RISPERIDONE BEKER ORO

Tablets, USP contains risperidone, an atypical antipsychotic 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

C 23 H 27 FN 4 O and its molecular weight is 410.49.

The structural formula is

Risperidone is a white or almost white powder.

It is practically insoluble in water, freely soluble in methylene chloride, sparingly soluble in alcohol.

It dissolves in dilute acid solutions.

Tablets, USP are available in 0.25 mg (dark yellow), 0.5 mg (Reddish brown), 1 mg (white) strengths, 2 mg (pink), 3 mg (yellow) and 4 mg (green) strengths.

Each tablet for oral administration contains the following inactive ingredients: Anhydrous Lactose, Sodium Lauryl Sulfate, Microcrystalline Cellulose, Colloidal Silicon Dioxide, Sodium Starch Glycolate (Type A), Magnesium Stearate, HPMC 2910/ Hypromellose, Macrogol/ PEG (MW 400), Macrogol/ PEG (MW 8000), Titanium Dioxide.

Also, the tablet contains Polyvinyl Alcohol Part Hydrolyzed (used for 0.25, 0.5, 2, 3, 4 mg tablets), Macrogol/ PEG (MW 3350) (used for 0.25, 0.5, 2, 3, 4 mg tablets), Talc (used for 0.25, 0.5, 2, 3, 4 mg tablets), D&C Yellow #10 Aluminium Lake (used for 0.25, 4 mg tablets), FD&C Yellow #6/ Sunset Yellow FCF Aluminium Lake (used for 0.25, 2, 4 mg tablets), Iron Oxide Red (used for 0.5 mg tablets), Lactose Monohydrate, Triacetin & Stearic Acid (used for 1 mg tablets), FD&C Red #40/Allura Red AC Aluminum Lake (used for 2 mg tablets) , Iron Oxide Yellow (used for 3 mg tablets) and FD&C Blue #1/ Brilliant Blue FCF Aluminium Lake (used for 4 mg tablets).

is indicated for the treatment of moderate to severe manic episodes associated with bipolar disorders.

ALMUS is indicated for the short-term (up to 6 weeks) treatment of persistent aggressiveness in patients with moderate to severe Alzheimer's dementia who do not respond to non-pharmacological approaches and where there is a risk of harm to the patient himself or others.

ALMUS is indicated for the short-term (up to 6 weeks) symptomatic treatment of persistent aggressiveness in the conduct disorder in children aged 5 years and adolescents with lower-than-average intellectual functioning or mental retardation diagnosed according to the criteria of DSM-Intravenous, in which the severity of aggressive behaviour or other disruptive behaviour requires pharmacological treatment.

Pharmacological treatment should be an integral part of a broader treatment program, including psychosocial measures of the child and adolescent-in-the-child.

Observable mortality rate for patients with atypical antipsychotics in patients with atypical antipsychotics in patients with atypical antipsychotics in patients with atypical antipsychotics in patients with aberrants in patients with aberrants in patients with aberrants in patients with aberrants in patients with aberrants in patients with aberrants in patients with aberrants in patients with aberrants in patients with aberrants in patients with aberrants in patients with aberrants in patients with aberrants in patients with aberrants in patients with aberrants in patients with aberrants in patients with aberrants in patients with aberrants in patients with aberrants in patients with aberrants in patients with abers in patients with abers in patients with abers in patients with abers in patients with abers in patients with abers in patients with abers in patients with abers in patients with abers in patients with abers in patients with abers in patients with abers in patients with abers in patients with a.

The mechanism of action of risperidone in schizophrenia is unclear.

The drug's therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D 2 ) and serotonin Type 2 (5HT 2 ) receptor antagonism.

The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone (paliperidone) .

Antagonism at receptors other than

D and 5HT 2 may explain some of the other effects of risperidone. 12.2 Pharmacodynamics Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT 2 ), dopamine Type 2 (D 2 ), α 1 and α 2 adrenergic, and H 1 histaminergic receptors.

Risperidone showed low to moderate affinity (Ki of to 253 nM) for the serotonin 5HT 1c, 5HT 1D, and 5HT 1A receptors, weak affinity (Ki of to 800 nM) for the dopamine D and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations > 10 -5 M) for cholinergic muscarinic or β 1 and β 2 adrenergic receptors. 12.3 Pharmacokinetics Absorption Risperidone is well absorbed.

The absolute oral bioavailability of risperidone is 70% (CV=25%).

The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution.

Pharmacokinetic studies showed that risperidone orally disintegrating tablets and risperidone oral solution are bioequivalent to risperidone tablets.

Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of to 16 mg daily (0.5 to 8 mg twice daily).

Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour.

Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers.

Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers.

Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days (measured in extensive metabolizers).

Food does not affect either the rate or extent of absorption of risperidone.

Thus, risperidone can be given with or without meals.

Risperidone is rapidly distributed.

The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin and α 1 -acid glycoprotein.

The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%.

Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites.

High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.

Risperidone is extensively metabolized in the liver.

The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6.

A minor metabolic pathway is through

The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone.

Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.

CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs.

CYP 2D6 is subject to genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine.

CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly.

Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers.

Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces.

As illustrated by a mass balance study of a single 1 mg oral dose of 14 C-risperidone administered as solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces.

The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and 20 hours (CV=40%) in poor metabolizers.

The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor metabolizers.

The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours.

Risperidone could be subject to two kinds of drug-drug interactions.

First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone.

This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers.

The therapeutic benefits and adverse effects of risperidone in patients receiving quinidine have not been evaluated, but observations in a modest number (n≅70) of poor metabolizers given risperidone do not suggest important differences between poor and extensive metabolizers.

Second, co-administration of known enzyme inducers (e.g., carbamazepine, phenytoin, rifampin, and phenobarbital) with risperidone may cause a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone.

It would also be possible for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6.

Relatively weak binding of risperidone to the enzyme suggests this is unlikely.

In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6.

Therefore, risperidone 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.

In vitro studies demonstrated that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.

In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects.

Dosing should be modified accordingly in the elderly patients.

The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those in adults after correcting for the difference in body weight.

No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether corrected for body weight or not) or race.

(Risperidone is a selective monoaminergic antagonist with unique properties.

It has a high affinity for serotoninrgic receptors 5-HT2 and dopaminergic receptors.

Risperidone is also bound to alpha1-adrenergic receptors and, to a lesser extent, to histaminergic receptors H1 and alpha2-adrenergic receptors.

Risperidone is not an affinity for cholinergic receptors.

Although risperidone is a potent antagonist

D2, which is considered to be responsible for the beneficial effect on the positive symptoms of schizophrenia, it decreased the frequency of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the controlled dose of the.

The most frequently reported adverse reactions (ADRs) a frequency ≥ 10% of the patient's body are Parkinsonism, sedation/somnolence, headache and insomnia.

Adverse reactions that occurred in dose-dependent studies included Parkinsonism and l-akathisia.

The following

ARs are all reported with risperidone in clinical trials and postmarketing by category of frequency estimated from clinical trials of the risperidone specialty.

The following terms and frequencies are used: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10 000, < 1/1000), very rare (< 1/10,000), and unknown frequency (can be estimated from the available data) for the patient's disease, low-level of the patient's disease, low-level of the patient's disease, low-level of the patient's disease, low-level of the patient's disease, low-level of the patient's disease, low-level of the patient's disease, low-level of the patient's disease, low-level of the patient's disease, low-level.

Premarketing experience included eight reports of acute risperidone overdosage with estimated doses ranging from 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 risperidone 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 risperidone overdose include prolonged QT interval and convulsions.

Torsade de pointes has been reported in association with combined overdose of risperidone and paroxetine. 10.2 Management of Overdosage For the most up to date information on the management of risperidone overdosage, contact a certified poison control center (1-800-222-1222 or Provide supportive care including close medical supervision and monitoring.

Treatment should consist of general measures employed in the management of overdosage with any drug.

Consider the possibility of multiple drug overdosage.

Ensure an adequate airway, oxygenation, and ventilation.

Monitor cardiac rhythm and vital signs.

Use supportive and symptomatic measures.

There is no specific antidote to risperidone.

Risperidone is contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the risperidone formulation.

Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone.

Paliperidone is a metabolite of risperidone.

Known hypersensitivity to risperidone, paliperidone, or to any excipients in risperidone tablets.

Table 1.

Recommended Daily Dosage by Indication Initial Dose Titration (Increments) Target Dose Effective Dose Range Schizophrenia: adults 2 mg to 2 mg to 8 mg to 16 mg Schizophrenia: adolescents 0.5 mg 0.5 to 1 mg 3 mg to 6 mg Bipolar mania: adults to 3 mg 1 mg to 6 mg to 6 mg Bipolar mania: children and adolescents 0.5 mg 0.5 to 1 mg to 2.5 mg to 6 mg Irritability in autistic disorder 0.25 mg Can increase to 0.5 mg by Day 4: (body weight less than 20 kg) After Day 4, at intervals of > 2 weeks: 0.25 mg (body weight less than 20 kg) 0.5 mg: (body weight less than 20 kg) 0.5 to 3 mg 0.5 mg Can increase to 1 mg by Day 4: (body weight greater than or equal to 20 kg) 0.5 mg (body weight greater than or equal to 20 kg) 1 mg: (body weight greater than or equal to 20 kg) Severe Renal and Hepatic Impairment in Adults: use a lower starting dose of 0.5 mg twice daily.

