RISPERDAL® contains risperidone, a psychotropic agent belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C₂₃H₂₇FN₄O₂ and its molecular weight is 410.49. The structural formula is:

Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 N HCl.

RISPERDAL® Tablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. RISPERDAL® tablets contain the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn). The 0.25 mg, 0.5 mg, 2 mg, 3 mg, and 4 mg tablets also contain talc and titanium dioxide. The 0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets contain red iron oxide; the 2 mg tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg and 4 mg tablets contain D&C Yellow No. 10; the 4 mg tablets contain FD&C Blue No. 2 Aluminum Lake.

RISPERDAL® is also available as a 1 mg/mL oral solution. RISPERDAL® Oral Solution contains the following inactive ingredients: tartaric acid, benzoic acid, sodium hydroxide, and purified water.

RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg (light coral), 2 mg (light coral), 3 mg (coral), and 4 mg (coral) strengths. RISPERDAL® M-TAB® Orally Disintegrating Tablets contain the following inactive ingredients: Amberlite® resin, gelatin, mannitol, glycine, simethicone, carbomer, sodium hydroxide, aspartame, red ferric oxide, and peppermint oil. In addition, the 3 mg and 4 mg RISPERDAL® M-TAB® Orally Disintegrating Tablets contain xanthan gum.

Schizophrenia

Adults

RISPERDAL® (risperidone) is indicated for the acute and maintenance treatment of schizophrenia [see Clinical Studies].

Adolescents

RISPERDAL® is indicated for the treatment of schizophrenia in adolescents aged 13-17 years [see Clinical Studies].

Bipolar Mania

Monotherapy - Adults and Pediatrics

RISPERDAL® is indicated for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in adults and in children and adolescents aged 10-17 years [see Clinical Studies].

Combination Therapy -Adults

The combination of RISPERDAL® with lithium or valproate is indicated for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder [see Clinical Studies].

Irritability Associated with Autistic Disorder

Pediatrics

RISPERDAL® is indicated for the treatment of irritability associated with autistic disorder in children and adolescents aged 5-16 years, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods [see Clinical Studies].

Schizophrenia

Adults

Usual Initial Dose

RISPERDAL® can be administered once or twice daily. Initial dosing is generally 2 mg/day. Dose increases should then occur at intervals not less than 24 hours, in increments of 1-2 mg/day, as tolerated, to a recommended dose of 4-8 mg/day. In some patients, slower titration may be appropriate. Efficacy has been demonstrated in a range of 4-16 mg/day [see Clinical Studies]. However, doses above 6 mg/day for twice daily dosing were not demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal symptoms and other adverse effects, and are generally not recommended. In a single study supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of doses above 16 mg/day has not been evaluated in clinical trials.

Maintenance Therapy

While it is unknown how long a patient with schizophrenia should remain on RISPERDAL®, the effectiveness of RISPERDAL® 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a controlled trial in patients who had been clinically stable for at least 4 weeks and were then followed for a period of 1 to 2 years[see Clinical Studies]. Patients should be periodically reassessed to determine the need for maintenance treatment with an appropriate dose.

Adolescents

The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended dose of 3 mg/day. Although efficacy has been demonstrated in studies of adolescent patients with schizophrenia at doses between 1 and 6 mg/day, no additional benefit was seen above 3 mg/day, and higher doses were associated with more adverse events. Doses higher than 6 mg/day have not been studied.

Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.

There are no controlled data to support the longer term use of RISPERDAL® beyond 8 weeks in adolescents with schizophrenia. The physician who elects to use RISPERDAL® for extended periods in adolescents with schizophrenia should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Reinitiation of Treatment in Patients Previously Discontinued

Although there are no data to specifically address reinitiation of treatment, it is recommended that after an interval off RISPERDAL®, the initial titration schedule should be followed.

Switching From Other Antipsychotics

There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to RISPERDAL®, or treating patients with concomitant antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some schizophrenic patients, more gradual discontinuation may be most appropriate for others. The period of overlapping antipsychotic administration should be minimized. When switching schizophrenic patients from depot antipsychotics, initiate RISPERDAL® therapy in place of the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated periodically.

Bipolar Mania

Usual Dose Adults

RISPERDAL® should be administered on a once-daily schedule, starting with 2 mg to 3 mg per day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible dosage range of 1-6 mg per day [see Clinical Studies]. RISPERDAL® doses higher than 6 mg per day were not studied.

Pediatrics

The dosage of RISPERDAL® should be initiated at 0.5mg once daily, administered as a single-daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended dose of 2.5 mg/day. Although efficacy has been demonstrated in studies of pediatric patients with bipolar mania at doses between 0.5 and 6 mg/day, no additional benefit was seen above 2.5 mg/day, and higher doses were associated with more adverse events. Doses higher than 6 mg/day have not been studied.

Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.

Maintenance Therapy

There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during treatment of an acute manic episode with RISPERDAL®. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of RISPERDAL® in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to use RISPERDAL® for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Irritability Associated with Autistic Disorder - Pediatrics (Children and Adolescents)

The safety and effectiveness of RISPERDAL® in pediatric patients with autistic disorder less than 5 years of age have not been established.

The dosage of RISPERDAL® should be individualized according to the response and tolerability of the patient. The total daily dose of RISPERDAL® can be administered once daily, or half the total daily dose can be administered twice daily.

Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for patients ≥ 20 kg. After a minimum of four days from treatment initiation, the dose may be increased to the recommended dose of 0.5 mg per day for patients < 20 kg and 1 mg per day for patients ≥ 20 kg. This dose should be maintained for a minimum of 14 days. In patients not achieving sufficient clinical response, dose increases may be considered at ≥ 2-week intervals in increments of 0.25 mg per day for patients < 20 kg or 0.5 mg per day for patients ≥ 20 kg. Caution should be exercised with dosage for smaller children who weigh less than 15 kg.

In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on ABC-I, [see Clinical Studies] received doses of RISPERDAL® between 0.5 mg and 2.5 mg per day. The maximum daily dose of RISPERDAL® in one of the pivotal trials, when the therapeutic effect reached plateau, was 1 mg in patients < 20 kg, 2.5 mg in patients ≥ 20 kg, or 3 mg in patients > 45 kg. No dosing data is available for children who weighed less than 15 kg.

Once sufficient clinical response has been achieved and maintained, consideration should be given to gradually lowering the dose to achieve the optimal balance of efficacy and safety. The physician who elects to use RISPERDAL® for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Patients experiencing persistent somnolence may benefit from a once-daily dose administered at bedtime or administering half the daily dose twice daily, or a reduction of the dose.

Dosage in Special Populations

The recommended initial dose is 0.5 mg twice daily in patients who are elderly or debilitated, patients with severe renal or hepatic impairment, and patients either predisposed to hypotension or for whom hypotension would pose a risk. Dosage increases in these patients should be in increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily should generally occur at intervals of at least 1 week. In some patients, slower titration may be medically appropriate.

Elderly or debilitated patients, and patients with renal impairment, may have less ability to eliminate RISPERDAL® than normal adults. Patients with impaired hepatic function may have increases in the free fraction of risperidone, possibly resulting in an enhanced effect [see CLINICAL PHARMACOLOGY]. Patients with a predisposition to hypotensive reactions or for whom such reactions would pose a particular risk likewise need to be titrated cautiously and carefully monitored [see Warnings and PRECAUTIONS]. If a once-daily dosing regimen in the elderly or debilitated patient is being considered, it is recommended that the patient be titrated on a twice-daily regimen for 2-3 days at the target dose. Subsequent switches to a once-daily dosing regimen can be done thereafter.

Co-Administration of RISPERDAL® with Certain Other Medications

Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin, phenobarbital) with RISPERDAL® would be expected to cause decreases in the plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead to decreased efficacy of RISPERDAL® treatment. The dose of RISPERDAL® needs to be titrated accordingly for patients receiving these enzyme inducers, especially during initiation or discontinuation of therapy with these inducers [see DRUG INTERACTIONS].

Fluoxetine and paroxetine 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%. The dose of RISPERDAL® needs to be titrated accordingly when fluoxetine or paroxetine is co-administered [see DRUG INTERACTIONS].

Administration of RISPERDAL® Oral Solution

RISPERDAL® Oral Solution can be administered directly from the calibrated pipette, or can be mixed with a beverage prior to administration. RISPERDAL® Oral Solution is compatible in the following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with either cola or tea.

Directions for Use of RISPERDAL® M-TAB® Orally Disintegrating Tablets

Tablet Accessing

RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg

RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in blister packs of 4 tablets each.

Do not open the blister until ready to administer. For single tablet removal, separate one of the four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the tablet.

RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg

RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a child-resistant pouch containing a blister with 1 tablet each.

The child-resistant pouch should be torn open at the notch to access the blister. Do not open the blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT push the tablet through the foil, because this could damage the tablet.

Tablet Administration

Using dry hands, remove the tablet from the blister unit and immediately place the entire RISPERDAL® M-TAB® Orally Disintegrating Tablet on the tongue. The RISPERDAL® M-TAB® Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be stored once removed from the blister unit. RISPERDAL® M-TAB® Orally Disintegrating Tablets disintegrate in the mouth within seconds and can be swallowed subsequently with or without liquid. Patients should not attempt to split or to chew the tablet.

