Risperdal

RISPERDAL (4 mg o.d.) did not show an effect on the pharmacokinetics of valproate (1000 mg/day) (n=9). However, more subjects reported adverse events with the risperidone-valproate therapy compared to the placebo-valproate group in the clinical trial.

The metabolism of RISPERDAL, a substrate of the hepatic cytochrome P450 isozyme 2D6 (CYP 2D6), is affected by the debrisoquine hydroxylation polymorphism (see Action and Clinical Pharmacology, Pharmacokinetics). CYP 2D6 is also responsible for the metabolism of a variety of drugs, including phenothiazines, antidepressants (tricyclics and SSRIs), antiarrhythmics and some β-blockers. Consequently, potential interaction between RISPERDAL and drugs that are also substrates of CYP 2D6, should also be considered.

RISPERDAL (3 mg b.i.d.) did not show an effect on the pharmacokinetics of lithium (400, 450 or 560 mg b.i.d.) (n=13).

A drug-drug interaction study conducted in 52 patients with various types of bipolar disorder (24 males, 28 females), ages 19-56 years, evaluated the steady-state pharmacokinetics of risperidone and topiramate when administered concomitantly. Eligible subjects were stabilized on a risperidone dose of 1-6 mg/day for 2 to 3 weeks. Topiramate was then titrated up to escalating doses of 100, 250 and 400 mg/day along with risperidone for up to 6 weeks. Risperidone was then tapered and discontinued over 4 weeks while maintaining topiramate (up to 400 mg/day). There was a statistically significant reduction in risperidone systemic exposure (16% and 33% for AUC₁₂ and 13% and 34% for C_max at the 250 and 400 mg/day doses, respectively). Minimal alterations were observed in the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined and of 9-hydroxyrisperidone. Topiramate systemic exposure was slightly reduced (12.5% for mean C_max and 11% for mean AUC₁₂) in the presence of risperidone, which achieved statistical significance. There were no clinically significant changes in the systemic exposure of risperidone and 9-hydroxyrisperidone combined or of topiramate. The effects of higher doses of topiramate (>400 mg/day) are unknown. Therefore, if combination therapy is chosen, patients receiving both risperidone and topiramate should be closely monitored.

The cholinesterase inhibitors, galantamine (n=15) and donepezil (n=24), did not show an effect on the pharmacokinetics of risperidone or risperidone and 9-hydroxyrisperidone combined. Galantamine 12 mg o.d. was co-administered with risperidone 0.5 mg o.d. in healthy elderly volunteers. Donepezil 5 mg o.d. was co-administered with risperidone 0.5 mg b.i.d. in healthy male volunteers.

The effect of RISPERDAL (0.5 mg/day administered b.i.d.) on the steady-state plasma concentrations of digoxin (0.125 mg/day) was examined in a double-blind, two-way, crossover trial in healthy elderly volunteers (median age 68 years, range 61 to 75 years, n=19). RISPERDAL did not affect the steady-state pharmacokinetics of digoxin, and concurrent administration of the two drugs was well tolerated.

In vitro studies, in which risperidone was given in the presence of various, highly protein-bound agents, indicated that clinically relevant changes in protein binding would not occur either for RISPERDAL or for any of the drugs tested.

Erythromycin, a CYP 3A4 inhibitor, did not change the pharmacokinetics of risperidone or risperidone and 9-hydroxyrisperidone combined. Risperidone was administered as a single dose of 1 mg with multiple doses of erythromycin (500 mg q.i.d.) in healthy volunteers (n=18).

Given the primary central nervous system effects of RISPERDAL, caution should be used when it 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. RISPERDAL may antagonize the effects of levodopa and dopamine agonists.

Clinically significant hypotension has been observed postmarketing with concomitant use of risperidone and antihypertensive medications.

Caution is advised when prescribing RISPERDAL with drugs known to prolong the QT interval.

Carbamazepine has been shown to decrease substantially the plasma levels of risperidone and its active metabolite, 9-hydroxyrisperidone (n=11). Similar effects may be observed with other CYP 3A4 hepatic enzyme inducers. Consequently, in the presence of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dose of RISPERDAL may have to be adjusted. On discontinuation of these drugs, the dosage of RISPERDAL should be re-evaluated and, if necessary, decreased.

Risperidone was administered as a single dose of 1 mg with multiple doses of either cimetidine (400 mg b.i.d.) or ranitidine (150 mg b.i.d.) in healthy young adult volunteers (n=12). The effect of the drug interaction of cimetidine and ranitidine on risperidone and 9-hydroxyrisperidone combined was minimal.

Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.

RISPERDAL oral solution is compatible with the following beverages: water, coffee, orange juice and low-fat milk. However, it is not compatible with cola or tea. Also see Dosage and Administration.

