RISPERDAL® Oral Solution RISPERDAL® Tablets
Janssen-Ortho
Risperidone Tartrate
Risperidone
Antipsychotic Agent
Action And Clinical Pharmacology: Risperidone, a benzisoxazole derivative, is a novel antipsychotic drug which binds with high affinity to the serotonin type 2 (5-HT2), dopamine D2, and a1-adrenergic receptors. Risperidone binds with a lower affinity to the a2-adrenergic and histamine H1 receptors. Risperidone does not bind to dopamine D1 or muscarinic cholinergic receptors.
Receptor occupancy was also demonstrated in vivo in humans. Using positron emission tomography, risperidone was shown to block both 5-HT2 and dopamine D2 receptors in 3 healthy volunteers.
Pharmacokinetics: Risperidone was well absorbed after oral administration, had high bioavailability, and showed dose-proportionality in the therapeutic dose range, although inter-individual plasma concentrations varied considerably. Food did not affect the extent of absorption, thus, risperidone can be given with or without meals.
The bioequivalence of the oral formulations (oral solution and tablets) has been demonstrated. A summary table of comparative bioavailability data for unchanged risperidone is presented in Table I.
Peak plasma concentrations of parent drug are reached within 1 to 2 hours after drug intake. Risperidone is mainly metabolized via hydroxylation and oxidative N-dealkylation. The major metabolite is 9-hydroxy-risperidone which has similar activity to the parent drug. Consequently, the clinical effect is brought about by the active moiety, namely risperidone plus 9-hydroxy-risperidone.
The hydroxylation of risperidone is dependent upon debrisoquine 4-hydroxylase i.e., the metabolism of risperidone is sensitive to the debrisoquine hydroxylation type genetic polymorphism. Consequently, the concentrations of parent drug and active metabolite differ substantially in extensive and poor metabolizers. However, the concentration of the active moiety (risperidone plus 9-hydroxy-risperidone) did not differ substantially between extensive and poor metabolizers, and elimination half-lives were similar in all subjects (approximately 20 to 24 hours).
Risperidone is rapidly distributed. The volume of distribution is 1 to 2 L/kg. Steady-state concentrations of risperidone and the active moiety were reached within 1 to 2 days and 5 to 6 days, respectively. In plasma, risperidone is bound to albumin and alpha1-acid glycoprotein (AGP). The plasma protein binding of risperidone is approximately 88%, that of the metabolite 77%. One week after administration, 70% of the dose is excreted in the urine and 14% in the feces. In urine, risperidone plus 9-hydroxy-risperidone represent 35 to 45% of the dose. The remainder is inactive metabolites.
The results indicate that a 1 mg dose of risperidone produced modest pharmacokinetic changes in elderly subjects. In patients with impaired renal function, the changes were substantial; Cmax and AUC were increased, half-life prolonged and clearance decreased.
In patients with impaired liver function, the unbound fraction of risperidone was somewhat increased due to diminished concentration of both a1-AGP and albumin.
Clinical Studies: In controlled trials, risperidone was evaluated in a dose range of 1 to 16 mg/day and compared to both placebo and haloperidol. The studies indicated that risperidone is an effective antipsychotic agent improving both positive and negative symptoms. Optimal therapeutic response was seen in the 4 to 8 mg/day dose range, indicating a bell-shaped dose-response relationship. Parkinsonian side effects were mild but dose-related. Risperidone elevated serum prolactin levels. Due to the a1-adrenergic blocking activity, orthostatic hypotension with compensatory tachycardia was also observed.
Indications And Clinical Uses: For the management of manifestations of schizophrenia and related psychotic disorders. In controlled clinical trials, risperidone was found to improve both positive and negative symptoms of schizophrenia.
Contra-Indications: In patients with a known hypersensitivity to the drug or the excipients of the product.
Manufacturers’ Warnings In Clinical States: Cardiovascular: During clinical trials, risperidone has been observed to cause orthostatic hypotension and tachycardia, especially during the initial dose titration period and the first few weeks of treatment. Rare cases of syncope, cardiac arrhythmias and first degree AV-block have been reported. The likelihood of excessive hypotension or syncope can be minimized by limiting the initial dose of the drug to 1 mg b.i.d. in adult patients and to 0.5 mg b.i.d. in special patient populations, and by increasing the dose slowly (see Dosage). A dose reduction should be considered if hypotension occurs.
