1. Name Of The Medicinal Product
Risperidone 1 mg/ml oral solution
2. Qualitative And Quantitative Composition
Each 1 ml of oral solution contains 1 mg risperidone.
For a full list of excipients, see section 6.1
3. Pharmaceutical Form
Oral solution
clear, colourless solution
4. Clinical Particulars
4.1 Therapeutic Indications
Risperidone 1 mg/ml oral solution is indicated for the treatment of:
- schizophrenia.
- risperidone is effective as maintenance therapy for the prevention of relapse in chronic schizophrenic patients who have shown an initial treatment response with risperidone.
- moderate to severe manic episodes in patients with bipolar affective disorder
Risperidone 1mg/ml oral solution is not licensed:
- as maintenance therapy for the prevention of manic or depressive episodes in bipolar affective disorder
- for the treatment of behavioural symptoms of dementia (see section 4.4).
4.2 Posology And Method Of Administration
Risperidone 1 mg/ml oral solution is for oral use .
Schizophrenia
Switching from other antipsychotics to Risperidone 1mg/ml oral solution
If possible, gradual discontinuation of the previous antipsychotic treatment while Risperidone 1 mg/ml oral solution therapy is initiated is recommended. When switching from long-acting antipsychotics to Risperidone 1 mg/ml oral solution, it is recommended to initiate Risperidone 1 mg/ml oral solution therapy instead of the next scheduled injection. The need for continuing existing antiparkinson medication should be re-evaluated periodically.
Adults and adolescents
Risperidone 1 mg/ml oral solution may be taken once or twice daily. The starting dose is 2 mg risperidone daily. The dosage may be increased on the second day to 4 mg. After that the dosage can be adjusted individually according to clinical response. The optimal therapeutic dosage is usually 4 to 6 mg per day. In some patients a slower titration phase and a lower starting and maintenance dose may be more appropriate.
Daily doses exceeding 10 mg have not been shown in clinical studies to increase the antipsychotic efficacy and they may cause extrapyramidal symptoms. The safety of daily doses exceeding 16 mg risperidone has not been established and, therefore, doses above this level should not be used. A benzodiazepine may be added to Risperidone 1 mg/ml oral solution when additional sedation is required.
The elderly.
A starting dose of 0.5 mg risperidone twice daily is recommended. This dosage can be increased according to clinical response with 0.5 mg twice daily increments to 1 to 2 mg twice daily).
Children and adolescents (< 15 years).
There is no clinical experience of the use of Risperidone 1 mg/ml oral solution for the treatment of schizophrenia in children and adolescents aged below 15 years. Therefore it can not be recommended to use Risperidone 1 mg/ml oral solution for this patient group.
Manic episodes
Adults
Risperidone 1 mg/ml oral solution should be administered once daily. The initial dose is 2 mg risperidone. If necessary the dose can be adjusted with 1 mg every 24 hours. The recommended dose range is 2-6 mg daily.
Children and adolescents (< 18 years)
There is no experience in the treatment of manic episodes in children and adolescents younger than 18 years.
Renal and liver diseases.
Half the starting and maintenance dose as well as slower dose titration is recommended for patients with impaired renal function. No dose adjustment is needed in patients with mild hepatic impairment. Caution is advised when treating patients with moderate to severe hepatic impairment due to limited experience in such patients (see section 5.2).
Elderly
Since clinical experience in elderly is limited, caution should be exercised.
As in all symptomatic treatments, long-term Risperidone 1 mg/ml oral solution treatment should be evaluated and justified regularly
4.3 Contraindications
- Hypersensitivity to risperidone or any of the excipients (for excipients see section 6.1)
- preexisting, not drug induced hyperprolactinemia
4.4 Special Warnings And Precautions For Use
During long term treatment with antipsychotic medicinal products (especially when high doses are used) tardive dyskinesia can occur. These symptoms can aggravate temporarily or even appear for the first time after discontinuation of treatment. The risk of irreversibility is increased in elderly patients and in patients with an organic brain damage. It is recommended to monitor patients for this periodically from 3-6 months after the start of the therapy and to inform patients about this risk before the treatment. The occurrence of extrapyramidal undesirable effects is less when using risperidone in the optimal antipsychotic dosage than when using haloperidole.
If symptoms of tardive dyskinesia appear a termination of risperidone therapy should be considered.
Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia have rarely been described after abrupt cessation of high doses of antipsychotic medicinal products.
Recurrence of psychotic symptoms may also occur, and the mergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Therefore, gradual withdrawal is advisable.