Dosage Forms And Strengths

RIPSERDAL® Tablets are available in the following strengths and colors: 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green). All are capsule shaped, and imprinted with “JANSSEN” on one side and either “Ris 0.25”, “Ris 0.5”, “R1”, “R2”, “R3”, or “R4” on the other side according to their respective strengths.

RISPERDAL® Oral Solution is available in a 1 mg/mL strength.

RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in the following strengths, colors, and shapes: 0.5 mg (light coral, round), 1 mg (light coral, square), 2 mg (light coral, round), 3 mg (coral, round), and 4 mg (coral, round). All are biconvex and etched on one side with “R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.

Storage And Handling

RISPERDAL® (risperidone) Tablets

RISPERDAL® (risperidone) Tablets are imprinted "JANSSEN" on one side and either “Ris 0.25”, “Ris 0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.

0.25 mg dark yellow, capsule-shaped tablets: bottles of 60 NDC 50458-301-04, bottles of 500 NDC 50458-301-50, hospital unit dose blister packs of 100 NDC 50458-301-01.

0.5 mg red-brown, capsule-shaped tablets: bottles of 60 NDC 50458-302-06, bottles of 500 NDC 50458-302-50, hospital unit dose blister packs of 100 NDC 50458-302-01.

1 mg white, capsule-shaped tablets: bottles of 60 NDC 50458-300-06, hospital unit dose blister packs of 100 NDC 50458-300-01, bottles of 500 NDC 50458-300-50.

2 mg orange, capsule-shaped tablets: bottles of 60 NDC 50458-320-06, hospital unit dose blister packs of 100 NDC 50458-320-01, bottles of 500 NDC 50458-320-50.

3 mg yellow, capsule-shaped tablets: bottles of 60 NDC 50458-330-06, hospital unit dose blister packs of 100 NDC 50458-330-01, bottles of 500 NDC 50458-330-50.

4 mg green, capsule-shaped tablets: bottles of 60 NDC 50458-350-06, hospital unit dose blister packs of 100 NDC 50458-350-01.

RISPERDAL® (risperidone) Oral Solution

RISPERDAL® (risperidone) 1 mg/mL Oral Solution (NDC 50458-305-03) is supplied in 30 mL bottles with a calibrated (in milligrams and milliliters) pipette. The minimum calibrated volume is 0.25 mL, while the maximum calibrated volume is 3 mL.

RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets

RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets are etched on one side with “R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths. RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are packaged in blister packs of 4 (2 X 2) tablets. Orally Disintegrating Tablets 3 mg and 4 mg are packaged in a child-resistant pouch containing a blister with 1 tablet.

0.5 mg light coral, round, biconvex tablets: 7 blister packages (4 tablets each) per box, NDC 50458-395-28, long-term care blister packaging of 30 tablets NDC 50458-395-30.

1  mg light coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box, NDC 50458-315-28, long-term care blister packaging of 30 tablets NDC 50458-315-30.

2  mg light coral, round, biconvex tablets: 7 blister packages (4 tablets each) per box, NDC 50458-325-28.

3 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-335-28.

4 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-355-28.

Storage and Handling

RISPERDAL® Tablets should be stored at controlled room temperature 15°-25°C (59°-77°F).

Protect from light and moisture.

RISPERDAL® 1 mg/mL Oral Solution should be stored at controlled room temperature 15°-25°C (59°-77°F). Protect from light and freezing.

RISPERDAL® M-TAB® Orally Disintegrating Tablets should be stored at controlled room temperature 15°-25°C (59°-77°F).

Keep out of reach of children.

Revised August 2008. ©Janssen 2007. RISPERDAL® Tablets are manufactured by: Janssen Ortho LLC, Gurabo, Puerto Rico. RISPERDAL® Oral Solution is manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium. RISPERDAL® M-TAB® Orally Disintegrating Tablets are manufactured by: Janssen Ortho LLC, Gurabo, Puerto Rico. RISPERDAL® Tablets, RISPERDAL® M-TAB® Orally Disintegrating Tablets, and Oral Solution are distributed by: Janssen, L.P. Titusville, NJ 08560. FDA Rev date: 8/14/2008

The following findings are based on the short-term, placebo-controlled, North American, premarketing trials for schizophrenia and acute bipolar mania, and are followed by a description of adverse events and other safety measures in short-term, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder. In patients with Bipolar I Disorder, treatment-emergent adverse events are presented separately for risperidone as monotherapy and as adjunctive therapy to mood stabilizers.

Certain portions of the discussion below relating to objective or numeric safety parameters, namely dose-dependent adverse events, vital sign changes, weight gain, laboratory changes, and ECG changes are derived from studies in patients with schizophrenia. However, this information is also generally applicable to bipolar mania and pediatric patients with autistic disorder.