Patients with a history of clinically significant cardiac disorders were excluded from clinical trials. Therefore, risperidone should be used with caution in patients with cardiovascular diseases (e.g., heart failure, myocardial infarction, cerebrovascular disease, conduction abnormalities) and other conditions such as dehydration and hypovolemia. Special care should be taken to avoid hypotension in patients with a history of cerebrovascular insufficiency or ischemic heart disease, and in patients taking medications to lower blood pressure.
Neuroleptic Malignant Syndrome (NMS): Neuroleptic malignant syndrome is a potentially fatal symptom complex that has been reported in association with neuroleptic drugs, including risperidone.
Clinical manifestations of NMS are hyperthermia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular blood pressure, tachycardia, cardiac arrhythmias and diaphoresis). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.
In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary CNS pathology.
The management of NMS should include: 1) immediate discontinuation of all antipsychotic drugs including risperidone, and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrence of NMS has been reported.
Tardive Dyskinesia (TD): A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with conventional antipsychotic drugs. Although TD appears to be most prevalent in the elderly, especially elderly females, it is impossible to predict at the onset of treatment which patients are likely to develop TD.
It has been suggested that the occurrence of parkinsonian side effects is a predictor for the development of TD. In clinical studies, the observed incidence of drug-induced parkinsonism was lower with risperidone than with haloperidol. In the optimal clinical dose range, the difference between risperidone and haloperidol was significant. The risk of developing TD may be less with risperidone.
The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although less commonly, after relatively brief periods of treatment at low doses. There is no known treatment for established cases of TD. The syndrome may remit, partially or completely, if antipsychotic drug treatment is withdrawn. Antipsychotic drug treatment itself, however, may suppress the signs and symptoms of TD, thereby masking the underlying process. The effect of symptom suppression upon the long-term course of TD is unknown.
In view of these considerations, risperidone should be prescribed in a manner that is most likely to minimize the risk of TD. As with any antipsychotic drug, risperidone should be reserved for patients who appear to be obtaining substantial benefit from the drug. In such patients, the smallest dose and the shortest duration of treatment should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of TD develop during treatment with risperidone, withdrawal of the drug should be considered. However, some patients may require treatment with risperidone despite the presence of the syndrome.
Precautions: Occupational Hazards: Interference with Mental Alertness: Risperidone may interfere with activities requiring mental alertness. Therefore, patients should be cautioned not to drive or operate machinery until their individual susceptibility is known.
Seizures: Conventional neuroleptics are known to lower seizure threshold. In clinical trials, seizures have occurred in a few risperidone-treated patients. Therefore, caution should be used in administering risperidone to patients having a history of seizures or other predisposing factors.
Drug Interactions: The risk for potential interaction between risperidone and other drugs has not been evaluated systematically. Risperidone may enhance the effects of alcohol, centrally-acting drugs, as well as the effects of antihypertensive agents. Because of its potential for inducing hypotension, risperidone may enhance the hypotensive effects of other therapeutic agents with this potential.
Risperidone may antagonize the effects of levodopa and dopamine agonists.
Carbamazepine has been shown to decrease substantially the plasma levels of risperidone and its active metabolite, 9-hydroxy-risperidone. Similar effects may be observed with other hepatic enzyme inducers. Consequently, in the presence of carbamazepine or other hepatic enzyme inducers, the dose of risperidone may have to be adjusted. On discontinuation of these drugs, the dosage of risperidone should be re-evaluated and, if necessary, decreased.
The metabolism of risperidone, a substrate of the hepatic cytochrome P450 isozyme (P450IID6), is affected by the debrisoquine hydroxylation polymorphism (see Pharmacology, Pharmacokinetics). Potential interaction between risperidone and drugs that are also substrates of this enzyme, namely phenothiazines, tricyclic antidepressants, selective serotonin reuptake inhibitors, and some beta-blockers, should be considered.
In vitro studies, in which risperidone was given in the presence of various, highly protein-bound agents, indicated that clinically relevant changes in protein binding would not occur either for risperidone or for any of the drugs tested.
