Drug Name

Risperdal (Risperidone)

Generic Name

Risperidone (ris-PER-i-done)

Looks like

• Risperdal 0.5 mg-light coral, round, biconvex tablets
• Risperdal 1 mg-light coral, square, biconvex tablets
• Risperdal 2 mg-light coral, round, biconvex tablets
• Risperdal 3 mg-coral, round, biconvex tablets: 28 blisters per box
• Risperdal 4 mg-coral, round, biconvex tablets: 28 blisters per box

Dosage Form

Tablets

Route Of Administration

ORAL

Imprint Code

JANSSEN;Ris0.5 / JANSSEN;R1 / JANSSEN;R2 / JANSSEN;R3 / JANSSEN;R4

Size

9mm / 12mm / 12mm / 14mm / 15mm

Alternatives

Bipolar Disorder
Seroquel (Quetiapine), Zoloft (Sertraline), Lamictal (Lamotrigine), Abilify (Aripiprazole)
Schizophrenia
Seroquel (Quetiapine), Abilify (Aripiprazole), Geodon (Ziprasidone), Zyprexa (Olanzapine)
Mania
Depakote (Divalproex), Zyloprim (Allopurinol), Haldol

Drug Uses

Risperdal is used to treat schizophrenia and symptoms of bipolar disorder (manic depression). Risperdal is also used in autistic children to treat symptoms of irritability.

Drug class

Risperdal is an antipsychotic medication. It works by changing the effects of chemicals in the brain.

Contains

Risperdal 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 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 Tablets contain xanthan gum.

Chemical formula

Risperdal (risperidone) is 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.

Mechanism of Action

The mechanism of action of Risperdal (risperidone), 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. Antagonism at receptors other than D2 and 5HT2 may explain some of the other effects of Risperdal.

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),a1 and a2 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 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M) for cholinergic muscarinic or b1 and b2 adrenergic receptors.

How Taken

Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label.

Risperdal can be taken with or without food.

To take risperidone orally disintegrating tablets (Risperdal):

• Keep the tablet in its blister pack until you are ready to take the medicine. Open the package and peel back the foil from the tablet blister. Do not push a tablet through the foil or you may damage the tablet.
• Using dry hands, remove the tablet and place it in your mouth. It will begin to dissolve right away.
• Do not swallow the tablet whole. Allow it to dissolve in your mouth without chewing.
• Swallow several times as the tablet dissolves. If desired, you may drink liquid after the tablet is completely dissolved.

It is important to take Risperdal regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Measure the liquid form of Risperdal with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Do not mix the liquid form of Risperdal with cola or tea. It may take several weeks of using this medicine before your symptoms improve. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve. Store Risperdal at room temperature away from moisture, light, and heat. Do not allow the liquid form of Risperdal to freeze.

Dosage and Administration

Schizophrenia

Usual Initial Dose
Risperdal (risperidone) can be administered on either a BID or a QD schedule. In early clinical trials, Risperdal was generally administered at 1 mg BID initially, with increases in increments of 1 mg BID on the second and third day, as tolerated, to a target dose of 3 mg BID by the third day. Subsequent controlled trials have indicated that total daily risperidone doses of up to 8 mg on a QD regimen are also safe and effective. However, regardless of which regimen is employed, in some patients a slower titration may be medically appropriate. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 1 week, since steady state for the active metabolite would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, small dose increments/decrements of 1-2 mg are recommended.

Efficacy in schizophrenia was demonstrated in a dose range of 4 to 16 mg/day in the clinical trials supporting effectiveness of Risperdal; however, maximal effect was generally seen in a range of 4 to 8 mg/day. Doses above 6 mg/day for BID dosing were not demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal symptoms and other adverse effects, and are not generally recommended. In a single study supporting QD 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 there is no body of evidence available to answer the question of how long the schizophrenic patient treated with Risperdal should remain on it, 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. In this trial, Risperdal was administered on a QD schedule, at 1 mg QD initially, with increases to 2 mg QD on the second day, and to a target dose of 4 mg QD on the third day. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment with an appropriate dose.

Reinitiation of Treatment in Patients Previously Discontinued
Although there are no data to specifically address reinitiation of treatment, it is recommended that when restarting patients who have had 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 concerning concomitant administration with other 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. In all cases, the period of overlapping antipsychotic administration should be minimized. When switching schizophrenic patients from depot antipsychotics, if medically appropriate, initiate Risperdal therapy in place of the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated periodically.

Pediatric UseThe safety and effectiveness of Risperdal in pediatric patients with schizophrenia have not been established.

Bipolar Mania

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

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 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).

Pediatric Use
The safety and effectiveness of Risperdal in pediatric patients with bipolar mania have not been established.

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 PHARMACOLOGY - Clinical Trials) 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 1.0 mg in patients < 20 kg, 2.5 mg in patients ≥ 20 kg, or 3.0 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.