Associated With Discontinuation of Treatment

Schizophrenia

Approximately 9% (244/2607) of RISPERDAL® (risperidone)-treated patients in Phase 2 and 3 studies discontinued treatment due to an adverse event, compared with about 7% on placebo and 10% on active control drugs. The more common events (≥0.3%) associated with discontinuation and considered to be possibly or probably drug-related included:

Adverse Event	RISPERDAL®	Placebo
Extrapyramidal symptoms	2.1%	0%
Dizziness	0.7%	0%
Hyperkinesia	0.6%	0%
Somnolence	0.5%	0%
Nausea	0.3%	0%

Suicide attempt was associated with discontinuation in 1.2% of RISPERDAL®-treated patients compared to 0.6% of placebo patients, but, given the almost 40-fold greater exposure time in RISPERDAL® compared to placebo patients, it is unlikely that suicide attempt is a RISPERDAL®-related adverse event (see PRECAUTIONS). Discontinuation for extrapyramidal symptoms was 0% in placebo patients, but 3.8% in active-control patients in the Phase 2 and 3 trials.

Bipolar Mania

In the US placebo-controlled trial with risperidone as monotherapy, approximately 8% (10/134) of RISPERDAL®-treated patients discontinued treatment due to an adverse event, compared with approximately 6% (7/125) of placebo-treated patients. The adverse events associated with discontinuation and considered to be possibly, probably, or very likely drug-related included paroniria, somnolence, dizziness, extrapyramidal disorder, and muscle contractions involuntary. Each of these events occurred in one RISPERDAL®-treated patient (0.7%) and in no placebo-treated patients (0%).

In the US placebo-controlled trial with risperidone as adjunctive therapy to mood stabilizers, there was no overall difference in the incidenceof discontinuation due to adverse events (4% for RISPERDAL® vs. 4% for placebo).

Incidence in Controlled Trials

Commonly Observed Adverse Events in Controlled Clinical Trials

Schizophrenia

In two 6- to 8-week placebo-controlled trials, spontaneously-reported, treatment-emergent adverse events with an incidence of 5% or greater in at least one of the RISPERDAL® groups and at least twice that of placebo were anxiety, somnolence, extrapyramidal symptoms, dizziness, constipation, nausea, dyspepsia, rhinitis, rash, and tachycardia.

Adverse events were also elicited in one of these two trials (i.e., in the fixed-dose trial comparing RISPERDAL® at doses of 2, 6, 10, and 16 mg/day with placebo) utilizing a checklist for detecting adverse events, a method that is more sensitive than spontaneous reporting. By this method, the following additional common and drug-related adverse events occurred at an incidence of at least 5% and twice the rate of placebo: increased dream activity, increased duration of sleep, accommodation disturbances, reduced salivation, micturition disturbances, diarrhea, weight gain, menorrhagia, diminished sexual desire, erectile dysfunction, ejaculatory dysfunction, and orgastic dysfunction.

Bipolar Mania

In the U.S. placebo-controlled trial with risperidone as monotherapy, the most commonly observed adverse events associated with the use of RISPERDAL® (incidence of 5% or greater and at least twice that of placebo) were somnolence, dystonia, akathisia, dyspepsia, nausea, parkinsonism, vision abnormal, and saliva increased. In the U.S. placebo-controlled trial with risperidone as adjunctive therapy to mood stabilizers, the most commonly observed adverse events associated with the use of RISPERDAL® were somnolence, dizziness, parkinsonism, saliva increased, akathisia, abdominal pain, and urinary incontinence.

Adverse Events Occurring at an Incidence of 1% or More Among RISPERDAL®-Treated Patients - Schizophrenia

The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent among RISPERDAL®-treated patients treated at doses of 10 mg/day than among placebo-treated patients in the pooled results of two 6- to 8-week controlled trials. Patients received RISPERDAL® doses of 2, 6, 10, or 16 mg/day in the dose comparison trial, or up to a maximum dose of 10 mg/day in the titration study. This table shows the percentage of patients in each dose group (≤10 mg/day or 16 mg/day) who spontaneously reported at least one episode of an event at some time during their treatment. Patients given doses of 2, 6, or 10 mg did not differ materially in these rates. Reported adverse events were classified using the World Health Organization preferred terms.

The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in this clinical trial. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.