A drug-drug interaction study between risperidone and topiramate was conducted in 12 healthy volunteers (6 males, 6 females), ages 28-40 years, with single-dose administration of risperidone (2 mg) and multiple doses of topiramate (titrated up to 200 mg/day). In the presence of topiramate, systemic exposure of risperidone and 9-hydroxyrisperidone combined was reduced such that mean AUC_0-∞ was 11% lower and mean C_max was statistically significantly (18%) lower. In the presence of topiramate, systemic exposure of risperidone was statistically significantly reduced such that mean C_max and AUC_0-∞ were 29% and 23% lower, respectively. The pharmacokinetics of 9-hydroxyrisperidone were unaffected. The effects of a single dose (2 mg/day) of risperidone on the pharmacokinetics of multiple doses of topiramate have not been studied.

Interactions with laboratory tests have not been established.

Fluoxetine and paroxetine, CYP 2D6 inhibitors, increase the plasma concentration of risperidone but less so of risperidone and 9-hydroxyrisperidone combined. Pharmacokinetic interaction with fluoxetine was examined in a study which measured steady-state plasma levels of risperidone and its metabolites before and following 3 weeks of co-treatment with fluoxetine (n=10). The addition of fluoxetine resulted in about a 2- to 3-fold increase in peak and AUC levels of risperidone and about a 50% increase in peak and AUC levels for risperidone and 9-hydroxyrisperidone combined. Similarly, pharmacokinetic interaction with paroxetine was examined in a study which measured steady-state plasma levels of risperidone and its metabolites before and following 4 weeks of co-treatment with paroxetine (n=10). After 4 weeks of paroxetine treatment, the sum of the concentrations of risperidone and 9-hydroxyrisperidone increased significantly by 45% over baseline. When concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of RISPERDAL.

See Warnings and Precautions, Special Populations regarding increased mortality in elderly patients with dementia concomitantly receiving furosemide.

Interactions with herbal products have not been established.

RISPERDAL should be used with caution in patients with renal impairment.

Patients with renal impairment have less ability to eliminate the active antipsychotic fraction than normal adults. In general, starting and consecutive dosing should be halved, and dose titration should be slower for patients with renal impairment, administered on a b.i.d. schedule. The recommended initial dose is 0.5 mg b.i.d. and dosage increases should be in increments of no more than 0.5 mg b.i.d. Increases to dosages above 1.5 mg b.i.d. should generally occur at intervals of at least 1 week. In some patients, slower titration may be medically appropriate (see Warnings and Precautions, Renal, Action and Clinical Pharmacology, Pharmacokinetics and Table 8).

Risperidone is substantially excreted by the kidneys. Thus, 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, caution should be taken in dose selection and titration. It may also be useful to monitor renal function in these patients (see Warnings and Precautions, Special Populations, Action and Clinical Pharmacology, Pharmacokinetics and Table 8).

In elderly schizophrenic patients, the doses of RISPERDAL should be adjusted slowly from a 0.25 mg b.i.d. starting dose to a maximum daily dose of 3 mg. Since the elimination of RISPERDAL is somewhat slower in these patients, the potential for accumulation should be considered (see Action and Clinical Pharmacology, Pharmacokinetics and Table 8).

RISPERDAL can be administered on either a o.d. or b.i.d. schedule, generally beginning with 1 to 2 mg per day. The dose should be adjusted gradually over several days based on clinical response to a target dose of 4 to 6 mg per day. Some patients may benefit from lower initial doses and/or a slower adjustment schedule.

Further dosage adjustments, if indicated, should generally occur at intervals of not less than one week since steady state for the active metabolite would not be achieved for approximately one week in the typical patient. When dosage adjustments are necessary, small increments/decrements of 1 mg are recommended.

In controlled clinical trials, optimal therapeutic effects were seen in the 4 to 8 mg per day dose range. However, clinical experience indicates that in the majority of patients adequate therapeutic effect is achieved at the 6 mg per day dose. Doses above 10 mg per day have not been shown to be more efficacious than lower doses and were associated with more extrapyramidal symptoms and other adverse events.

The safety of RISPERDAL has not been established above 16 mg total daily dose, administered twice daily. If administered once daily, safety has not been established beyond a single dose of 8 mg.

Physicians are advised to assess the risks and benefits of the use of RISPERDAL in elderly patients with dementia, taking into account risk predictors for stroke or existing cardiovascular comorbidities in the individual patient (see Indications and Clinical Use, Warnings and Precautions and Adverse Reactions).

Discontinuation should be considered if signs and symptoms of cerebrovascular adverse events occur.

A starting dose of RISPERDAL 0.25 mg b.i.d. is recommended. This dosage should be adjusted by increments of 0.25 mg per day approximately every 2 to 4 days. The optimal dose is 0.5 mg b.i.d. (1.0 mg per day) for most patients. Some patients, however, may benefit from higher doses up to a maximum of 1.0 mg b.i.d. (2.0 mg per day).

Periodic dosage adjustments (increase or decrease) or discontinuation of treatment should be considered because of the instability of the symptoms treated.

Since there is no experience in younger patients, dosage recommendations cannot be made.

It is recommended that responding patients be continued on RISPERDAL at the lowest dose needed to maintain remission. Patients should be reassessed periodically to determine the need for maintenance treatment. While there is no body of evidence available to answer the question of how long the patient should be treated with RISPERDAL, the effectiveness of maintenance treatment is well established for many other antipsychotic drugs.

