The P-I-E-N-O Parkinsn's List Drug Database
risperidone / RisperdalTM
MODERATE RISK
Description: Risperidone is an oral antipsychotic agent. It is a first-line option for treating the many fragments of psychosis. Psychotic disorders, including acute and chronic schizophrenic psychoses, and affective symptoms associated with schizophrenia have responded to treatment. Controlled clinical trials are also underway studying the efficacy of risperidone in the treatment of Tourette's Syndrome. Advantages over other currently available antipsychotic agents are a reduction in negative symptoms and reduced incidence of extrapyramidal symptoms. Unlike clozapine, the first serotonin-dopamine blocking agent marketed, risperidone is not associated with agranulocytosis. Risperidone was approved for the treatment of schizophrenia by the FDA in December 1993.
Mechanism of Action: Risperidone is a selective monoaminergic antagonist with a high affinity for both serotonergic 5-HTA and dopaminergic DA receptors. Conventional antipsychotic therapy was based on the assumption that overactive dopaminergic pathways contributed to schizophrenia. Serotonin transmission is also thought to be involved in schizophrenia. Compared with haloperidol, risperidone has about 200 times the affinity for serotonin receptors, while the dopaminergic effect is about the same.
Antagonism of serotonin receptors was found to alleviate negative symptoms of schizophrenia such as a flattening effect on normal function, apathy, and social withdrawal. The potent cortical serotonin-blocking activity of risperidone both complements and rectifies dopamine antagonism.
Even though risperidone possesses antidopaminergic action, it produces less depression of motor activity than do classical neuroleptics. Blockade of DA receptors alleviates positive symptoms of schizophrenia such as hallucinations, delusions, and erratic behavior and speech. This blockade, however, is considered responsible for the appearance of extrapyramidal symptoms. Another characteristic of dopamine antagonism is hyperprolactinemia, which can lead to adverse effects such as weight gain and menstrual irregularity. Prolactin increases are reversible on drug withdrawal. Excessive doses can increase the incidence of prolactin-mediated carcinoma.
Like other 5-HTA antagonists, risperidone also exhibits pharmacological properties at other receptors. Binding occurs at ›A-adrenergic receptors and, to a lesser extent, at histamine HA and ›A-adrenergic receptors. The affinity of risperidone for ›A receptors can cause hypotension.
Pharmacokinetics: Risperidone is administered orally. Absorption is complete; risperidone can be administered without regard to meals. Peak plasma concentrations are achieved within 1-2 hours. Plasma concentrations are dose-proportional for both the parent compound and the main active metabolite, 9-hydroxy-risperidone. Plasma-protein binding for risperidone and 9-hydroxy-risperidone is 90% and 70%, respectively. Hepatic disease increases the amount of unbound risperidone. Animal studies show that risperidone crosses the placenta to some extent and is rapidly transferred to milk. Evaluations have not been made for humans.
Risperidone is metabolized by cytochrome P450IID enzyme. Both the parent drug and main metabolite are preferentially distributed to the frontal cortex and striatum in the brain, where half-lives are longer than in the plasma. Excretion is mainly renal, with a small amount excreted in the feces. About 90% of an oral dose is eliminated, with a half-life of about 3 hours; half-life of the metabolite is about 24 hours. Renal disease reduces total clearance and prolongs elimination half-life. Reduced dosage levels are indicated in patients with hepatic or renal disease.
CONTRAINDICATIONS/PRECAUTIONS: Secondary to ›-blockade, risperidone can inhibit vasoconstriction and can produce vasodilation. The resultant drop in blood pressure through decreased peripheral resistance can precipitate orthostatic hypotension. Risperidone should be used cautiously in patients with preexisting hypotension or cerebrovascular disease. Risperidone also should be used with caution in patients with cardiac disease, especially those with heart failure, history of myocardial infarction or ischemia, or conduction abnormalities. Existent QT prolongation can produce an increased risk of developing arrhythmias. Conditions that may predispose patients to hypotension, such as hypovolemia and dehydration, should if possible be corrected before instigation of risperidone therapy; or administer with extreme caution.
As with all schizophrenic patients, possible enhancement of suicidal ideation is a reality in those taking risperidone. Close supervision and control of medication is advisable.
Risperidone should be used with caution in patients with Parkinson's disease because of possible development of extrapyramidal symptoms. Patients with a seizure disorder or brain tumor should be treated cautiously because risperidone can precipitate seizures.
Antiemesis produced by risperidone can obscure evidence of GI obstruction.
Risperidone is metabolized by cytochrome P450 enzyme and should be used with caution in patients with hepatic disease. Lower initial doses are recommended for the elderly and for those with hepatic or renal impairment.
Although to date there is insufficient evidence linking chronic administration of risperidone and tumorigenicity, the increase in prolactin levels associated with antagonism of dopaminergic DA receptors contraindicates use in patients with breast carcinoma.
Risperidone is classified as pregnancy category C. At this time, evidence is insufficient to establish the safe use of risperidone in humans during pregnancy. Animal studies have not shown evidence of teratogenicity or mutagenicity, but they have shown an increase in deaths during the immediate post-natal period. Because risperidone is known to cross the placenta in animals, the drug is recommended for use during pregnancy only when the benefits outweigh the risks. Animal studies also show that risperidone is excreted into breast milk; although this has not been established in humans, the drug should not be used in breast-feeding women.
Risperidone should not be used in children under the age of 15 years. Safe use has not been established.
DRUG INTERACTIONS: Drugs that are potent inducers of the cytochrome P-450 mixed-function oxidase system can increase the metabolism of risperidone and potentially decrease its effectiveness. Higher doses of risperidone may be required during concomitant therapy with carbamazepine, clozapine, or phenobarbital. Cimetidine inhibits the cytochrome P-450 enzyme system. Concomitant use of cimetidine with risperidone can increase the risk of developing risperidone-induced extrapyramidal symptoms. Lower doses of risperidone may be indicated during concomitant therapy with cimetidine.