When risperidone is to be prescribed to patients suffering from dementia with Lewy bodies or Parkinson's disease, the benefit/risk ratio should be evaluated owing to an increased risk of the neuroleptic malignant syndrome or an impairment of parkinsonism.
Data concerning risperidone in combination with sodium valproate or lithium for moderate to severe manic episodes in patients with bipolar affective disorder are limited and not consistent. Furthermore no data from controlled clinical research are available on combination therapy longer than 3 weeks.
Risperidone can cause orthostatic hypotension by means of it's α-blocking properties, especially at the start of the treatment when the dose is increased. Risperidone should be used with caution in patients with cardiovascular diseases (e.g. heart failure, heart attack, cardial conduction impairment, dehydration, hypovolemia, or cerebrovascular diseases) and the dosage should be increased gradually (see section 4.2.)
The frequency of dizziness, bradycardia and injuries caused by a tendency to fall down seems to be higher in elderly than in younger patients.
A dosage reduction should be considered at hypotension.
It is recommended to half the initial dose and the subsequent dose increases in patients with hepatic or renal function disorders and in elderly (see section 4.2).
A pharmacokinetic interaction with carbamazepine may lead to lower plasma concentrations. Therefore, the dose of risperodone should be adapted (see section 4.5).
Like with other antipsychotic medicinal products one should be prepared for the occurrence of the so-called malign neuroleptic syndrome with the typical symptoms of hyperthermia, extreme muscle rigidity, and autonomous instability. Also an increase in the serum creatininefosfokinase level, leucocytosis, tachypnoe, changes in consciousness, and sweating can occur. Life-threatening is usually the occurrence of rabdomyolysis and the complementary renal insufficiency. All antipsychotic medicinal products must be withdrawn. Except for the common supportive measures (external cooling and rehydration) in first instance usually anticholinergic medicinal products and benzodiazepines are administered. In severe cases these medicinal products are not sufficiently effective and dantrolene and/or a dopamine agonist should be administered. If this therapy is not effective or in case of an utmost life threatening situation electroconvulsive therapy can be life saving.
In patients with psycho-organic disturbances there is an increased risk on undesirable effects.
As with other antipsychotic medicinal products, risperidone might decrease the excitability threshold of neuronal excitability. Risperidone should be administered therefore with caution in epileptic patients.
Since risperidone might induce weight gain, patients should be advised about their eating habits.
Until now there is limited experience with risperidone treatment in elderly.
There is no experience in the treatment of manic episodes in children and adolescents younger than 18 years of age.
Since experience in children younger than 15 years of age is lacking in the treatment of schizophrenia it can not be recommended to use the product for this patient group in this indication.
Paradoxically, antipsychotic medicinal products can increase symptoms like excitation, agitation and aggressiveness. When these symptoms occur, a dose reduction of risperidone or stopping of treatment can be necessary, just like with the other antipsychotic medicinal products.
An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomized placebo controlled clinical trials in the dementia population with some atypical antipsychotics. 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.
Elderly patients with dementia treated with atypical antipsychotic drugs had an increased mortality compared to placebo in a meta-analysis of 17 controlled trials of atypical antipsychotic drugs, 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 mean age (range) of patients who died was 86 years (67-100).
In these trials treatment with furosemide plus risperidone was associated with a higher incidence of mortality compared to treatment with risperidone or furosemide alone, however the mechanism for an interaction is unclear. Concomitant use of risperidone with other diuretics (mainly thiazide diuretics used in low dose) was not associated with similar findings.
No consistent pattern for cause of death observed. Nevertheless caution should be exercised and the risks and benefits of the combination of risperidone and furosemide or co-medication with other potent diuretics considered prior to the decision to use. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.
Hyperglycaemia or exacerbation of pre-existing diabetes has been reported in very rare cases during risperidone treatment. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus.
As with other antipsychotics, caution is advised when prescribing with medicinal products known to prolong QTc interval. Risperidone should be used with caution in patients with known cardiovascular disease (e.g. congenital long QTc syndrome, coronary heart disease, disturbances in conduction, arrhythmia) or concomitant treatment with drugs, which also induce QT interval prolongation or hypokalemia.
Concomitant administration of neuroleptics should be avoided during treatment with risperidone (see section 4.5).
Special caution should be exercised in patients with prolactin-dependent tumors (e.g. hypophysal prolactinoma) and possibly prolactin dependent tumors (e.g. breast cancer).
