent myalgia. Rare arthrosis, synostosis, bursitis, arthritis, skeletal pain. Reproductive Disorders, Female Frequent menorrhagia* , orgastic ysfunction* , dry vagina* . Infrequent nonpuerperal lactation, amenorrhea, female breast pain, leukorrhea, mastitis, dysmenorrhea, female perineal pain, intermenstrual bleeding, vaginal hemorrhage. Liver and Biliary System Disorders Infrequent increased SGOT, increased SGPT. Rare hepatic failure, cholestatic hepatitis, cholecystitis, cholelithiasis, hepatitis, hepatocellular damage. Platelet, Bleeding, and Clotting Disorders Infrequent epistaxis, purpura. Rare hemorrhage, superficial phlebitis, thrombophlebitis, thrombocytopenia. Hearing and Vestibular Disorders Rare tinnitus, hyperacusis, decreased hearing. Red Blood Cell Disorders Infrequent anemia, hypochromic anemia. Rare normocytic anemia. Reproductive Disorders, Male Frequent erectile dysfunction* . Infrequent ejaculation failure. White Cell and Resistance Disorders Rare leukocytosis, lymphadenopathy, leucopenia, Pelger-Huet anomaly. Endocrine Disorders Rare gynecomastia, male breast pain, antidiuretic hormone disorder. Special Senses Rare bitter taste. * Incidence based on elicited reports. Postintroduction Reports Adverse events reported since market ntroduction which were temporally ( but not necessarily causally) related to RISPERDAL ® therapy, include the following: anaphylactic reaction, angioedema, apnea, atrial fibrillation, cerebrovascular disorder, including cerebrovascular accident, hyperglycemia, diabetes mellitus aggravated, including diabetic ketoacidosis, intestinal obstruction, jaundice, mania, pancreatitis, Parkinson's disease aggravated, pulmonary embolism. There have been rare reports of sudden death and/ or cardiopulmonary arrest in patients receiving RISPERDAL ® . A causal relationship with RISPERDAL ® has not been established. It is important to note that sudden and unexpected death may occur in psychotic patients whether they remain untreated or whether they are treated with other antipsychotic drugs. Drug Interactions The interactions of RISPERDAL ® and other drugs have not been systematically evaluated. Given the primary CNS effects of risperidone, caution should be used when RISPERDAL ® is taken in combination with other centrally acting drugs and alcohol. Because of its potential for inducing hypotension, RISPERDAL ® may enhance the hypotensive effects of other therapeutic agents with this potential. RISPERDAL ® may antagonize the effects of levodopa and dopamine agonists. Amytriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction. Cimetidine and ranitidine increased the bioavailability of risperidone, but only marginally ncreased the plasma concentration of the active antipsychotic fraction.
Chronic administration of clozapine with risperidone may decrease the clearance of risperidone. Carbamazepine and Other Enzyme Inducers
In a drug interaction study in schizophrenic patients, 11 subjects received 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. The dose of risperidone may need to be titrated accordingly for patients receiving carbamazepine, particularly during initiation or discontinuation of carbamazepine therapy. Co-administration of other known 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 risperidone treatment. Fluoxetine and Paroxetine Fluoxetine ( 20 mg QD) and paroxetine ( 20 mg QD) 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 an average of 13% . When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of RISPERDAL ® . 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 ( C max ) 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 ( C max ) 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 s 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) 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 nhibitor of CYP 2D6. Therefore, RISPERDAL ® is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6. Carcinogenesis, Mutagenesis, Impairment of Fertility 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) ( 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/ m 2 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. The following table summarizes the multiples of the human dose on a mg/ m 2 ( mg/ kg) basis at which these tumors occurred. 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 ( see PRECAUTIONS, General -Hyperprolactinemia) . 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. 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/ m 2 basis. The effect appeared to be in females, since mpaired 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/ m 2 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. 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/ m 2 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/ m 2 basis) . The incidence of malformations was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the MRHD on a mg/ m 2 basis. In three reproductive studies in rats ( two Segment III and a multigenerational study) , there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16-5 mg/ kg or 0.1 to 3 times the MRHD on a mg/ m 2 basis. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams. There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was an increase in stillborn rat pups at a dose of 2.5 mg/ kg or 1.5 times the MRHD on a mg/ m 2 basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a decrease in the number of live pups and an increase in the number of dead pups at birth ( Day 0) , and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup body weight gain and survival ( from Day 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams. These effects were all noted at the one dose of risperidone tested, i. e. , 5 mg/ kg or 3 times the MRHD on a mg/ m 2 basis. Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled studies in pregnant women. However, there was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero . The causal relationship to RISPERDAL ® therapy is unknown. RISPERDAL ® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery The effect of RISPERDAL ® 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 receiving risperidone should not breast-feed. Pediatric Use Safety and effectiveness in children have not been established. Geriatric Use Clinical studies of RISPERDAL ® did not nclude 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 dentified differences in responses between elderly and younger patients. In general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy ( see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION) . 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 ( see PRECAUTIONS) . Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function ( see DOSAGE AND ADMINISTRATION) . Page: << Prev | 1 | 2 | 3 | 4 | 5
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