1. Name Of The Medicinal Product
Risperidone 3mg Tablets
2. Qualitative And Quantitative Composition
Each tablet contains 3 mg risperidone
Excipients:
Each tablet contains 120 mg Lactose-Monohydrate.
For a full list of excipients, see section 6.1
3. Pharmaceutical Form
Film-coated tablet
Product description:
Yellow, biconvex, oblong tablets with score line on one side
4. Clinical Particulars
4.1 Therapeutic Indications
Risperidone is indicated for the treatment of schizophrenia.
Risperidone is indicated for the treatment of moderate to severe manic episodes associated with bipolar disorders.
Risperidone is indicated for the short-term treatment (up to 6 weeks) of persistent aggression in patients with moderate to severe Alzheimer's dementia unresponsive to non pharmacological approaches and when there is a risk of harm to self or others.
Risperidone is indicated for the short-term symptomatic treatment (up to 6 weeks) of persistent aggression in conduct disorder in children from the age of 5 years and adolescents with subaverage intellectual functioning or mental retardation diagnosed according to DSM-IV criteria, in whom the severity of aggressive or other disruptive behaviours require pharmacologic treatment. Pharmacological treatment should be an integral part of a more comprehensive treatment programme, including psychosocial and educational intervention. It is recommended that risperidone be prescribed by a specialist in child neurology and child and adolescent psychiatry or physicians well familiar with the treatment of conduct disorder of children and adolescents.
4.2 Posology And Method Of Administration
Schizophrenia
Adults
Risperidone may be given once daily or twice daily. Patients should start with 2 mg/day risperidone. The dosage may be increased on the second day to 4 mg.
Subsequently, the dosage can be maintained unchanged, or further individualised, if needed. Most patients will benefit from daily doses between 4 and 6 mg. In some patients, a slower titration phase and a lower starting and maintenance dose may be appropriate.
Doses above 10 mg/day have not demonstrated superior efficacy to lower doses and may cause increased incidence of extrapyramidal symptoms. Safety of doses above 16 mg/day has not been evaluated, and are therefore not recommended.
Elderly
A starting dose of 0.5 mg* twice daily is recommended. This dosage can be individually adjusted with 0.5 mg* twice daily increments to 1 to 2 mg twice daily.
* for doses not achievable with Risperidone other risperidone presentations are available
Paediatric population
Risperidone is not recommended for use in children below age 18 with schizophrenia due to a lack of data on efficacy.
Manic episodes in bipolar disorder
Adults
Risperidone should be administered on a once daily schedule, starting with 2 mg risperidone. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments of 1 mg per day. Risperidone can be administered in flexible doses over a range of 1 to 6 mg per day to optimize each patient's level of efficacy and tolerability. Daily doses over 6 mg risperidone have not been investigated in patients with manic episodes.
As with all symptomatic treatments, the continued use of Risperidone must be evaluated and justified on an ongoing basis.
Elderly
A starting dose of 0.5 mg* twice daily is recommended. This dosage can be individually adjusted with 0.5 mg* twice daily increments to 1 to 2 mg twice daily. Since clinical experience in elderly is limited, caution should be exercised.
* for doses not achievable with Risperidone other risperidone presentations are available
Paediatric population
Risperidone is not recommended for use in children below age 18 with bipolar mania due to a lack of data on efficacy.
Persistent aggression in patients with moderate to severe Alzheimer's dementia
A starting dose of 0.25 mg* twice daily is recommended. This dosage can be individually adjusted by increments of 0.25 mg* twice daily, not more frequently than every other day, if needed. The optimum dose is 0.5 mg* twice daily for most patients. Some patients, however, may benefit from doses up to 1 mg twice daily.
Risperidone should not be used more than 6 weeks in patients with persistent aggression in Alzheimer's dementia. During treatment, patients must be evaluated frequently and regularly, and the need for continuing treatment reassessed.