Risperidone should be administered with caution in patients who will be exposed to temperature extremes as both hypothermia and hyperthermia have been associated with risperidone therapy (see section 4.8).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Pharmacodynamic interactions
The interactions of risperidone with other medicinal products have not been evaluated systematically. As a centrally acting medicinal product, it should be used with caution in combination with other centrally acting agents (e.g. opiates, antihistaminic medicinal products and benzodiazepines). Risperidone 1 mg/ml oral solution may weaken the effect of levodopa and other dopamine agonists.
Concomitant treatment with other antipsychotic medicinal products, lithium, antidepressants, anti-parkinsonian medicinal products, and medicinal products with a central anticholinergic effect increases the risk on tardive dyskinesia.
As with other antipsychotics, caution is advised when prescribing with medicinal products known to prolong QT interval (neuroleptics, antiarrhythmics class IA or III, antibiotics (e.g.the macrolide antibiotic erythromycin), medicinal products against malaria, antihistamines, antidepressants) or to cause hypokalemia or hypomagnesemia (certain diuretics), or to increase the excretion of water, sodium and sometimes chlorides to a large extent (diuretics like furosemide and chlorothiazide), or to inhibit the hepatic metabolism of risperidone.
The anti-α1-adrenergic effect can increase the blood pressure lowering effect of phenoxybenzamine, labetalol and other α-blocking sympathicomimetic active substances, also of methyldopa, reserpine and other centrally acting antihypertensive active substances. On the contrary, the blood pressure lowering effect of guanethidine is blocked.
Interactions concerning furosemide in elderly patients with dementia see section 4.4.
Pharmacokinetic interactions
Effects of other drugs on the pharmacokinetics of risperidone
Enzyme inducers:
Carbamazepine treatment has been shown to decrease the plasma levels of risperidone and its active metabolite. Similar effects may be observed with other hepatic enzyme inducers such as rifampicin, phenytoin, phenobarbital, barbiturates and St. John's wort (Hypericum perforatum). On initiation and discontinuation of enzyme inducing medicinal products , the dose of Risperidon 1 mg/ml oral solution should be re-evaluated.
Drugs which inhibit the enzyme CYP2D6:
Quinidine, fluoxetine, paroxetine, terbinafine and other strong inhibitors of CYP2D6 might increase the plasma concentrations of the active moiety. Therefore, the dose of risperidone should be re-evaluated at introduction and cessation of concomitant treatment with such medicinal products.
Phenothiazines, tricyclic antidepressants and some beta-adrenergic blocking agents may increase plasma concentration of risperidone. Because of the decreased metabolism the fraction of the active metabolite is lowered in return. Therefore the total effect (antipsychotic fraction) is not changed to a clinically relevant extent
Ranitidine and cimetidine may increase the plasma concentration of risperidone, but the antipsychotic effect is not necessarily increased, because the fraction of the active metabolite is decreased.
Antacida reduce the oral absorption of antipsychotic medicinal products.
The cholinesterase-inhibitors galantamine and donepezil show no clinically relevant effect on the pharmacokinetic of risperidone and the aktive antipsychotic fraction.
Risperidone has no clinically relevant effect on the pharmacokinetics of lithium, valproate, digoxine or topiramate.
Concomitant use of risperidone and alcohol should be avoided, because risperidone increases the effect of alcohol.
4.6 Pregnancy And Lactation
Pregnancy
There are no adequate data from the use of risperidone during pregnancy. Risperidone was not teratogenic in animal studies, but other types of reproductive toxicity were seen (see section 5.3). The use of antipsychotic drugs during the last trimester of pregnancy has resulted in long term but reversible neurological disturbances of extrapyramidal nature and in withdrawal symptoms in the infant. Risperidone should only be used during pregnancy if the benefit for the mother outweighs the possible risk for the foetus/newborn child.
Lactation
Risperidone and its active metabolite 9-hydroxy-risperidone are excreted in the breast milk to such an extent that effects on the suckling child are likely if therapeutic doses are administered to breast-feeding women. Risperidone should not be used while breast feeding.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effect on the ability to drive and use machines have been performed.
Antipsychotic medicinal products like risperidone can influence the ability to react. Patients should be advised not to drive vehicles or operate machines until the individual reaction to risperidone has been evaluated.