Endocrine Effects: Antipsychotic drugs elevate prolactin levels with the effect persisting during chronic administration. In controlled clinical trials, risperidone elevated substantially serum prolactin levels; in female patients, mean levels ranged between 48 and 57 ng/mL at doses ranging from 4 to 16 mg/day. The prolactin levels were considerably higher in risperidone-treated patients than in haloperidol-treated patients. Since tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, risperidone should only be administered to patients with previously detected breast cancer if the benefits outweigh the potential risks. Caution should also be exercised when considering risperidone treatment in patients with pituitary tumors. Possible manifestations associated with elevated prolactin levels are amenorrhea, galactorrhea, and menorrhagia (see Adverse Effects).
In carcinogenicity studies, the administration of risperidone resulted in an increase in the incidence of mammary neoplasms in both rats and mice. In addition, adenomas of the endocrine pancreas in male rats and pituitary adenomas in female mice have been noted. These changes have been attributed to elevated prolactin levels and have also been observed with other dopamine receptor antagonists. To date, neither clinical studies nor epidemiological studies have shown an association between chronic administration of these drugs and mammary tumorigenesis.
With continued treatment, weight gain (mean: 2.3 kg in long-term studies) has been seen.
Pregnancy: The safety of risperidone for use during pregnancy has not been established. In animal studies, risperidone did not show direct reproductive toxicity. However, due to its prolactin elevating and CNS depressant activities, reproductive performance and pup survival were adversely affected in rats. Risperidone was not teratogenic in either rats or rabbits.
Risperidone should not be used during pregnancy unless the expected benefits outweigh the potential risks to the fetus.
Lactation: It is not known whether risperidone is excreted in human milk. Risperidone appeared in the milk of lactating dogs. The concentration of risperidone was similar in milk and plasma, while that of 9-hydroxy-risperidone was higher in the milk than in plasma.
Nursing should not be undertaken while a patient is receiving risperidone.
Geriatrics: Since the elimination of risperidone is somewhat slower in the elderly (see Pharmacology, Pharmacokinetics), doses exceeding 3 mg/day are not recommended in these patients (see Dosage).
Children: The safety and efficacy of risperidone in children under the age of 18 have not been established.
Patients with Hepatic Impairment: To date, clinical experience is lacking in this patient population. Although the pharmacokinetics in patients with liver insufficiency were comparable to those in young volunteers, the free fraction of risperidone was increased. Since this may lead to a more pronounced pharmacological effect, it is recommended to halve the starting dose and the subsequent dose increments (see Dosage).
Patients with Renal Impairment: The pharmacokinetics of risperidone were significantly altered in patients with renal disease (see Pharmacology, Pharmacokinetics). Since clinical experience is lacking in this patient population, dosage recommendations cannot be made at this time.
Patients with Parkinson’s Disease: Risperidone, like other dopamine antagonists, may cause a deterioration in the condition of parkinsonian patients and should therefore be used with caution.
Adverse Reactions: The most frequent adverse reactions observed during clinical trials with risperidone were insomnia, agitation, extrapyramidal disorder, anxiety, and headache (see Tables III and IV). In some instances it has been difficult to differentiate adverse events from symptoms of the underlying psychosis.
The most serious adverse reactions were rare cases of syncope, cardiac arrhythmias, first degree AV-block, and seizures.
An estimated 9% of approximately 1 800 patients who received risperidone in controlled clinical trials discontinued treatment due to adverse reactions. The more common events causing discontinuation included: Psychiatric (4.1%): primarily psychosis, agitation, suicide attempt, somnolence. Neurological (3.2%): primarily extrapyramidal disorder, dizziness. Cardiovascular (1.2%): primarily hypotension. Other events leading to discontinuation included: tachycardia/palpitations (0.6%), nervousness (0.4%), nausea (0.3%) and insomnia (0.3%).
Parkinsonian side effects were usually mild and were reversible upon dose reduction and/or administration of antiparkinsonian medication.
Occasionally, hypotension (including orthostatic), and tachycardia (including reflex tachycardia) have been observed following the administration of risperidone (see Warnings).
Risperidone elevated plasma prolactin levels. Associated manifestations, namely amenorrhea, galactorrhea, and menorrhagia, have occurred.