* for doses not achievable with Risperidone other risperidone presentations are available
Conduct disorder
Children and adolescents from 5 to 18 years of age
For subjects
* for doses not achievable with Risperidone other risperidone presentations are available
As with all symptomatic treatments, the continued use of Risperidone must be evaluated and justified on an ongoing basis.
Risperidone is not recommended in children less than 5 years of age, as there is no experience in children less than 5 years of age with this disorder.
Renal and hepatic impairment
Patients with renal impairment have less ability to eliminate the active antipsychotic fraction than in adults with normal renal function. Patients with impaired hepatic function have increases in plasma concentration of the free fraction of risperidone.
Irrespective of the indication, starting and consecutive dosing should be halved, and dose titration should be slower for patients with renal or hepatic impairment.
Risperidone should be used with caution in these groups of patients.
Method of administration
Risperidone is for oral use. Food does not affect the absorption of Risperidone.
Upon discontinuation, gradual withdrawal is advised. Acute withdrawal symptoms, including nausea, vomiting, sweating, and insomnia have very rarely been described after abrupt cessation of high doses of antipsychotic medicines (see section 4.8). Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported.
Switching from other antipsychotics.
When medically appropriate, gradual discontinuation of the previous treatment while Risperidone therapy is initiated is recommended. Also, if medically appropriate, when switching patients from depot antipsychotics, initiate Risperidone therapy in place of the next scheduled injection. The need for continuing existing anti-Parkinson medicines should be re-evaluated periodically.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients. (for excipients see section 6.1)
4.4 Special Warnings And Precautions For Use
Elderly patients with dementia
Overall mortality
Elderly patients with dementia treated with atypical antipsychotics have an increased mortality compared to placebo in a meta-analysis of 17 controlled trials of atypical antipsychotics, including Risperidone. In placebo-controlled trials with Risperidone in this population, the incidence of mortality was 4.0% for Risperidone -treated patients compared to 3.1% for placebo-treated patients. The odds ratio (95% exact confidence interval) was 1.21 (0.7, 2.1). The mean age (range) of patients who died was 86 years (range 67-100).
Concomitant use with furosemide
In the Risperidone placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone (7.3%; mean age 89 years, range 75-97) when compared to patients treated with risperidone alone (3.1%; mean age 84 years, range 70-96) or furosemide alone (4.1%; mean age 80 years, range 67-90). The increase in mortality in patients treated with furosemide plus risperidone was observed in two of the four clinical trials. Concomitant use of risperidone with other diuretics (mainly thiazide diuretics used in low dose) was not associated with similar findings.
No pathophysiological mechanism has been identified to explain this finding, and no consistent pattern for cause of death observed. Nevertheless, caution should be exercised and the risks and benefits of this combination or co-treatment with other potent diuretics should be considered prior to the decision to use.
There was no increased incidence of mortality among patients taking other diuretics as concomitant treatment with risperidone. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.
Cerebrovascular Adverse Events (CVAE)
In placebo-controlled trials in elderly patients with dementia there was a significantly higher incidence (approximately 3-fold increased) of CVAEs, such as stroke (including fatalities) and transient ischaemic attack in patients treated with Risperidone compared with patients treated with placebo (mean age 85 years; range 73 to 97). The pooled data from six placebo-controlled studies in mainly elderly patients (>65 years of age) with dementia showed that CVAEs (serious and non-serious, combined) occurred in 3.3% (33/1009) of patients treated with risperidone and 1.2% (8/712) of patients treated with placebo. The odds ratio (95% exact confidence interval) was 2.96 (1.34, 7.50). The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations.
Risperidone should be used with caution in patients with risk factors for stroke.
The risk of CVAEs was significantly higher in patients with mixed or vascular type of dementia when compared to Alzheimer's dementia. Therefore, patients with other types of dementias than Alzheimer's should not be treated with risperidone.
Physicians are advised to assess the risks and benefits of the use of Risperidone in elderly patients with dementia, taking into account risk predictors for stroke in the individual patient. Patients/caregivers should be cautioned to immediately report signs and symptoms of potential CVAEs such as sudden weakness or numbness in the face, arms or legs, and speech or vision problems. All treatment options should be considered without delay, including discontinuation of risperidone.