May increase to dosages above 1.5 mg twice daily at intervals of one week or longer.

Recommended daily dosage

Initial Dose Target Dose Effective Dose Range Schizophrenia: adults 2 mg to 8 mg to 16 mg Schizophrenia: adolescents 0.5 mg 3 mg to 6 mg Bipolar mania: adults to 3 mg to 6 mg to 6 mg Bipolar mania: in children and adolescents 0.5 mg to 2.5 mg to 6 mg Irritability associated with autistic disorder 0.25 mg (Weight < 20 kg) 0.5 mg (Weight ≥ 20 kg) 0.5 mg (< 20 kg) 1 mg (≥ 20 kg) 0.5 to 3 mg Severe Renal or Hepatic Impairment in Adults: Use a lower starting dose of 0.5 mg twice daily.

May increase to dosages above 1.5 mg twice daily at intervals of at least one week. 2.1 Schizophrenia Adults Usual Initial Dose Risperidone can be administered once or twice daily.

Initial dosing is 2 mg per day. May increase the dose at intervals of 24 hours or greater, in increments of to 2 mg per day, as tolerated, to a recommended dose of to 8 mg per day. In some patients, slower titration may be appropriate.

Efficacy has been demonstrated in a range of 4 mg to 16 mg per day. However, doses above 6 mg per 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 per day has not been evaluated in clinical trials.

The initial dose is 0.5 mg once daily, administered as a single-daily dose in the morning or evening.

The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to a recommended dose of 3 mg per day. Although efficacy has been demonstrated in studies of adolescent patients with schizophrenia at doses between 1 mg to 6 mg per day, no additional benefit was observed above 3 mg per day, and higher doses were associated with more adverse events.

Doses higher than 6 mg per day have not been studied.

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

While it is unknown how long a patient with schizophrenia should remain on risperidone, the effectiveness of risperidone 2 mg per day to 8 mg per day at delaying relapse was demonstrated in a controlled trial in adult patients who had been clinically stable for at least 4 weeks and were then followed for a period of to 2 years.

Both adult and adolescent patients who respond acutely should generally be maintained on their effective dose beyond the acute episode.

Patients should be periodically reassessed to determine the need for maintenance treatment.

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 Risperidone, the initial titration schedule should be followed.

There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to Risperidone, or treating patients with concomitant antipsychotics. 2.2 Bipolar Mania Usual Dose Adults The initial dose range is 2 mg to 3 mg per day. The dose may be adjusted at intervals of 24 hours or greater, in increments of 1 mg per day. The effective dose range is 1 mg to 6 mg per day, as studied in the short-term, placebocontrolled trials.

In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible dosage range of 1 mg to 6 mg per day.

Risperidone doses higher than 6 mg per day were not studied.

The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to the recommended target dose of 1 mg to 2.5 mg per day. Although efficacy has been demonstrated in studies of pediatric patients with bipolar mania at doses between 0.5 mg and 6 mg per day, no additional benefit was observed above 2.5 mg per day, and higher doses were associated with more adverse events.

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 risperidone.

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 risperidone in such longer-term treatment (i.e., beyond 3 weeks).

The physician who elects to use risperidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient. 2.3 Irritability Associated with Autistic Disorder.

• Pediatrics (Children and Adolescents) The dosage of risperidone should be individualized according to the response and tolerability of the patient.

The total daily dose of risperidone can be administered once daily, or half the total daily dose can be administered twice daily.

For patients with body weight less than 20 kg, initiate dosing at 0.25 mg per day. For patients with body weight greater than or equal to 20 kg, initiate dosing at 0.5 mg per day. After a minimum of four days, the dose may be increased to the recommended dose of 0.5 mg per day for patients less than 20 kg and 1.0 mg per day for patients greater than or equal to 20 kg. Maintain this dose for a minimum of 14 days.

In patients not achieving sufficient clinical response, the dose may be increased at intervals of 2 weeks or greater, in increments of 0.25 mg per day for patients less than 20 kg, or increments of 0.5 mg per day for patients greater than or equal to 20 kg. The effective dose range is 0.5 mg to 3 mg per day. No dosing data are available for children who weigh less than 15 kg. Once sufficient clinical response has been achieved and maintained, consider gradually lowering the dose to achieve the optimal balance of efficacy and safety.