RISPERDAL may be given as tablets or oral solution. RISPERDAL M-TAB is given as orally disintegrating tablets. All may be taken with or without meals. In order to avoid orthostatic hypotension, the dose of RISPERDAL should be adjusted gradually.

RISPERDAL M-TAB tablets should not be split into halves.

The missed dose should be taken at the next scheduled dose. Doses should not be doubled.

RISPERDAL should be used with caution in patients with hepatic impairment.

Patients with impaired hepatic function have increases in plasma concentration of the free fraction of risperidone and this may result in an enhanced effect. In general, starting and consecutive dosing should be halved, and dose titration should be slower for patients with hepatic impairment, administered on a b.i.d. schedule.

In patients with schizophrenia and related psychotic disorders with impaired liver function, the starting dose should be 0.25 to 0.5 mg b.i.d. This dosage can be individually adjusted in 0.5 mg b.i.d. increments to 1 to 2 mg b.i.d. Increases to dosages above 1.5 mg b.i.d. should generally occur at intervals of at least 1 week (see Warnings and Precautions, Hepatic/Biliary/Pancreatic, Action and Clinical Pharmacology, Pharmacokinetics and Table 8).

RISPERDAL should be administered on a once-daily schedule, starting with 2 mg to 3 mg per day. Dosage adjustments, based on clinical response and tolerability, should occur at intervals of not less than 24 hours and in dosage increments or decrements of 1 mg per day. RISPERDAL doses higher than 6 mg per day were not studied in patients with bipolar disorder.

In two controlled trials, the most common daily dose was 1-4 mg/day. In each of the three controlled trials, RISPERDAL was effective across the dose range used, although the effect size in the 3-4 mg/day mean modal dose group was larger than in the 5-6 mg/day mean modal dose group (mean modal dose is the average of the most frequent daily dose across the three trials).

The safety and effectiveness of RISPERDAL for long-term use and for prophylactic use in bipolar disorder have not been evaluated. Physicians who elect to use RISPERDAL for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

When medically appropriate, gradual discontinuation of the previous treatment, while RISPERDAL therapy is initiated, is recommended. In all cases, the period of overlapping antipsychotic administration should be minimized. When switching patients from depot antipsychotics, initiate RISPERDAL therapy in place of the next scheduled injection. The need for continuing existing antiparkinsonian medications should be re-evaluated periodically.

Refer to Special Populations for dosing recommendations in the following patients: patients prone to hypotension; geriatrics; patients with renal impairment; patients with hepatic impairment.

Caution should be exercised in patients prone to hypotension and the use of lower starting doses of 0.25 to 0.5 mg b.i.d. should be considered.

Adverse events reported since market introduction of RISPERDAL, which were temporally (but not necessarily causally) related to RISPERDAL therapy, include the following: edema, angioedema, increased hepatic enzyme levels, skin manifestations of allergy including cases of Stevens-Johnson syndrome, systemic manifestations of allergy including a case of anaphylactic shock, neuroleptic malignant syndrome, body temperature dysregulation, urinary incontinence, gynecomastia, seizures, tardive dyskinesia, hypertension, leukopenia, priapism, neutropenia, thrombopenia, apnea, atrial fibrillation, benign pituitary adenomas, cerebrovascular disorder including cerebrovascular accident, intestinal obstruction, jaundice, mania, pancreatitis, Parkinson's disease aggravated and pulmonary embolism.

Hyperglycemia and exacerbation of pre-existing diabetes have been reported in very rare cases during RISPERDAL treatment. Diabetic ketoacidosis has also been reported (see Warnings and Precautions, Endocrine and Metabolism).

As with other neuroleptics, sudden death, Torsades de Pointe, ventricular tachycardia, arrhythmia, cardiopulmonary arrest and QT prolongation have been reported during RISPERDAL treatment. Many of the patients had pre-existing cardiovascular disease, were on concomitant medications known to prolong the QT interval, had risk factors for QT prolongation, took an overdose of risperidone, and/or were morbidly obese. Very rarely, QT prolongation has been reported in the absence of confounding factors.

In one study in which testosterone levels were measured, testosterone decreased below the normal range in 6 out of 85 patients.

In 6 placebo-controlled dementia trials for elderly patients taking RISPERDAL for 4 to 12 weeks within the approved dosage range, the pooled incidence rate of CVAEs was 3%, compared to 1% for age-matched patients taking placebo. Five patients died in the RISPERDAL group (5/1009) versus 1 patient in the placebo group (1/712) (see Indications and Clinical Use, Warnings and Precautions and Dosage and Administration).

Erectile dysfunction, ejaculatory dysfunction, orgastic dysfunction, and rash have also been reported during treatment with RISPERDAL. As with other antipsychotics, cases of water intoxication, either due to polydipsia or to syndrome of inappropriate secretion of antidiuretic hormone (SIADH), have occasionally been reported during treatment with RISPERDAL.