Risperidone should only be used short term for persistent aggression in patients with moderate to severe Alzheimer's dementia to supplement non-pharmacological approaches which have had limited or no efficacy and when there is potential risk of harm to self or others.
Patients should be reassessed regularly, and the need for continuing treatment reassessed.
Orthostatic hypotension
Due to the alpha-blocking activity of risperidone, (orthostatic) hypotension can occur, especially during the initial dose-titration period. Clinically significant hypotension has been observed postmarketing with concomitant use of risperidone and antihypertensive treatment. Risperidone should be used with caution in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolemia, or cerebrovascular disease), and the dosage should be gradually titrated as recommended (see section 4.2). A dose reduction should be considered if hypotension occurs.
Tardive dyskinesia/extrapyramidal symptoms (TD/EPS)
Medicines with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterised by rhythmical involuntary movements, predominantly of the tongue and/or face.
The onset of extrapyramidal symptoms is a risk factor for tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics should be considered.
Neuroleptic malignant syndrome (NMS)
Neuroleptic Malignant Syndrome, characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels has been reported to occur with antipsychotics. Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. In this event, all antipsychotics, including Risperidone, should be discontinued.
Parkinson's disease and dementia with Lewy bodies
Physicians should weigh the risks versus the benefits when prescribing antipsychotics, including Risperidone, to patients with Parkinson's Disease or Dementia with Lewy Bodies (DLB). Parkinson's Disease may worsen with risperidone. Both groups may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotic medicinal products; these patients were excluded from clinical trials. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.
Hyperglycemia
Hyperglycemia or exacerbation of pre-existing diabetes has been reported in very rare cases during treatment with Risperidone. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus.
Hyperprolactinaemia
Tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin.
Although no clear association with the administration of antipsychotics has so far been demonstrated in clinical and epidemiological studies, caution is recommended in patients with relevant medical history.
Risperidone should be used with caution in patients with pre-existing hyperprolactinaemia and in patients with possible prolactin-dependent tumours.
QT prolongation
QT prolongation has very rarely been reported postmarketing. As with other antipsychotics, caution should be exercised when risperidone is prescribed in patients with known cardiovascular disease, family history of QT prolongation, bradycardia, or electrolyte disturbances (hypokalaemia, hypomagnesaemia), as it may increase the risk of arrhythmogenic effects, and in concomitant use with medicines known to prolong the QT interval.
Seizures
Risperidone should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.
Priapism
Priapism may occur with Risperidone treatment due to its alpha-adrenergic blocking effects.
Body temperature regulation
Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic medicines. Appropriate care is advised when prescribing Risperidone to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant treatment with anticholinergic activity, or being subject to dehydration.
Venous thromboembolism
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Risperidone and preventive measures undertaken.
Children and adolescents
Before risperidone is prescribed to a child or adolescent with conduct disorder they should be fully assessed for physical and social causes of the aggressive behaviour such as pain or inappropriate environmental demands.
The sedative effect of risperidone should be closely monitored in this population because of possible consequences on learning ability. A change in the time of administration of risperidone could improve the impact of the sedation on attention faculties of children and adolescents.
Risperidone was associated with mean increases in body weight and body mass index (BMI). Changes in height in the long-term open-label extension studies were within expected age-appropriate norms. The effect of long-term risperidone treatment on sexual maturation and height have not been adequately studied. Because of the potential effects of prolonged hyperprolactinemia on growth and sexual maturation in children and adolescents, regular clinical evaluation of endocrinological status should be considered, including measurements of height, weight, sexual maturation, monitoring of menstrual functioning, and other potential prolactin-related effects.
During treatment with risperidone regular examination for extrapyramidal symptoms and other movement disorders should also be conducted.
For specific posology recommendations in children and adolescents see Section 4.2.