Table 1: Incidence of Treatment-Emergent Adverse Events in 6- to 8-Week Controlled Clinical Trials in
Schizophrenia ¹

	RISPERDAL®
Body System/ Preferred Term	<10mg/day (N=324)	16 mg/day (N=77)	Placebo (N=142)
Psychiatric
Insomnia	26%	23%	19%
Agitation	22%	26%	20%
Anxiety	12%	20%	9%
Somnolence	3%	8%	1%
Aggressive reaction	1%	3%	1%
Central & peripheral nervous system
Extrapyramidal symptoms2	17%	34%	16%
Headache	14%	12%	12%
Dizziness	4%	7%	1%
Gastrointestinal
Constipation	7%	13%	3%
Nausea	6%	4%	3%
Dyspepsia	5%	10%	4%
Vomiting	5%	7%	4%
Abdominal pain	4%	1%	0%
Saliva increased	2%	0%	1%
Toothache	2%	0%	0%
Respiratory system
Rhinitis	10%	8%	4%
Coughing	3%	3%	1%
Sinusitis	2%	1%	1%
Pharyngitis	2%	3%	0%
Dyspnea	1%	0%	0%
Body as a whole - general
Back pain	2%	0%	1%
Chest pain	2%	3%	1%
Fever	2%	3%	0%
Dermatological
Rash	2%	5%	1%
Dry skin	2%	4%	0%
Seborrhea	1%	0%	0%
Infections
Upper respiratory	3%	3%	1%
Visual
Abnormal vision	2%	1%	1%
Musculo-Skeletal
Arthralgia	2%	3%	0%
Cardiovascular
Tachycardia	3%	5%	0%
1Events reported by at least 1% of patients treated with RISPERDAL® 10 mg/day are included, and are rounded to the nearest %. Comparative rates for RISPERDAL® 16 mg/day and placebo are provided as well. Events for which the RISPERDAL® incidence (in both dose groups) was equal to or less than placebo are not listed in the table, but included the following: nervousness, injury, and fungal infection. 2Includes tremor, dystonia, hypokinesia, hypertonia, hyperkinesia, oculogyric crisis, ataxia, abnormal gait, involuntary muscle contractions, hyporeflexia, akathisia, and extrapyramidal disorders. Although the incidence of 'extrapyramidal symptoms' does not appear to differ for the '10 mg/day' group and placebo, the data for individual dose groups in fixed dose trials do suggest a dose/response relationship (see ADVERSE REACTIONS - Dose Dependency of Adverse Events).

Adverse Events Occurring at an Incidence of 2% or More Among RISPERDAL®-Treated Patients - Bipolar Mania

Tables 2 and 3 display adverse events that occurred at an incidence of 2% or more, and were more frequent among patients treated with flexible doses of RISPERDAL® (1-6 mg daily as monotherapy and as adjunctive therapy to mood stabilizers, respectively) than among patients treated with placebo. Reported adverse events were classified using the World Health Organization preferred terms.

Table 2: Incidence of Treatment-Emergent Adverse Events in a 3-Week,
Placebo-Controlled Trial - Monotherapy in Bipolar Mania¹

Body System/ Preferred Term	RISPERDAL® (N=134)	Placebo (N=125)
Central & peripheral nervous system
Dystonia	18%	6%
Akathisia	16%	6%
Dizziness	11%	9%
Parkinsonism	6%	3%
Hypoaesthesia	2%	1%
Psychiatric
Somnolence	28%	7%
Agitation	8%	6%
Manic reaction	8%	6%
Anxiety	4%	2%
Concentration impaired	2%	1%
Gastrointestinal system
Dyspepsia	11%	6%
Nausea	11%	2%
Saliva increased	5%	1%
Mouth dry	3%	2%
Body as a whole - general
Pain	5%	3%
Fatigue	4%	2%
Injury	2%	0%
Respiratory system
Sinusitis	4%	1%
Rhinitis	3%	2%
Coughing	2%	2%
Skin and appendages
Acne	2%	0%
Pruritus	2%	1%
Musculo-Skeletal
Myalgia	5%	2%
Skeletal pain	2%	1%
Metabolic and nutritional
Weight increase	2%	0%
Vision disorders
Vision abnormal	6%	2%
Cardiovascular, general
Hypertension	3%	1%
Hypotension	2%	0%
Heart rate and rhythm
Tachycardia	3%	2%
1Events reported by at least 2% of patients treated with RISPERDAL® are included and are rounded to the nearest %. Events reported by at least 2% of patients treated with RISPERDAL® that were less than the incidence reported by patients treated with placebo are not listed in the table, but included the following: headache, tremor, insomnia, constipation, back pain, upper respiratory tract infection, pharyngitis, and arthralgia.