Hypotension (including orthostatic) and tachycardia (including reflex tachycardia) have been observed following the administration of RISPERDAL (see Warnings and Precautions, Cardiovascular).

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Treatment-emergent Adverse Events Reported in Double-blind Monotherapy Trials in Bipolar Disorder (≥1% and More Frequent Than Placebo)

Other adverse events which occurred with a high incidence but with similar frequencies in the patients treated with RISPERDAL and placebo included injury (28 to 38%), falls (13 to 25%), urinary tract infection (13 to 21%), and purpura (10 to 17%).

In the 3-week placebo-controlled trials, a total of 4.2% of patients discontinued from the studies because of an adverse event: 4.1% for placebo, 4.8% for RISPERDAL and 2.8% for haloperidol. The most common adverse event leading to discontinuation was manic reaction: 1.0% for placebo and 1.6% for RISPERDAL.

Parkinsonian side effects reported were usually mild but dose-related; they were reversible upon dose reduction and/or administration of antiparkinsonian medication.

Electrocardiograms were evaluated in patients treated with RISPERDAL (N=380), haloperidol (N=126) and placebo (N=120). In the RISPERDAL group, eight patients had a slight increase in QTc intervals from less than 450 msec at baseline to intervals ranging from 450 to 474 msec during treatment. Changes of this type were not seen in placebo-treated patients but were observed in three haloperidol-treated subjects.

In controlled clinical trials, patients treated with RISPERDAL had higher prolactin levels than patients treated with placebo or haloperidol. Associated manifestations that occurred in fewer than 1% of patients treated with RISPERDAL during the bipolar clinical trials, which are not listed in Table 7, included ejaculation failure, abnormal sexual function, decreased libido, and impotence.

In a pool of 6- to 8-week placebo-controlled clinical trials, which compared RISPERDAL and placebo in the treatment of schizophrenia, 18% of patients treated with RISPERDAL and 9% of placebo-treated patients met a weight gain criterion of ≥7% of baseline body weight. This difference was statistically significant. With continued treatment, weight gain (mean: 2.3 kg in long-term studies) has been seen.

The most frequent adverse reactions reported during clinical trials with RISPERDAL were insomnia, agitation, extrapyramidal disorder, anxiety, headache and rhinitis (see Table 3 and Table 4). In some instances, it has been difficult to differentiate adverse events from symptoms of the underlying psychosis.

Review of the global post-marketing database for the elderly dementia patient population (over 2.4 million patient-years as of October 2002) identified approximately 37 cases of cerebrovascular adverse events such as strokes and transient ischemic attacks. Of these cases, 16 were fatal.

There is insufficient information to determine whether CVAEs in elderly patients with dementia are associated specifically with RISPERDAL or other antipsychotic agents.

Adverse events related to extrapyramidal symptoms (EPS) were reported more frequently in all clinical trials for bipolar disorder than schizophrenia, regardless of study population demographics, and this may be consistent with a greater susceptibility to EPS-related adverse reactions in bipolar patients that has been observed in clinical practice. The lower mean body weight and body mass index (BMI) of an Indian study population (RIS-IND-2) and a higher mean risperidone dose may have contributed to a higher incidence of EPS-related AEs in this trial (45%, mean modal dose 5.6 mg/day; mean modal dose is the average of individual subjects' most frequent daily dose) compared to the US (36.6%, mean modal dose 4.0 mg/day) and international (31.2%, mean modal dose 4.2 mg/day) trials. EPS-related adverse events in all studies were usually mild, dose-related and reversible upon dose reduction and/or administration of antiparkinsonian medication.

The most serious adverse reactions reported were rare cases of syncope, cardiac arrhythmias, first degree AV-block, and seizures.

In the 3-week double-blind phase of controlled clinical trials, suicide-related adverse events occurred at an incidence of 0.45% for patients treated with risperidone (2 patients/448) compared to 0 for patients treated with placebo (0 patients/424). Suicide attempt and completed suicide occurred in one patient each.

The incidence of suicide-related adverse events was 0.67% (3 patients/446) during 9 weeks of open-label risperidone treatment. Suicide attempts were reported for two patients and completed suicide occurred in one patient.

Long-term clinical trials with RISPERDAL were carried out in 1235 chronic schizophrenic patients, with 671 patients receiving the drug for at least one year. The pattern of adverse events observed in patients receiving RISPERDAL in long-term clinical trials is consistent with those observed in short-term trials.

Adverse events were collected through spontaneous reporting, open questioning or utilization of the UKU side effect rating scale. Listed (in decreasing order) are those events which developed or showed deterioration during treatment compared to baseline in at least 10% of patients. Psychic: asthenia/lassitude/increased fatiguability, concentration difficulties, sleepiness/sedation, reduced duration of sleep, increased duration of sleep, failing memory, increased dream activity, insomnia; Autonomic: orthostatic dizziness, constipation, nausea/vomiting, polyuria/polydipsia, palpitations/tachycardia, reduced salivation, accommodation disturbances, increased tendency to sweating, diarrhea, micturition disturbances; Other: weight gain, weight loss, amenorrhea, ejaculatory dysfunction, erectile dysfunction, diminished sexual desire, tension headache, headache, increased sexual desire, orgastic dysfunction, pruritus.