The physician who elects to use risperidone 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. 2.4 Dosing in Patients with Severe Renal or Hepatic Impairment For patients with severe renal impairment (Cl cr < 30 mL/min) or hepatic impairment (10-15 points on Child Pugh System), the initial starting dose is 0.5 mg twice daily.

The dose may be increased in increments of 0.5 mg or less, administered twice daily.

For doses above 1.5 mg twice daily, increase in intervals of one week or greater. 2.5 Dose Adjustments for Specific Drug Interactions When risperidone is co-administered with enzyme inducers (e.g., carbamazepine), the dose of risperidone should be increased up to double the patient's usual dose.

It may be necessary to decrease the risperidone dose when enzyme inducers such as carbamazepine are discontinued.

Similar effect may be expected with co-administration of risperidone with other enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital).

When fluoxetine or paroxetine is co-administered with risperidone, the dose of risperidone should be reduced.

The risperidone dose should not exceed 8 mg per day in adults when co-administered with these drugs.

When initiating therapy, risperidone should be titrated slowly.

It may be necessary to increase the risperidone dose when enzyme inhibitors such as fluoxetine or paroxetine are discontinued.

Tablets, USP 0.25 mg are available as dark yellow, film-coated, capsule-shaped, convex tablet, debossed "R1" on one side and "R" on the other side, packaged as follows: Bottles of 60: (NDC 69367-368-60) Bottles of 500: (NDC 69367-368-05) Bottles of 1000: (NDC 69367-368-10) Risperidone Tablets, USP 0.5 mg are available as reddish brown, film-coated, capsule-shaped, convex tablet, debossed "R2" on one side and "R" on the other side, packaged as follows: Bottles of 60: (NDC 69367-369-60) Bottles of 500: (NDC 69367-369-05) Bottles of 1000: (NDC 69367-369-10) Risperidone Tablets, USP 1 mg are available as white, film-coated, capsule-shaped, convex tablet, debossed "R3" on one side and "R" on the other side, packaged as follows: Bottles of 60: (NDC 69367-370-60) Bottles of 500: (NDC 69367-370-05) Bottles of 1000: (NDC 69367-370-10) Risperidone Tablets, USP 2 mg are available as pink, film-coated, capsule-shaped, convex tablet, debossed "R4" on one side and "R" on the other side, packaged as follows: Bottles of 60: (NDC 69367-371-60) Bottles of 500: (NDC 69367-371-05) Bottles of 1000: (NDC 69367-371-10) Risperidone Tablets, USP 3 mg are available as yellow, film-coated, capsule-shaped, convex tablet, debossed "R5" on one side and "R" on the other side, packaged as follows: Bottles of 60: (NDC 69367-372-60) Bottles of 500: (NDC 69367-372-05) Bottles of 1000: (NDC 69367-372-10) Risperidone Tablets, USP 4 mg are available as green, film-coated, capsule-shaped, convex tablet, debossed "R6" on one side and "R" on the other side, packaged as follows: Bottles of 60: (NDC 69367-373-60) Bottles of 500: (NDC 69367-373-05) 16.2 Storage and Handling Store at 20-25°C (68-77°F); excursions permitted to 15°-30°C (59°-86°F) .

Protect from light and moisture.

Keep out of reach of children.

Store at 20-25°C (68-77°F); excursions permitted to 15°-30°C (59°-86°F) .

Protect from light and moisture.

Keep out of reach of children.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including risperidone, during pregnancy.

Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

Overall, available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including risperidone, during pregnancy.

Oral administration of risperidone to pregnant mice caused cleft palate at doses to 4 times the maximum recommended human dose (MRHD) with maternal toxicity observed at 4-times MRHD based on mg/m 2 body surface area.

Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the MRHD based on mg/m 2 body surface area.

Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the MRHD based on mg/m 2 body surface area.

Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the MRHD and offspring mortality increased at doses 0.1 to 3 times the MRHD based on mg/m 2 body surface area.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide.

Schizophrenia and bipolar

I disorder are associated with increased adverse perinatal outcomes, including preterm birth.

It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy.

These symptoms have varied in severity.

Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.

Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects.

A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone.

A retrospective cohort study from a

Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.

There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02–1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88–1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.

Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area: maternal toxicity occurred at 4 times the MRHD.

Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2 body surface area.

Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at and 2 mg/kg/day which are 0.6 and 1.2 times the MRHD based on mg/m 2 body surface area; postnatal development and growth of the offspring were also delayed.

Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area.

It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined.

The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the MRHD based on mg/m 2 body surface area.

In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats.

In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered.

Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams.