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 BID 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 BID. Increases to dosages above 1.5 mg BID 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.
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. If a once-a-day dosing regimen in the elderly or debilitated patient is being considered, it is recommended that the patient be titrated on a twice-a-day regimen for 2-3 days at the target dose. Subsequent switches to a once-a-day 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 risperidone would be expected to cause decreases in the plasma concentrations of active moiety (the sum of risperidone and 9-hydroxyrisperidone), which could lead to decreased efficacy of risperidone treatment. The dose of risperidone needs to be titrated accordingly for patients receiving these enzyme inducers, especially during initiation or discontinuation of therapy with these inducers.

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 risperidone needs to be titrated accordingly when fluoxetine or paroxetine is co-administered.

Missed Dose

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.

Overdose

Seek emergency medical treatment if you think you have used too much of this medicine.

Overdose symptoms may include drowsiness, fast heart rate, feeling light-headed, fainting, and restless muscle movements in your eyes, tongue, jaw, or neck.

Storage

Store Risperdal between 59 and 77 degrees F (15 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Risperdal out of the reach of children and away from pets.

How Supplied

Risperdal Tablets are etched on one side with "R0.5", "R1", "R2", "R3", and "R4", respectively. Risperdal Tablets 0.5 mg, 1 mg, and 2 mg are packaged in blister packs of 4 (2 X 2) tablets. Risperdal 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 per box, NDC 50458-395-28, long-term care packaging of 30 tablets NDC 50458-395-30.

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

2 mg light coral, round, biconvex tablets: 7 blister packages 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.

What is the most important information I should know about Risperdal (Risperidone)?

Risperdal is not for use in psychotic conditions that are related to dementia. Risperdal has caused fatal heart attack and stroke in older adults with dementia-related conditions.
Do not give this medication to a child without a doctor's advice.

While you are taking Risperdal, you may be more sensitive to temperature extremes such as very hot or cold conditions. Avoid getting too cold, or becoming overheated or dehydrated. Drink plenty of fluids, especially in hot weather and during exercise. It is easier to become dangerously overheated and dehydrated while you are taking this medication. Risperdal can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.
Avoid using other medicines that make you sleepy (such as cold medicine, pain medication, muscle relaxers, and medicine for seizures, depression or anxiety). They can add to sleepiness caused by Risperdal.

Avoid drinking alcohol. It can increase some of the side effects of Risperdal. Stop using this medication and call your doctor at once if you have fever, stiff muscles, confusion, sweating, fast or uneven heartbeats, restless muscle movements in your face or neck, tremor (uncontrolled shaking), trouble swallowing, feeling light-headed, or fainting.
There may be other drugs not listed that can affect this medication. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

What should I discuss with my doctor before taking Risperdal (Risperidone)?

Risperdal is not for use in psychotic conditions that are related to dementia. Risperdal has caused fatal heart attack and stroke in older adults with dementia-related conditions. You should not use this medication if you are allergic to risperidone.

Before taking this medication, tell your doctor if you are allergic to any drugs, or if you have:

• liver disease;
• kidney disease;
• heart disease, high blood pressure, heart rhythm problems;
• a history of heart attack or stroke;
• a history of breast cancer;
• seizures or epilepsy;
• diabetes (risperidone may raise your blood sugar);
• a history of suicidal thoughts;
• Parkinson's disease; or
• trouble swallowing.

Risperdal may cause you to have high blood sugar (hyperglycemia). Talk to your doctor if you have any signs of hyperglycemia such as increased thirst or urination, excessive hunger, or weakness. If you are diabetic, check your blood sugar levels on a regular basis while you are taking Risperdal.

The risperidone orally disintegrating tablet may contain phenylalanine. Talk to your doctor before using this form of risperidone if you have phenylketonuria (PKU).

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether this medication passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Do not give this medication to a child without a doctor's advice.

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 Risperdal Tablets and Risperdal Oral Solution are bioequivalent to Risperdal Tablets.

Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg BID). 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).

Distribution

Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin and a1-acid glycoprotein. The plasma protein binding of risperidone is 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 (10 mcg/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.

Metabolism and Drug Interactions

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 N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug (e.g., the active moiety) 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. Extensive 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 the active moiety, after single and multiple doses, are similar in extensive and poor metabolizers.

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 of poor metabolizers given risperidone do not suggest important differences between poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g., 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 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. 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 (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%.

Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or peak plasma concentrations (Cmax) of lithium (n=13).

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.

There were no significant interactions between risperidone (1 mg QD) and erythromycin (500 mg QID).

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%.

Amitriptyline did not affect the pharmacokinetics of risperidone or the active moiety.

In drug interaction studies, risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which were metabolized by CYP 2D6.

Risperdal (0.25 mg BID) did not show a clinically relevant effect on the pharmacokinetics of digoxin.

Excretion

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 14C-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 the active moiety, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours.

Special Populations

Renal Impairment

In patients with moderate to severe renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60% compared to young healthy subjects. Risperdal doses should be reduced in patients with renal disease.

Hepatic Impairment

While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and a1-acid glycoprotein. Risperdal doses should be reduced in patients with liver disease.

Elderly

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.

Pediatric

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

Race and Gender Effects

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 o