The safety and efficacy of RISPERDAL in children under the age of 18 have not been established.

See Warnings and Precautions, Serious Warnings and Precautions Box and Special Populations.

RISPERDAL (risperidone) is indicated for the acute treatment and maintenance treatment of schizophrenia and related psychotic disorders. In controlled clinical trials, RISPERDAL was found to improve both positive and negative symptoms of schizophrenia.

RISPERDAL has been shown to be effective in maintaining clinical improvement during long-term therapy (1 year).

RISPERDAL may be useful in severe dementia for the short-term symptomatic management of inappropriate behaviour due to aggression and/or psychosis. Other behavioural disturbances seen in this patient population as well as disease stage remained unaffected by RISPERDAL treatment.

Physicians are advised to assess the risks and benefits of the use of RISPERDAL in elderly patients with dementia, taking into account risk predictors for stroke or existing cardiovascular comorbidities in the individual patient (see Warnings and Precautions; Adverse Reactions and Dosage and Administration).

RISPERDAL is indicated as monotherapy for the acute management of manic episodes associated with Bipolar I disorder.

The efficacy of RISPERDAL in the treatment of acute bipolar mania was established in three 3-week, placebo-controlled trials. The safety and effectiveness of RISPERDAL for long-term use, and for prophylactic use in bipolar disorder have not been evaluated. Physicians who elect to use RISPERDAL for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient (see Dosage and Administration).

Since there is no specific antidote to RISPERDAL, treatment is primarily supportive. A patent airway must be established and maintained to ensure adequate ventilation and oxygenation. Gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered.

Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids. Epinephrine should not be used since beta stimulation may worsen hypotension in the setting of RISPERDAL-induced alpha blockade. In cases of severe extrapyramidal reactions, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

In managing overdosage, the physician should consider the possibility of multiple drug involvement.

Each orally disintegrating, light coral, square, biconvex tablet, marked “R1”, contains: risperidone 1 mg. Nonmedicinal ingredients: aspartame, carbomer 934P, gelatin, glycine, mannitol, peppermint oil, polacrilex resin, red ferric oxide, simethicone and sodium hydroxide. Blisters of 28 per carton.

Each yellow, oblong, biconvex tablet, marked “JANSSEN” on one side and “Ris 0.25” on the other side, contains: risperidone 0.25 mg. Nonmedicinal ingredients: colloidal silicon dioxide, cornstarch, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, talc, titanium dioxide and yellow ferric oxide. Bottles of 100.

Each orally disintegrating, coral, round, biconvex tablet, marked “R4”, contains: risperidone 4 mg. Nonmedicinal ingredients: aspartame, carbomer 934P, gelatin, glycine, mannitol, peppermint oil, polacrilex resin, red ferric oxide, simethicone, sodium hydroxide and xanthan gum. Blisters of 28 per carton.

Each mL of oral solution contains: risperidone 1 mg as risperidone tartrate. Nonmedicinal ingredients: benzoic acid, purified water, sodium hydroxide and tartaric acid. Bottles of 30 mL with a plastic child-resistant closure and a calibrated (in mg and in mL) pipette. The minimum calibrated volume is 0.25 mL, while the maximum calibrated volume is 3 mL. Calibration marks every 0.25 mL up to 3 mL are printed on this pipette. Patient Instructions (including illustrations) for using the RISPERDAL calibrated dispensing pipette are provided (see Information for the Patient). Tests indicate that RISPERDAL oral solution is compatible with the following beverages: water, coffee, orange juice and low-fat milk. However, it is not compatible with cola or tea.

Each orally disintegrating, light coral, round, biconvex tablet, marked “R0.5”, contains: risperidone 0.5 mg. Nonmedicinal ingredients: aspartame, carbomer 934P, gelatin, glycine, mannitol, peppermint oil, polacrilex resin, red ferric oxide, simethicone and sodium hydroxide. Blisters of 28 per carton.

Each orally disintegrating, coral, round, biconvex tablet, marked “R3”, contains: risperidone 3 mg. Nonmedicinal ingredients: aspartame, carbomer 934P, gelatin, glycine, mannitol, peppermint oil, polacrilex resin, red ferric oxide, simethicone, sodium hydroxide and xanthan gum. Blisters of 28 per carton.

Each orally disintegrating biconvex tablet, marked “R2”, contains: risperidone 2 mg. Tablets manufactured prior to 2006 are light coral and round. Tablets manufactured from 2006 onwards are coral and square. Nonmedicinal ingredients: aspartame, carbomer 934P, gelatin, glycine, mannitol, peppermint oil, polacrilex resin, red ferric oxide, simethicone, sodium hydroxide and xanthan gum. Blisters of 28 per carton.