All of these effects occurred at 5 mg/kg which is 3 times the MRHD based on mg/m and the only dose tested in the study.

The efficacy and safety of risperidone in the treatment of schizophrenia were demonstrated in 417 adolescents, aged to 17 years, in two short-term (6 and 8 weeks, respectively) double-blind controlled trials.

Additional safety and efficacy information was also assessed in one long-term (6-month) open-label extension study in of these adolescent patients with schizophrenia.

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

The efficacy and safety of risperidone in the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged to 17 years, were demonstrated in one double-blind, placebo-controlled, 3-week trial.

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

The efficacy and safety of risperidone in the treatment of irritability associated with autistic disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children and adolescent patients, aged to 16 years.

Additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short.

• and long-term studies in more than 1200 pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania who were of similar age and weight, and who received similar dosages of risperidone as patients treated for irritability associated with autistic disorder.

A third study was a 6-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects to 17 years of age with autistic disorder and associated irritability, and related behavioral symptoms.

There were two weight-based, fixed doses of risperidone (high-dose and low-dose).

The high dose was 1.25 mg per day for patients weighing to < 45 kg, and it was 1.75 mg per day for patients weighing ≥ 45 kg. The low dose was 0.125 mg per day for patients weighing to < 45 kg, and it was 0.175 mg per day for patients weighing ≥ 45 kg. The study demonstrated the efficacy of high-dose risperidone, but it did not demonstrate efficacy for low-dose risperidone.

Adverse Reactions in Pediatric Patients Tardive Dyskinesia In clinical trials in 1885 children and adolescents treated with risperidone, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of risperidone treatment.

Weight gain has been observed in children and adolescents during treatment with risperidone.

Clinical monitoring of weight is recommended during treatment.

Data derive from short-term placebo-controlled trials and longer-term uncontrolled studies in pediatric patients (ages to 17 years) with schizophrenia, bipolar disorder, autistic disorder, or other psychiatric disorders.

In the short-term trials (3 to 8 weeks), the mean weight gain for risperidone-treated patients was 2 kg, compared to 0.6 kg for placebotreated patients.

In these trials, approximately 33% of the risperidone group had weight gain ≥ 7%, compared to 7% in the placebo group.

In longer-term, uncontrolled, open-label pediatric studies, the mean weight gain was 5.5 kg at Week and 8 kg at Week 48.

Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients with autistic disorder.

Most cases were mild or moderate in severity.

These events were most often of early onset with peak incidence occurring during the first two weeks of treatment, and transient with a median duration of 16 days.

Somnolence was the most commonly observed adverse reaction in the clinical trial of bipolar disorder in children and adolescents, as well as in the schizophrenia trials in adolescents.

As was seen in the autistic disorder trials, these adverse reactions were most often of early onset and transient in duration.

Patients experiencing persistent somnolence may benefit from a change in dosing regimen.

Risperidone has been shown to elevate prolactin levels in children and adolescents as well as in adults.

In double-blind, placebo-controlled studies of up to 8 weeks duration in children and adolescents (aged to 17 years) with autistic disorder or psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of patients who received risperidone had elevated prolactin levels compared to 2% of patients who received placebo.

Similarly, in placebo-controlled trials in children and adolescents (aged to 17 years) with bipolar disorder, or adolescents (aged to 17 years) with schizophrenia, 82-87% of patients who received risperidone had elevated levels of prolactin compared to 3-7% of patients on placebo.

Increases were dosedependent and generally greater in females than in males across indications.

In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of risperidone-treated patients and gynecomastia was reported in 2.3% of risperidone-treated patients.

The long-term effects of risperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.

Juvenile dogs were treated with oral risperidone from weeks to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day, which are 1.2, 3.4, and 13.5 times the MRHD of 6 mg/day for children, based on mg/m 2 body surface area.

Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUC of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) that were similar to those in children and adolescents receiving the MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females.

The above effects showed little or no reversibility in females after a 12 week drug-free recovery period.

Juvenile rats, treated with oral risperidone from days to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the MRHD of 6 mg/day for children, based on mg/m 2 body surface area.

This dose produced plasma

AUC of risperidone plus paliperidone about half the exposure observed in humans at the MRHD.

No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the MRHD and produced plasma AUC of risperidone plus paliperidone that were about two thirds of those observed in humans at the MRHD of 6 mg/day for children.

Clinical studies of risperidone in the treatment of schizophrenia did not include sufficient numbers of patients aged and over to determine whether or not they respond differently than younger patients.

Other reported clinical experience has not identified differences in responses between elderly and younger patients.

In general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful titration.

Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern.

This drug is substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.