Weight gain, erectile dysfunction, ejaculatory dysfunction, orgastic dysfunction, and rash have also been observed during treatment with risperidone. In one study, in which testosterone levels were measured, testosterone decreased below the normal range in 6 out of 85 patients.
As with classical neuroleptics, cases of water intoxication, either due to polydipsia or to inappropriate secretion of antidiuretic hormone (ADH), have occasionally been reported during treatment with risperidone.
Adverse Events for North American Studies: Table III enumerates adverse events that occurred at an incidence of 1% or more, and were at least as frequent among risperidone-treated patients receiving doses of £10 mg/day than among placebo-treated patients in the pooled results of two 6- to 8-week controlled trials. Patients received risperidone 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 substantially in these rates. Reported adverse events were classified using the World Health Organization preferred terms.
Adverse Reactions During Long-term Treatment: Long-term treatment with risperidone was carried out in 386 chronic schizophrenic patients, with 213 patients receiving the drug for at least 1 year. The UKU side effect rating scale was used to elicit adverse events.
Listed (in decreasing order) are those events which showed deterioration during treatment compared to baseline in at least 10% of patients. Psychic: asthenia/lassitude/increased fatiguability, concentration difficulties, sleepiness/sedation, reduced duration of sleep, increased duration of sleep, failing memory, increased dream activity. Autonomic: orthostatic dizziness, constipation, nausea/vomiting, polyuria/polydipsia, palpitations/tachycardia, reduced salivation, accommodation disturbances, increased tendency to sweating, diarrhea. Other: weight gain, weight loss, amenorrhea, ejaculatory dysfunction, erectile dysfunction, diminished sexual desire, tension headache, increased sexual desire, orgastic dysfunction.
Postmarketing: International postmarketing reporting revealed the following adverse drug reactions during risperidone treatment: edema, increased hepatic enzyme levels, skin manifestations of allergy including a case of Stevens-Johnson syndrome, systemic manifestations of allergy including a case of anaphylactic shock, neuroleptic malignant syndrome and rare cases of tardive dyskinesia, hypertension, leukopenia and priapism. Rarely, mild to moderate neutropenia associated in a few cases with thrombopenia has been reported. To date, a causal relationship to risperidone has not been established. As with other neuroleptics, sudden deaths have been reported during risperidone treatment. Most of the patients had pre-existing cardiovascular disease or were morbidly obese. A relationship to risperidone has not been established at this time.
Symptoms And Treatment Of Overdose: Symptoms: Cases of overdosing have been reported with risperidone; the estimated doses were between 20 and 360 mg. Symptoms observed were due to excessive pharmacological effects, namely drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. In 1 case (240 mg) hyponatremia and hypokalemia were observed, with prolonged QTc and widened QRS complex on the ECG. Additionally, hypokalemia and prolonged QT interval were observed in 1 patient who ingested 360 mg of risperidone.
Treatment: Since there is no specific antidote to risperidone, treatment is primarily supportive. Gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered.
A patent airway must be established and maintained to ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Hypotension and circulatory collapse may be counteracted by use of i.v. fluids. Epinephrine should not be used. In cases of severe extrapyramidal reactions, antiparkinsonian medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.
In managing overdosage, the physician should consider the possibility of multiple drug involvement.
Dosage And Administration: In order to avoid orthostatic hypotension, the dose of risperidone should be titrated gradually.
Adults: Patients should be titrated gradually over 3 days on a b.i.d. schedule to a 6 mg daily dose, generally beginning with a 2 mg daily dose. The dosage should be increased to 4 mg on the second day and to 6 mg on the third day. Some patients may benefit from lower initial doses and/or a slower titration schedule.
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 are recommended.
Once a therapeutically effective maintenance dose has been established, risperidone may be administered once daily or twice daily.
In controlled clinical trials, optimal therapeutic effects were seen in the 4 to 8 mg/day dose range. Some patients may need higher doses, while in some patients further dosage increases may result in decreased therapeutic effect. Higher doses were associated with more extrapyramidal symptoms and other adverse effects. Since the safety of doses above 16 mg total daily dose has not been evaluated, doses above this level should not be used.