The pharmacokinetics of RISPERDAL were significantly altered in patients with renal disease. In patients with moderate to severe renal disease, clearance of risperidone and its active metabolite 9-hydroxyrisperidone, combined, decreased by 60%, compared to young, healthy subjects (see Action and Clinical Pharmacology, Pharmacokinetics and Table 8). Therefore, lower starting doses and lower maximal doses of risperidone are recommended in patients with any degree of renal impairment. It may also be useful to monitor renal function in these patients (see Dosage and Administration).

Analysis of clinical trials in elderly patients with dementia suggests that the use of RISPERDAL in dementia patients may be associated with an increased incidence of reports of CVAEs such as stroke and transient ischemic attacks, including fatalities. In placebo-controlled trials, there was a significantly higher incidence of CVAEs in patients treated with RISPERDAL compared to placebo-treated patients (see Adverse Reactions). There is insufficient information to determine whether CVAEs in elderly patients with dementia are associated specifically with RISPERDAL or other antipsychotic agents.

Therefore, physicians are advised to assess risks and benefits of the use of RISPERDAL in elderly patients with dementia taking into account risk predictors for stroke in the individual patient. Patients/caregivers should be advised to immediately report signs and symptoms of potential CVAEs such as sudden weakness or numbness in the face, arms or legs, and speech or vision problems (see Indications and Clinical Use, Adverse Reactions and Dosage and Administration).

All treatment options should be considered without delay, including discontinuation. Furthermore, caution should be exercised in prescribing RISPERDAL to patients with vascular comorbidities, such as hypertension and cardiovascular disease (see Warnings and Precautions, Cardiovascular).

A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with conventional antipsychotic drugs. Although TD appears to be most prevalent in the elderly, especially elderly females, it is impossible to predict at the onset of treatment which patients are likely to develop TD. It has been suggested that the occurrence of parkinsonian side effects is a predictor for the development of TD. In clinical studies, the observed incidence of drug-induced parkinsonism was lower with RISPERDAL than with haloperidol. In the optimal clinical dose range, the difference between risperidone and haloperidol was significant. The risk of developing TD may be less with RISPERDAL. In longer-term clinical studies, RISPERDAL was associated with a lower incidence of treatment-emergent dyskinesia compared to haloperidol.

The risk of developing TD 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 less commonly, after relatively brief periods of treatment at low doses. There is no known treatment for established cases of TD. The syndrome may remit, partially or completely, if antipsychotic drug treatment is withdrawn. However, antipsychotic drug treatment itself may suppress the signs and symptoms of TD, thereby masking the underlying process. The effect of symptom suppression upon the long-term course of TD is unknown.

In view of these considerations, RISPERDAL should be prescribed in a manner that is most likely to minimize the risk of TD. As with any antipsychotic drug, RISPERDAL should be reserved for patients who appear to be obtaining substantial benefit from the drug. In such patients, the smallest dose and the shortest duration of treatment should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of TD develop during treatment with RISPERDAL, withdrawal of the drug should be considered. However, some patients may require treatment with RISPERDAL despite the presence of the syndrome.

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- to 6-fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine 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 tumours is unknown (see Warnings and Precautions, Endocrine and Metabolism).

Antipsychotic drugs elevate prolactin levels with the effect persisting during chronic administration.

The safety of RISPERDAL during pregnancy has not been established. In animal studies, risperidone did not show direct reproductive toxicity. However, due to its prolactin-elevating and CNS-depressant activities, reproductive performance and pup survival were adversely affected in rats. Risperidone was not teratogenic in either rats or rabbits.

Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled studies in pregnant women. However, there was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero. The causal relationship to risperidone therapy is unknown.

Reversible extrapyramidal symptoms in the neonate were observed following post-marketing use of risperidone during the last trimester of pregnancy.

RISPERDAL should not be used during pregnancy unless the expected benefits to the patient markedly outweigh the potential risks to the fetus.

As with other antipsychotics, caution should be exercised when RISPERDAL is prescribed in patients with a history of cardiac arrhythmias, in patients with congenital long QT syndrome, and in concomitant use with drugs known to prolong the QT interval.

Although the pharmacokinetics of RISPERDAL in patients with hepatic impairment were comparable to those in young volunteers, the free fraction of risperidone was increased by about 35% (see Action and Clinical Pharmacology, Pharmacokinetics and Table 8). Since this may lead to a more pronounced pharmacological effect, lower starting doses and lower maximal doses are recommended in patients with any degree of hepatic impairment (see Dosage and Administration).

Consistent with its dopamine antagonistic effects, RISPERDAL may have an antiemetic effect. Such an effect may mask signs of toxicity due to overdosage with other drugs, or may mask symptoms of disease such as brain tumour or intestinal obstruction or Reye's syndrome.

See Indications and Clinical Use.

Geriatric patients generally have decreased renal, hepatic and cardiac function, and an increased tendency to postural hypotension. Therefore, lower starting doses, lower rates of dose adjustment and lower maximal doses are recommended in these patients.

Risperidone is substantially excreted by the kidneys. Thus, 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, caution should be taken in dose selection and titration. It may also be useful to monitor renal function in these patients (see Dosage and Administration, Action and Clinical Pharmacology, Pharmacokinetics and Table 8).