Other drugs that are metabolized by the cytochrome P-450 enzyme system, such as fluoxetine and tricyclic antidepressants, may compete for preferential metabolism and should be used concomitantly with caution or not at all because of possible increases in plasma levels of either drug.
Dopamine agonists, such as bromocriptine and levodopa, are pharmacological opposites of risperidone. Concomitant therapy with risperidone and any of these agents should be avoided whenever possible.
Ethanol and other CNS depressants should be used cautiously during therapy with risperidone.
Other central dopamine antagonists, such as phenothiazines and haloperidol, should be avoided or used cautiously in patients receiving risperidone to minimize the risk of additive toxicity.
Some œ-blockers can increase risperidone plasma levels.
ADVERSE REACTIONS: Risperidone is a potent ›A-adrenergic antagonist and can produce hypotension. Orthostatic hypotension is more likely to occur during the initiation of therapy. Dizziness can lead to syncope. Patient tolerance develops fairly rapidly, providing the initial dosage is carefully titrated.
The incidence of extrapyramidal symptoms (e.g., akathisia, dystonia, parkinsonism) is much lower with risperidone than with other antipsychotics such as haloperidol. This is probably due to the high serotonin antagonism exhibited by risperidone, counteracting its dopaminergic activity. Data from clinical trials suggest that the low incidence of extrapyramidal symptoms is dose-related, and dosage above 10 mg/day increases the risk of inducing these symptoms. The incidence of akathisia and dystonia is significantly lower than with haloperidol.
Tardive dyskinesia is associated with antipsychotic therapy. Evidence to date suggests that there is actually an antidyskinetic effect obtained from risperidone treatment, especially in patients with severe tardive dyskinesia. The occurrence of extrapyramidal symptoms generally predicts the development of tardive dyskinesia. However, there is insufficient evidence to exclude the development of tardive dyskinesia during long-term therapy, and the possibility should be considered, especially among the elderly (elderly women being most at risk). It is also possible that risperidone may mask the signs and symptoms of developing tardive dyskinesia. These symptoms may emerge upon withdrawal of the drug. However, the syndrome of tardive dyskinesia may remit partially or completely after the drug is withdrawn. Discontinuation of therapy should be considered if signs or symptoms of tardive dyskinesia do develop.
Risperidone and its main metabolite 9-hydroxyrisperidone have been shown to lengthen the QT interval. The occurrence of torsade de pointes has been associated with prolonged QT interval in other drug therapy. Patients with preexisting conditions related to QT prolongation are most at risk of developing these cardiac arrhythmias. Ventricular tachycardia has been reported.
Hyperprolactinemia is a response to the dopaminergic antagonism caused by risperidone. Increased levels of prolactin are associated with weight gain and menstrual irregularity. Prolactin levels return to normal following withdrawal of risperidone.
Photosensitivity can occur during risperidone therapy, and patients should be warned either to keep out of the sun or to use effective sunscreens (SPF 15+) on exposed areas of the body.
Reported adverse effects of risperidone on the gastrointestinal system include dyspepsia, constipation, abdominal pain, nausea/vomiting, and changes in salivation.
Severe adverse CNS reactions induced by risperidone may appear similar to neurologic symptoms of CNS disorders. The drug can suppress the symptoms of Reye's syndrome or those associated with brain tumor. Other CNS adverse effects reported for risperidone are agitation, anxiety, drowsiness, insomnia, headache, and nausea.
The following adverse reactions from risperidone have also been reported: blurred vision, fatigue, rhinitis, libido increase, libido decrease, impotence and ejaculation dysfunction.
PATIENT INFORMATION:
What do risperidone tablets do?
Risperidone (RisperdalTM ) helps to treat schizophrenia. Risperidone can help you to keep in touch with reality and reduce your mental problems. It is for patients that have not been helped by other medicines. Generic risperidone tablets are not yet available.
What should my doctor, dentist, or pharmacist know before I take risperidone?
They need to know if you have any of these conditions:
How should I take this medicine?
Take risperidone tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. If risperidone upsets your stomach you can take it with food. Take your doses at regular intervals. Do not take your medicine more often than directed. Do not stop taking except on your doctor's advice.
Special precautions for use in children:
This medicine is not for children under 15 years old.
Elderly patients over age 65 years may have a stronger reaction to this medicine and need smaller doses.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.
What other medicines can interact with risperidone?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking risperidone?
Serious side effects with risperidone include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with risperidone include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take risperidone?
Visit your doctor for regular checks on your progress. It may be several weeks before you see the full effects of risperidone. Do not suddenly stop taking risperidone. You may need to gradually reduce the dose. Only stop taking risperidone on your doctor's advice.
You may get dizzy or drowsy. Do not drive, use machinery, or do anything that needs mental alertness until you know how risperidone affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol can increase dizziness and drowsiness. Avoid alcoholic drinks. You can get a hangover effect the morning after a bedtime dose.
Do not treat yourself for colds, diarrhea or allergies. Ask your doctor or pharmacist for advice, some nonprescription medicines may increase possible side effects.
If you are going to have surgery tell your doctor or dentist that you are taking risperidone.
Risperidone may make you more sensitive to sun or ultraviolet light. Keep out of the sun, or wear protective clothing outdoors and use a sunscreen (at least SPF 15). Do not use sun lamps, or sun tanning beds or booths. To protect your eyes wear sunglasses even on cloudy days.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15 and 30C (59 and 86F). Throw away any unused medicine after the expiration date.
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