Excipients
The film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
As with other antipsychotics, caution is advised when prescribing risperidone with medicinal products known to prolong the QT interval, e.g., class Ia antiarrhythmics (e.g., quinidine, dysopiramide, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), tricyclic antidepressant (i.e., amitriptyline), tetracyclic antidepressants (i.e., maprotiline), some antihistaminics, other antipsychotics, some antimalarials (i.e., chinice and mefloquine), and with medicines causing electrolyte imbalance (hypokalaemia, hypomagnesiaemia), bradycardia, or those which inhibit the hepatic metabolism of risperidone. This list is indicative and not exhaustive.
Potential for Risperidone to affect other medicinal products
Risperidone should be used with caution in combination with other centrally-acting substances notably including alcohol, opiates, antihistamines and benzodiazepines due to the increased risk of sedation.
Risperidone may antagonise the effect of levodopa and other dopamine agonists. If this combination is deemed necessary, particularly in end-stage Parkinson's disease, the lowest effective dose of each treatment should be prescribed.
Clinically significant hypotension has been observed postmarketing with concomitant use of risperidone and antihypertensive treatment.
Risperidone does not show a clinically relevant effect on the pharmacokinetics of lithium, valproate, digoxin or topiramate.
Potential for other medicinal products to affect Risperidone
Carbamazepine has been shown to decrease the plasma concentrations of the active antipsychotic fraction of risperidone. Similar effects may be observed with e.g. rifampicin, phenytoin and phenobarbital which also induce CYP 3A4 hepatic enzyme as well as P-glycoprotein. When carbamazepine or other CYP 3A4 hepatic enzyme/P-glycoprotein (P-gp) inducers are initiated or discontinued, the physician should re-evaluate the dosing of Risperidone.
Fluoxetine and paroxetine, CYP 2D6 inhibitors, increase the plasma concentration of risperidone, but less so of the active antipsychotic fraction. It is expected that other CYP 2D6 inhibitors, such as quinidine, may affect the plasma concentrations of risperidone in a similar way. When concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of Risperidone.
Verapamil, an inhibitor of CYP 3A4 and P-gp, increases the plasma concentration of risperidone. Galantamine and donepezil do not show a clinically relevant effect on the pharmacokinetics of risperidone and on the active antipsychotic fraction.
Phenothiazines, tricyclic antidepressants, and some beta-blockers may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction. Cimetidine and ranitidine increase the bioavailability of risperidone, but only marginally that of the active antipsychotic fraction. Erythromycin, a CYP 3A4 inhibitor, does not change the pharmacokinetics of risperidone and the active antipsychotic fraction.
The combined use of psychostimulants (e.g., methylphenidate) with Risperidone in children and adolescents did not alter the pharmacokinetics and efficacy of Risperidone.
See section 4.4 regarding increased mortality in elderly patients with dementia concomitantly receiving furosemide.
Concomitant use of oral Risperidone with paliperidone is not recommended as paliperidone is the active metabolite of risperidone and the combination of the two may lead to additive active antipsychotic fraction exposure.
4.6 Pregnancy And Lactation
Pregnancy
There are no adequate data from the use of risperidone in pregnant women. According to postmarketing data reversible extrapyramidal symptoms in the neonate were observed following the use of risperidone during the last trimester of pregnancy. Consequently newborns should be monitored carefully. Risperidone was not teratogenic in animal studies but other types of reproductive toxicity were seen (see section 5.3). The potential risk for humans is unknown. Therefore, Risperidone should not be used during pregnancy unless clearly necessary. If discontinuation during pregnancy is necessary, it should not be done abruptly.
Lactation
In animal studies, risperidone and 9-hydroxy-risperidone are excreted in the milk. It has been demonstrated that risperidone and 9-hydroxy-risperidone are also excreted in human breast milk in small quantities. There are no data available on adverse reactions in breast-feeding infants. Therefore, the advantage of breastfeeding should be weighed against the potential risks for the child.
4.7 Effects On Ability To Drive And Use Machines
Risperidone can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects (see section 4.8). Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.