In schizophrenic patients, doses exceeding 3 mg per day are not recommended. In patients with behavioural disturbances due to severe dementia, the optimal dose is 0.5 mg b.i.d. (1.0 mg per day) and the maximal dose is 1 mg b.i.d. (2.0 mg per day).

Risperidone had no mutagenic effects when tested by the DNA-repair test in rat hepatocytes, the Ames reverse mutation test in S. typhimurium and E. coli, the mammalian cell gene mutation test in mouse lymphoma cells, the sex-linked recessive lethal test in D. melanogaster, the chromosome aberration test in human lymphocytes and Chinese hamster lung cells, and the micronucleus test in the mouse bone marrow cells.

In risperidone placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone (7.3%; mean age 89 years, range 75-97) when compared to patients treated with risperidone alone (3.1%; mean age 84 years, range 70-96), furosemide alone (4.1%; mean age 80 years, range 67-90) or placebo without furosemide (2.9%; mean age 88 years, range 71-100). The increase in mortality in patients treated with furosemide plus risperidone was observed in two of the four clinical trials.

No pathophysiological mechanism has been identified to explain this finding, and no consistent pattern for cause of death observed. Nevertheless, caution should be exercised and the risks and benefits of this combination should be considered prior to the decision to use. There was no increased incidence of mortality among patients taking other diuretics as concomitant medication with risperidone. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.

Since RISPERDAL may cause somnolence, patients should be cautioned against driving a car or operating hazardous machinery until they are reasonably certain that RISPERDAL does not affect them adversely.

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 behaviour 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.

The safety and efficacy of RISPERDAL in children under the age of 18 have not been established.

Phenylalanine is a component of aspartame. RISPERDAL M-TAB tablets contain phenylalanine (0.14, 0.28, 0.42-0.56, 0.63 and 0.84 mg) per 0.5, 1, 2, 3 and 4 mg tablets, respectively.

As with some other antipsychotics, hyperglycemia and exacerbation of pre-existing diabetes have been reported very rarely during the use of RISPERDAL (see Adverse Reactions, Post-Market Adverse Drug Reactions). Diabetic ketoacidosis has also been reported.

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.

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 antidiabetic treatment despite discontinuation of the suspect drug. 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. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.

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 and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

In controlled clinical trials (see Adverse Reactions, Table 3 and Table 4), the incidence of somnolence in patients on RISPERDAL was clinically similar to placebo (3-4% of patients on RISPERDAL ≤10 mg versus 1% of patients on placebo).

Physicians should weigh the risks versus the benefits when prescribing antipsychotics, including RISPERDAL, to patients with Parkinson's Disease or Dementia with Lewy Bodies (DLB) since both groups may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotic medications. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.

Neuroleptic malignant syndrome is a potentially fatal symptom complex that has been reported in association with antipsychotic drugs, including RISPERDAL.

Clinical manifestations of NMS are hyperthermia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular blood pressure, tachycardia, cardiac arrhythmias, and diaphoresis). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.

In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms. 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 all antipsychotic drugs including RISPERDAL, 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 recurrence of NMS has been reported.

Rare cases of priapism have been reported with RISPERDAL. This adverse reaction, as with other psychotropic drugs, did not appear to be dose-dependent and did not correlate with the duration of treatment. The most likely mechanism of priapism is a relative decrease in sympathetic tone.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic drugs. Appropriate care is advised when prescribing RISPERDAL for patients who will be experiencing conditions which may contribute to an elevation or reduction of core temperature, e.g., exercising strenuously, exposure to extreme heat or cold, receiving concomitant medication with anticholinergic activity, or being subject to dehydration (see Adverse Reactions, Post-Market Adverse Drug Reactions).

Elderly patients with dementia treated with atypical antipsychotic drugs have an increased mortality compared to placebo in a meta-analysis of 13 controlled trials of various atypical antipsychotic drugs. In six placebo-controlled trials with RISPERDAL in this population, the incidence of mortality was 4.0% for RISPERDAL-treated patients compared to 3.1% for placebo-treated patients.

Antipsychotic drugs are known to lower the seizure threshold. In clinical trials, seizures have occurred in a few patients treated with RISPERDAL. Therefore, caution should be used in administering RISPERDAL to patients having a history of seizures or other predisposing factors.

The possibility of suicide or attempted suicide is inherent in psychosis and bipolar mania, and thus, close supervision and appropriate clinical management of high-risk patients should accompany drug therapy.

In controlled clinical trials for the acute management of manic episodes (see Adverse Reactions, Table 7), the incidence of somnolence was higher in patients treated with RISPERDAL compared to placebo or haloperidol (12% of patients on RISPERDAL 1-6 mg/day versus 4% of patients on placebo and 4% of patients on haloperidol).

Risperidone appeared in the milk of lactating dogs. The concentration of risperidone was similar in milk and plasma, while that of 9-hydroxyrisperidone was higher in the milk than in plasma. It has been demonstrated that risperidone and 9-hydroxyrisperidone are also excreted in human breast milk.