Table 3: Incidence of Treatment-Emergent Adverse Events in a 3-Week, Placebo-Controlled Trial -
Adjunctive Therapy in Bipolar Mania¹

Body System/ Preferred Term	RISPERDAL® + Mood Stabilize r(N=52)	Placebo+ Mood Stabilizer (N=51)
Gastrointestinal system
Saliva increased	10%	0%
Diarrhea	8%	4%
Abdominal pain	6%	0%
Constipation	6%	4%
Mouth dry	6%	4%
Tooth ache	4%	0%
Tooth disorder	4%	0%
Central & peripheral nervous system
Dizziness	14%	2%
Parkinsonism	14%	4%
Akathisia	8%	0%
Dystonia	6%	4%
Psychiatric
Somnolence	25%	12%
Anxiety	6%	4%
Confusion	4%	0%
Respiratory system
Rhinitis	8%	4%
Pharyngitis	6%	4%
Coughing	4%	0%
Body as a whole - general
Asthenia	4%	2%
Urinary system
Urinary incontinence	6%	2%
Heart rate and rhythm
Tachycardia	4%	2%
Metabolic and nutritional
Weight increase	4%	2%
Skin and appendages
Rash	4%	2%
1Events reported by at least 2% of patients treated with RISPERDAL® are included and are rounded to the nearest %. Events reported by at least 2% of patients treated with RISPERDAL® that were less than the incidence reported by patients treated with placebo are not listed in the table, but included the following: dyspepsia, nausea, vomiting, headache, tremor, insomnia, chest pain, fatigue, pain, skeletal pain, hypertension, and vision abnormal.

Dose Dependency of Adverse Events

Extrapyramidal Symptoms

Data from two fixed-dose trials provided evidence of dose-relatedness for extrapyramidal symptoms associated with risperidone treatment.

Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of risperidone (2, 6, 10, and 16 mg/day), including (1) a parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS:

Dose Groups	Placebo	Ris 2	Ris 6	Ris 10	Ris 16
Parkinsonism	1.2	0.9	1.8	2.4	2.6
EPS Incidence	13%	13%	16%	20%	31%

Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day):

Dose Groups	Ris 1	Ris 4	Ris 8	Ris 12	Ris 16
Parkinsonism	0.6	1.7	2.4	2.9	4.1
EPS Incidence	7%	12%	18%	18%	21%

Other Adverse Events

Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p<0.05) for the following adverse events: sleepiness, increased duration of sleep, accommodation disturbances, orthostatic dizziness, palpitations, weight gain, erectile dysfunction, ejaculatory dysfunction, orgastic dysfunction, asthenia/lassitude/increased fatigability, and increased pigmentation.

Vital Sign Changes

RISPERDAL® is associated with orthostatic hypotension and tachycardia (see PRECAUTIONS).

Weight Changes

The proportions of RISPERDAL® and placebo-treated patients meeting a weight gain criterion of ≥7% of body weight were compared in a pool of 6- to 8-week, placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain for RISPERDAL® (18%) compared to placebo (9%).

Laboratory Changes

A between-group comparison for 6- to 8-week placebo-controlled trials revealed no statistically significant RISPERDAL®/placebo differences in the proportions of patients experiencing potentially important changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no RISPERDAL®/placebo differences in the incidence of discontinuations for changes in serum chemistry, hematology, or urinalysis. However, RISPERDAL® administration was associated with increases in serum prolactin (see PRECAUTIONS).

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).

Adverse Events and Other Safety Measures in Pediatric Patients With Autistic Disorder

In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n=156), two patients (one treated with RISPERDAL® and one treated with placebo) discontinued treatment due to an adverse event.

In addition to spontaneous reporting, in one of the studies, adverse events were also elicited from a checklist for detecting selected events, a method that is more sensitive than spontaneous reporting.

The most common adverse events with RISPERDAL® that occurred at an incidence equal to or greater than 5% and at a rate of at least twice that of placebo are shown in Table 4.

Table 4 Incidence of Treatment-Emergent Adverse Events in Two 8-Week, Placebo-Controlled
Trials in Pediatric Patients with Autistic Disorder

Body System Preferred Term	RISPERDAL® (n=76)	Placebo (n=80)
Psychiatric
Somnolence	67%	23%
Appetite increased	49%	19%
Confusion	5%	0%
Gastrointestinal
Saliva increased	22%	6%
Constipation	21%	8%
Dry mouth	13%	6%
Body as a whole - general
Fatigue	42%	13%
Central & peripheral nervous system
Tremor	12%	1%
Dystonia	12%	6%
Dizziness	9%	3%
Automatism	7%	1%
Dyskinesia	7%	0%
Parkinsonism	8%	0%
Respiratory
Upper respiratory tract infection	34%	15%
Metabolic and nutritional
Weight increase	5%	0%
Heart rate and rhythm
Tachycardia	7%	0%

Weight increase was reported more frequently with RISPERDAL® than with placebo. The average weight increase over 8 weeks was 2.6 kg in patients treated with RISPERDAL® compared with 0.9 kg in patients treated with placebo. (See also PRECAUTIONS - Pediatric Use - Weight Gain.)