4.8 Undesirable Effects
In many instances it has been difficult to distinguish adverse events reported from symptoms of the underlying disease. Adverse events reported in association with risperidone are as follows:
Common :
Uncommon :
Very rare: <1/10.000, including isolated reports
Not known: cannot be estimated from the available data
Blood and lymphatic system disorders
Very rare: slight decrease in amount of neutrophils and thrombocytes
Metabolism and nutrition disorders
Very rare: hyperglycaemia, exacerbation of pre-existing diabetes
Psychiatric disorders
Common: agitation, anxiety
Nervous system disorders
Common: sleeplessness, headache, sedation 1)
Uncommon: drowsiness, somnolence, fatigue, dizziness, concentration difficulties, extrapyramidal symptoms 2) :tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia
Eye disorders
Uncommon: blurred vision
Cardiac disorders
Uncommon: hypotension (also orthostatic hypotension), tachycardia (also reflex tachycardia), orthostatic dizziness or hypertension
Rare: ventricular arrhythmias (VF, VT)
Not known: cardiac arrest 3), QT prolongation 3), torsades de pointes 3)
Respiratory, thoracic and mediastinal disorders
Uncommon: rhinitis
Gastrointestinal disorders
Common: weight increase
Uncommon: constipation, dyspepsia, nausea/vomiting, stomach ache
Hepato-biliary disorders
Very rare: increased hepatic enzyme levels
Skin and subcutaneous tissue disorders
Uncommon: rash and other allergic reactions
Very rare: swelling, pruritus, exanthema, photosensitivity
Musculoskeletal and connective tissue disorders
Very rare: muscle weakness
Renal and urinary disorders
Uncommon: incontinence
Reproductive system and breast disorders
Uncommon: priapism, erectile dysfunction, dysfunctional ejaculation, orgasm disturbances, impotence in men who previously did not have any sexual disturbances
Rare: galactorrhoea, gynaecomastia, cyclus disturbances in women and amenorrhoea (see also "Endocrine disorders" in this section).
1) Sedation has been reported more frequently in children and adolescents than in adults. In general, sedation is mild and transient.
2) These symptoms are usually mild and are reversible upon dose reduction and/or administration of anti-Parkinson treatment, if necessary.
3) Class effect of neuroleptics.
Endocrine disorders
Risperidone may lead to dose-related elevation of prolactin levels. Possible associated manifestations are galactorrhoea, gynaecomastia, disturbances of the menstrual cycle and even absence of menstruation (amenorrhoea) (see also “Reproductive system and breast disorders” in this section). In addition tissue culture studies indicate that cell growth in human breast tumours may be stimulated by prolactin. Although no clear connection between administration of antipsychotics and breast cancer has so far been demonstrated in clinical or epidemiological studies, caution is advisable if there is a relevant previous history.
Disturbances of the water balance due to of overdrinking or disturbances in the secretion of antidiuretic hormone, tardive dyskinesia (see section 4.4), malign neuroleptic syndrome, disturbances in the body thermoregulation and seizures have been reported during risperidone treatment.
Cerebrovascular events
Under treatment with risperidone cerebrovascular events including cerebrovascular accidents and transient ischaemic attacks (TIA) have been reported, particularly in elderly patients with dementia (see section 4.4).
Dyskinesia
After long term use of antipsychotic medicinal products (months to years) dyskinesia may occur (especially tardive dyskinesia), during, as well as after treatment (see section 4.4).
Others
Very rare: hypothermia, hyperthermia, oedema
Not known: sudden unexplained death (class effect of neuroleptics)
4.9 Overdose
Symptoms
The symptoms of overdose have been in accordance with the known pharmacological effects of risperidone. The most common symptoms have been fatigue, tachycardia, hypotension and extrapyramidal symptoms. The highest reported overdose of risperidone is 360 mg. According to the currently available evidence, Risperidone 1 mg/ml oral solution seems to have a wide safety margin. Isolated cases of a prolonged QT interval have been reported in connection with overdose (see also section 4.4).
In case of acute overdose, the possibility of multiple drug involvement should be considered.
Treatment.
A clear airway should be maintained and sufficient oxygen intake ensured. Gastric lavage (after intubation if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered. Cardiovascular monitoring should be started immediately including continual electrocardiographic monitoring to detect possible arrhythmias.