Nursing should not be undertaken while a patient is receiving RISPERDAL.

During clinical trials, RISPERDAL has been observed to cause orthostatic hypotension and tachycardia, especially during the initial dose titration period and the first few weeks of treatment. Rare cases of syncope, cardiac arrhythmias and first degree AV-block have been reported. Clinically significant hypotension has also been observed postmarketing with concomitant use of risperidone and antihypertensive treatment. The likelihood of excessive hypotension or syncope can be minimized by limiting the initial dose of the drug to 1-2 mg per day, q.d. or b.i.d., in adult patients and to 0.25 to 0.5 mg b.i.d. in special patient populations, and by increasing the dose slowly (see Dosage and Administration). A dose reduction should be considered if hypotension occurs.

Patients with a history of clinically significant cardiac disorders were excluded from clinical trials. Therefore, RISPERDAL should be used with caution in patients with cardiovascular diseases (e.g., heart failure, history of myocardial infarction or ischemia, cerebrovascular disease, conduction abnormalities) and other conditions such as dehydration and hypovolemia. Special care should be taken to avoid hypotension in patients with a history of cerebrovascular insufficiency or ischemic heart disease, and in patients taking medications to lower blood pressure. Monitoring of orthostatic vital signs should be considered in all such patients.

Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. Steady-state concentrations of risperidone and 9-hydroxyrisperidone were reached within 1-2 days and 5-6 days, respectively. In plasma, risperidone is bound to albumin and alpha₁-acid glycoprotein (AGP). The plasma protein binding of risperidone is approximately 88%, that of the metabolite 77%.

Risperidone was well absorbed after oral administration, had high bioavailability, and showed dose-proportionality in the therapeutic dose range, although inter-individual plasma concentrations varied considerably. Mean peak plasma concentrations of risperidone and 9-hydroxyrisperidone were reached at about 1 hour and 3 hours, respectively, after drug administration. Food did not affect the extent of absorption; thus, risperidone can be given with or without meals.

Risperidone, a benzisoxazole derivative, is a novel antipsychotic drug which binds with high affinity to serotonin type 2 (5-HT₂), dopamine type 2 (D₂), and α₁-adrenergic receptors. Risperidone binds with a lower affinity to the α₂-adrenergic and histamine H₁ receptors. Risperidone does not bind to dopamine D₁ receptors and has no affinity (when tested at concentrations >10⁻⁵ M) for muscarinic cholinergic receptors. Due to the lack of muscarinic receptor binding, risperidone is not expected to produce anticholinergic adverse effects.

Receptor occupancy was also demonstrated in vivo in humans. Using positron emission tomography, risperidone was shown to block both 5-HT_2A and dopamine D₂ receptors in three healthy volunteers. Although risperidone is a potent D₂ antagonist, which is considered to improve the positive symptoms of schizophrenia, it causes less depression of motor activity and induction of catalepsy in animal models than classical antipsychotics. Risperidone has also been found to be one of the most potent known antagonists of 5-HT_2A (cloned human receptor); 5-HT_2A antagonism has been shown to reverse deficits in several in vivo animal models predictive of novel antipsychotic activity (PCP-induced social deficit, microdialysis assessment of dopamine output in prefrontal cortex, glutamate antagonist-induced hyperlocomotion). Balanced central serotonin and dopamine antagonism may reduce extrapyramidal side-effect liability.

One week after administration, 70% of the dose is excreted in the urine and 14% in the faeces. In urine, risperidone plus 9-hydroxyrisperidone represents 35-45% of the dose. The remainder is inactive metabolites.

The results indicate that a 1 mg dose of risperidone produced modest pharmacokinetic changes in elderly subjects, including reduced clearance of the active antipsychotic fraction by about 30%. In patients with impaired liver function, the unbound fraction of risperidone was increased by about 35% due to diminished concentrations of both α₁-AGP and albumin. In patients with impaired renal function, the changes were substantial; C_max and AUC of risperidone and 9-hydroxyrisperidone combined were increased by about 40% and 160% respectively, half-life was prolonged by about 60% and clearance decreased by about 60%.

Risperidone is extensively metabolized in the liver by CYP 2D6 to a major active metabolite, 9-hydroxyrisperidone, which appears approximately equi-effective with risperidone with respect to receptor-binding activity. (A second minor pathway is N-dealkylation.) Consequently, the clinical effect of the drug likely results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. The hydroxylation of risperidone is dependent upon debrisoquine 4-hydroxylase, i.e., the metabolism of risperidone is sensitive to the debrisoquine hydroxylation type genetic polymorphism. Consequently, the concentrations of parent drug and active metabolite differ substantially in extensive and poor metabolizers. However, the concentration of risperidone and 9-hydroxyrisperidone combined did not differ substantially between extensive and poor metabolizers, and elimination half-lives were similar in all subjects (approximately 20 to 24 hours).

The plasma concentration of risperidone and 9-hydroxyrisperidone combined was dose proportional over the dosing range of 0.5 to 2 mg daily dose (0.25 to 1 mg b.i.d.).