There was a higher incidence of adverse events reflecting extrapyramidal symptoms (EPS) in the RISPERDAL® group (27.6%) compared with the placebo group (10.0%). In addition, between-group comparison of the severity of EPS were assessed objectively by the following rating instruments: the Simpson-Angus Rating Scale (SARS) and the Abnormal Involuntary Movement Scale (AIMS) in one study, and the Extrapyramidal Symptom Rating Scale (ESRS) in the other study. The mean changes between baseline and endpoint in the total ESRS score were -0.3 in the RISPERDAL® group and -0.4 in the placebo group. The median in both treatment groups for each EPS rating scale.

Somnolence was the most frequent adverse event, and was reported at a higher incidence in the RISPERDAL® group compared with the placebo group. The vast majority of cases (96%) were either mild or moderate in severity. These events were most often of early onset with peak incidence occurring during the first 2 weeks of treatment, and median duration was 16 days. Patients experiencing persistent somnolence may benefit from a change in dosing regimen (see DOSAGE AND ADMINISTRATION - Irritability Associated with Autistic Disorder - Pediatrics [Children and Adolescents]).

Other Events Observed During the Premarketing Evaluation of RISPERDAL®

During its premarketing assessment, multiple doses of RISPERDAL® were administered to 2607 adult patients with schizophrenia and 1923 pediatric 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 investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals 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 adult or 1923 pediatric 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. Serious adverse reactions experienced by the pediatric population were similar to those seen in the adult population (see WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS).

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, influenza-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 increase, creatine 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 dysfunction , 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

Infrequent: granulocytopenia. Rare: leukocytosis, lymphadenopathy, leucopenia, Pelger-Huet anomaly.

Endocrine Disorders

Rare: gynecomastia, male breast pain, antidiuretic hormone disorder.

Special Senses

Rare: bitter taste.

Postintroduction Reports

Adverse events reported since market introduction 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, diabetes mellitus aggravated, including diabetic ketoacidosis, hyperglycemia, intestinal obstruction, jaundice, mania, pancreatitis, Parkinson's disease aggravated, pituitary adenomas, pulmonary embolism, and precocious puberty. 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 Abuse And Dependence

Controlled Substance Class

RISPERDAL® (risperidone) is not a controlled substance.

Physical and Psychological Dependence

RISPERDAL® has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of RISPERDAL® misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

* Incidence based on elicited reports.

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.

Amitriptyline 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 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 by about 10%. 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 (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) 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® 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.

Included as part of the PRECAUTIONS section.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RISPERDAL® (risperidone) is not approved for the treatment of dementia-related psychosis [see Boxed Warning].

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 risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. RISPERDAL® is not approved for the treatment of patients with dementia-related psychosis. [See also Boxed Warnings and Warnings and PRECAUTIONS]

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 creatinine 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® 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®, drug discontinuation should be considered. However, some patients may require treatment with RISPERDAL® despite the presence of the syndrome.

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.

Hyperprolactinemia

As with other drugs that antagonize dopamine D₂ receptors, RISPERDAL® elevates prolactin levels and the elevation persists during chronic administration. RISPERDAL® is associated with higher levels of prolactin elevation than other antipsychotic agents.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Non-Clinical Toxicology]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

Orthostatic Hypotension

RISPERDAL® may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of RISPERDAL®-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment [see DOSAGE AND ADMINISTRATION]. Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. A dose reduction should be considered if hypotension occurs. RISPERDAL® should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia. Clinically significant hypotension has been observed with concomitant use of RISPERDAL® and antihypertensive medication.

Potential for Cognitive and Motor Impairment

Somnolence was a commonly reported adverse event associated with RISPERDAL® treatment, especially when ascertained by direct questioning of patients. This adverse event is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (RISPERDAL® 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of RISPERDAL® 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse event. Since RISPERDAL® 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 RISPERDAL® therapy does not affect them adversely.

Seizures

During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of RISPERDAL®-treated patients, two in association with hyponatremia. RISPERDAL® 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® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. [See also Boxed Warnings and Warnings and PRECAUTIONS]

Priapism

Rare cases of priapism have been reported. While the relationship of the events to 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.

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 for patients who will be exposed to temperature extremes.

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.

Suicide

The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania, including children and adolescent patients, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for RISPERDAL® should be written for the smallest quantity of tablets, consistent with good patient management, in order to reduce the risk of overdose.

Use in Patients with Concomitant Illness

Clinical experience with RISPERDAL® in patients with certain concomitant systemic illnesses is limited. Patients with Parkinson's Disease or Dementia with Lewy Bodies who receive antipsychotics, including RISPERDAL®, are reported to have an increased sensitivity to antipsychotic medications. Manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.

Caution is advisable in using RISPERDAL® in patients with diseases or conditions that could affect metabolism or hemodynamic responses. RISPERDAL® has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product's premarket testing.

Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m²), and an increase in the free fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose should be used in such patients [see DOSAGE AND ADMINISTRATION].