There is no known antidote to risperidone. Therefore, treatment of overdose of Risperidone 1 mg/ml oral solution is supportive. Hypotension and possible circulatory shock should be treated with appropriate measures such as intravenous infusions and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, anticholinergic medicinal products should be administered. Close medical supervision should be continued until the patient recovers.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: other antipsychotics
ATC code: N05AX08
Risperidone is a selective monoaminergic antagonist with pharmacological properties that differ from those of conventional antipsychotics . Risperidone is bound strongly to serotoninergic 5-HT2 and dopaminergic D2 receptors. Risperidone also antagonises alpha1-adrenergic receptors and somewhat less efficiently H1-histaminergic and alpha2-adrenergic receptors. Risperidone does not bind to cholinergic receptors. Risperidone is effective on positive symptoms and seems to be associated with the possible effect on negative symptoms.
5.2 Pharmacokinetic Properties
Risperidone is completely absorbed after oral administration, peak plasma concentration being reached within 1 to 2 hours. The absorption is not significantly affected by food intake. Risperidone is metabolised to 9-hydroxy-risperidone via the cytochrome P-450 2D6 (CYP 2D6) enzyme. This metabolite has similar pharmacological activity to risperidone. Risperidone and 9-hydroxy-risperidone together produce the active antipsychotic effect. After oral administration to psychotic patients, the elimination half-life of risperidone is 3 hours. The t1/2 of 9-hydroxy-risperidone is 24 hours.
The steady state of risperidone is in most patients reached within 24 hours and that of 9-hydroxy-risperidone within 4 - 5 days. Risperidone plasma concentrations are directly dose-proportionally within the therapeutic dose range.
Risperidone is distributed rapidly, the volume of distribution being 1 to 2 l/kg. In plasma, risperidone is bound to albumin and to acidic alpha1-glycoprotein. The plasma protein binding of risperidone is 88% and that of 9-hydroxy-risperidone 77%.
Within one week of oral administration, 70 % of the risperidone dose is excreted in the urine and 14% in the faeces. In urine, risperidone plus 9-hydroxy-risperidone account for 35 - 45% of the dose.
Special populations
Administration of risperidone to elderly patients and patients with impaired renal function resulted in increased plasma concentrations of active fraction and reduced clearance of the active fraction to an extent proportional to the creatinine clearance. No effect on the plasma concentrations was observed in patients with mild hepatic impairment. Data in patients with moderate hepatic impairment are insufficient.
Pharmacokinetics of risperidone, 9-hydroxy-risperidone and the active portion in children is similar to that in the adults.
CYP2D6 poor and ultrafast metabolisers:
A fraction of the population (so called CYP2D6 poor metabolisers) lack the enzyme CYP2D6 due to a genetic deficiency. Another fraction has multiple CYP2D6 genes (ultrafast metabolisers). Poor metabolisers have a lower metabolite to parent drug ratio but the differences lack clinical importance due to the equipotency of the substances.
5.3 Preclinical Safety Data
Conventional animal studies on pharmacodynamics, repeated dose toxicity, genotoxicity and carcinogenicity reveal no other risks for the patient than those which could be expected based on the pharmacological mechanism of action. In vitro and in vivo animal models show that at high doses risperidone may cause QT interval prolongation, which has been associated with a theoretically increased risk of torsades de pointes in patients. In animal reproduction studies pharmacologically active doses revealed maternal toxicity, prolongation of the partus and increased postnatal deaths related to the pharmacodynamic action. The effects on postnatal development were shown to be predominantly due to the pharmacodynamic action on the dams (e.g. sedation and reduced care for the pups). These effects are not relevant for the assessment of a potential risk in humans.
As a consequence of its antidopaminergic action risperidone causes hyperprolactinaemia and prolactin-induced functional changes in laboratory animals.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Benzoic acid (E 210)
water, purified
6.2 Incompatibilities
Risperidone 1 mg/ml oral solution must not be blended in tea.
6.3 Shelf Life
3 years
6 months after first opening of the bottle
6.4 Special Precautions For Storage
Do not freeze.
6.5 Nature And Contents Of Container
Amber glass bottle with a plastic child resistant closure (white, HDPE/PP screw cap), containing 30 ml, 60 ml, 100 ml or 120 ml oral solution .
A dosing pipette including pipette holder is enclosed.
The small pipette (98 mm long) and the large pipette (134 mm long) are both marked with a scale showing ml on one side and mg on the other. The graduation is in steps of 0.1 ml or mg respectively.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Sandoz Ltd
Frimley Business Park,
Frimley,
Camberley,
Surrey,
GU16 7SR.
United Kingdom
8. Marketing Authorisation Number(S)
PL 04416/0686
9. Date Of First Authorisation/Renewal Of The Authorisation
15/11/2006
10. Date Of Revision Of The Text
11/2010
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