4.8 Undesirable Effects
The most frequently reported adverse drug reactions (ADRs) (incidence
The following are all the ADRs that were reported in clinical trials and postmarketing. The following terms and frequencies are applied: very common (
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse Drug Reactions by System Organ Class and Frequency
| |
|
|
|
|
|
|
| |
|
|
|
|
| |
|
|
|
|
|
|
| |
|
|
|
|
|
|
|
|
| |
|
|
|
|
|
|
| |
|
|
| |
|
|
|
|
|
|
| |
|
|
|
|
|
|
| |
|
|
|
|
| |
|
|
|
|
|
|
| |
|
|
|
|
|
|
| |
|
|
| |
|
|
|
|
|
|
|
|
| |
|
|
|
|
|
|
| |
|
|
|
|
| |
|
|
|
|
|
|
| |
|
|
|
|
|
|
| |
|
|
| |
|
|
|
|
| |
|
|
|
|
|
|
|
|
a) Hyperprolactinemia can in some cases lead to gynaecomastia, menstrual disturbances, amenorrhoea, galactorrhea.
b) Extrapyramidal disorder may occur: Parkinsonism (salivary hypersecretion, musculoskeletal stiffness, parkinsonism, drooling, cogwheel rigidity, bradykinesia, hypokinesia, masked facies, muscle tightness, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, and glabellar reflex abnormal),akathisia ( akathisia, restlessness, hyperkinesia, and restless leg syndrome), tremor, dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia.
Dystonia includes dystonia, muscle spasms, hypertonia, torticollis, muscle contractions involuntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus. Tremor includes tremor and parkinsonian rest tremor. It should be noted that a broader spectrum of symptoms are included, that do not necessarily have an extrapyramidal origin.
Class effects
As with other antipsychotics, very rare cases of QT prolongation have been reported postmarketing with risperidone. Other class-related cardiac effects reported with antipsychotics which prolong QT interval include ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest and Torsades de Pointes.
Weight gain
The proportions of Risperidone and placebo-treated adult patients with schizophrenia meeting a weight gain criterion of
In a population of children and adolescents with conduct and other disruptive behaviour disorders, in longterm studies, weight increased by a mean of 7.3 kg after 12 months of treatment. The expected weight gain for normal children between 5-12 years of age is 3 to 5 kg per year. From 12-16 years of age, this magnitude of gaining 3 to 5 kg per year is maintained for girls, while boys gain approximately 5 kg per year.
Additional information on special populations
Adverse drug reactions that were reported with higher incidence in elderly patients with dementia or paediatric patients than in adult populations are described below:
Elderly patients with dementia
Transient ischaemic attack and cerebrovascular accident were ADRs reported in clinical trials with a frequency of 1.4% and 1.5%, respectively, in elderly patients with dementia. In addition, the following ADRs were reported with a frequency
Paediatric patients
The following ADRs were reported with a frequency
4.9 Overdose
Symptoms
In general, reported signs and symptoms have been those resulting from an exaggeration of the known pharmacological effects of risperidone. These include drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. In overdose, QT-prolongation and convulsions have been reported. Torsade de Pointes has been reported in association with combined overdose of Risperidone and paroxetine.
In case of acute overdose, the possibility of multiple drug involvement should be considered.
Treatment
Establish and maintain a clear airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered only when drug intake was less than one hour before. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
There is no specific antidote to Risperidone. Therefore, appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, an anticholinergic medicinal product should be administered. Close medical supervision and monitoring should continue until the patient recovers.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Other antipsychotics, ATC-code: N05AX08
Mechanism of action
Risperidone is a selective monoaminergic antagonist with unique properties. It has a high affinity for serotoninergic 5-HT2 and dopaminergic D2 receptors. Risperidone binds also to alpha1-adrenergic receptors, and, with lower affinity, to H1-histaminergic and alpha2 adrenergic receptors. Risperidone has no affinity for cholinergic receptors. Although risperidone is a potent D2 antagonist, which is considered to improve the positive symptoms of schizophrenia, it causes less depression of mot
No comments:
Post a Comment