Monitoring: Laboratory Tests

No specific laboratory tests are recommended.

NonClinical Toxicology

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 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis or 0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a mg/m² basis. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The following table summarizes the multiples of the human dose on a mg/m² (mg/kg) basis at which these tumors occurred.

Tumor Type	Species	Sex	Multiples of Maximum Human Dose in mg/m2 (mg/kg)
			Lowest Effect Level	Highest No- Effect Level
Pituitary adenomas	mouse	female	0.75 (9.4)	0.2 (2.4)
Endocrine pancreas adenomas	rat	male	1.5 (9.4)	0.4 (2.4)
Mammary gland adenocarcinomas	mouse	female	0.2 (2.4)	none
	rat	female	0.4 (2.4)	none
	rat	male	6.0 (37.5)	1.5 (9.4)
Mammary gland neoplasm, Total	rat	male	1.5 (9.4)	0.4 (2.4)

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 Warnings and PRECAUTIONS].

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/m² basis. The effect appeared to be in females, since impaired mating behavior was not noted in the Segment I study in which males only were treated. In a subchronic study in Beagle dogs in which risperidone was administered at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the MRHD on a mg/m² basis. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. No no-effect doses were noted in either rat or dog.

Use In Specific Populations

Pregnancy

Pregnancy Category C.

The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the maximum recommended human dose [MRHD] on a mg/m² basis) and in one Segment II study in New Zealand rabbits (0.31-5 mg/kg or 0.4 to 6 times the MRHD on a mg/m² basis). The incidence of malformations was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the MRHD on a mg/m² basis. In three reproductive studies in rats (two Segment III and a multigenerational study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16-5 mg/kg or 0.1 to 3 times the MRHD on a mg/m² basis. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams.

There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m² basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams. These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m² basis.

Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled studies in pregnant women. However, there was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero. The causal relationship to RISPERDAL® therapy is unknown. Reversible extrapyramidal symptoms in the neonate were observed following postmarketing use of RISPERDAL® during the last trimester of pregnancy.

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 RISPERDAL® should not breast-feed.

Pediatric Use

The efficacy and safety of RISPERDAL® in the treatment of schizophrenia were demonstrated in 417 adolescents, aged 13 — 17 years, in two short-term (6 and 8 weeks, respectively) double-blind controlled trials (see INDICATIONS AND USAGE, ADVERSE REACTIONS, and Clinical Studies]. Additional safety and efficacy information was also assessed in one long-term (6-month) open-label extension study in 284 of these adolescent patients with schizophrenia.

Safety and effectiveness of RISPERDAL® in children less than 13 years of age with schizophrenia have not been established.

The efficacy and safety of RISPERDAL® in the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 — 17 years, were demonstrated in one double-blind, placebo-controlled, 3-week trial (see INDICATIONS AND USAGE, ADVERSE REACTIONS, and Clinical Studies].

Safety and effectiveness of RISPERDAL® in children less than 10 years of age with bipolar disorder have not been established.

The efficacy and safety of RISPERDAL® in the treatment of irritability associated with autistic disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years [see INDICATIONS AND USAGE, ADVERSE REACTIONS and Clinical Studies]. Additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short- and long-term studies in more than 1200 pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania who were of similar age and weight, and who received similar dosages of RISPERDAL® as patients treated for irritability associated with autistic disorder.

The safety and effectiveness of RISPERDAL® in pediatric patients less than 5 years of age with autistic disorder have not been established.

Human Experience

Premarketing experience included eight reports of acute RISPERDAL® overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure.

Postmarketing experience includes reports of acute RISPERDAL® overdosage, with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions reported since market introduction related to RISPERDAL® overdose include prolonged QT intervaland convulsions. Torsade de pointes has been reported in association with combined overdose of RISPERDAL® and paroxetine.

Management of Overdosage

In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. Because of the rapid disintegration of RISPERDAL® M-TAB®Orally Disintegrating Tablets, pill fragments may not appear in gastric contents obtained with lavage.

The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of risperidone, resulting in problematic hypotension.

There is no specific antidote to RISPERDAL®. Therefore, appropriate supportive measures should be instituted. The possibility of multiple drug involvement should be considered. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients treated with risperidone. Therefore, RISPERDAL® is contraindicated in patients with a known hypersensitivity to the product.

Mechanism of Action

The mechanism of action of RISPERDAL®, as with other drugs used to treat schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine Type 2 (D₂) and serotonin Type 2 (5HT₂) receptor antagonism.

RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT₂), dopamine Type 2 (D₂), α₁ and α₂ adrenergic, and H₁ histaminergic receptors. RISPERDAL® acts as an antagonist at other receptors, but with lower potency. RISPERDAL® has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT_1C, 5HT_1D, and 5HT_1A re