Geriatrics: In elderly patients, the doses of risperidone should be titrated slowly from a 0.5 mg b.i.d. starting dose to a maximum daily dose of 3 mg. Since the elimination of risperidone is somewhat slower in these patients, the potential for accumulation should be considered (see Pharmacology, Pharmacokinetics).
Postmarketing, treatment with risperidone in the elderly has been reported in publications for over 300 patients.
Patients Prone to Hypotension: Caution should be exercised in patients prone to hypotension and the use of a lower starting dose (0.5 mg b.i.d.) should be considered.
Impaired Liver Function: The pharmacokinetics of risperidone did not change in patients with impaired liver function in response to a 1 mg single dose. However, clinical experience is lacking in these patients. Until further experience is gained, the following dosage schedule is recommended. The starting dose should be 0.5 mg b.i.d. This dosage can be individually adjusted in 0.5 mg b.i.d. increments to 1 to 2 mg b.i.d.
Impaired Kidney Function: Since the pharmacokinetics of risperidone changed substantially in patients with renal disease, even in response to a 1 mg single dose (see Pharmacology, Pharmacokinetics and Precautions), and since to date no clinical experience is available, dosage recommendations cannot be made in this patient population.
Switching from Other Antipsychotics: When medically appropriate, gradual discontinuation of the previous treatment, while risperidone therapy is initiated is recommended. In all cases the period of overlapping antipsychotic administration should be minimized. When switching patients from depot antipsychotics, initiate risperidone therapy in place of the next scheduled injection. The need for continuing existing anti-parkinsonian medications should be re-evaluated periodically.
Availability And Storage: Oral Solution: Each mL of oral solution contains: risperidone 1 mg as risperidone tartrate. Nonmedicinal ingredients: benzoic acid, purified water, sodium hydroxide and tartaric acid. Bottles of 100 mL with a calibrated (in mg and in mL) pipette. The minimum calibrated volume is 0.25 mL, while the maximum calibrated volume is 3 mL. Store between 15 and 30°C. Protect from light and freezing. Keep out of reach of children. Patient Instructions (including illustrations) for using the Risperdal calibrated dispensing-pipette are provided (see Blue Section – Information for the Patient). Tests indicate that risperidone oral solution is compatible in the following beverages: water, coffee, orange juice and low-fat milk; however, it is not compatible with cola or tea.
Tablets: 1 mg: Each white, film-coated, half-scored, oblong tablet, marked JANSSEN and R 1, contains: risperidone 1 mg. Nonmedicinal ingredients: colloidal anhydrous silica, hypromellose, lactose, magnesium stearate, maize starch, microcrystalline cellulose, propylene glycol and sodium lauryl sulfate. Blister packages of 60 and HDPE bottles of 250.
2 mg: Each orange, film-coated, oblong tablet, marked JANSSEN and R 2, contains: risperidone 2 mg. Nonmedicinal ingredients: colloidal anhydrous silica, hypromellose, lactose, magnesium stearate, maize starch, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, sunset yellow (E110) aluminum lake, talc and titanium dioxide (E171). Blister packages of 60 and HDPE bottles of 250.
3 mg: Each yellow, film-coated, oblong tablet, marked JANSSEN and R 3, contains: risperidone 3 mg. Nonmedicinal ingredients: colloidal anhydrous silica, hypromellose, lactose, magnesium stearate, maize starch, microcrystalline cellulose, propylene glycol, quinoline yellow (E104), sodium lauryl sulfate, talc and titanium dioxide (E171). Blister packages of 60 and HDPE bottles of 250.
4 mg: Each green, film-coated, oblong tablet, marked JANSSEN and R 4, contains: risperidone 4 mg. Nonmedicinal ingredients: colloidal anhydrous silica, hypromellose, indigotindisulfonate (E132) aluminum lake, lactose, magnesium stearate, maize starch, microcrystalline cellulose, propylene glycol, quinoline yellow (E104), sodium lauryl sulfate, talc and titanium dioxide (E171). Blister packages of 60 and HDPE bottles of 250.
Store tablets between 15 and 30°C, protected from light and moisture. Keep out of the reach of children.
RISPERDAL® Oral Solution RISPERDAL® Tablets Janssen-Ortho Risperidone TartrateRisperidone Antipsychotic Agent
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