Risperdal Tablets and Liquid and Risperdal Quicklet are indicated
for the treatment of acute and chronic schizophrenic psychoses, and
other psychotic conditions, in which positive symptoms (such as
hallucinations, delusions, thought disturbances, hostility,
suspiciousness), and/or negative symptoms (such as blunted affect,
emotional and social withdrawal, poverty of speech) are prominent.
Risperdal and Risperdal Quicklet also alleviate affective symptoms
(such as depression, guilt feelings, anxiety) associated with
schizophrenia.
Risperdal and Risperdal Quicklet are also effective in maintaining
the clinical improvement during continuation therapy in patients who
have shown an initial treatment response.
Risperdal and Risperdal Quicklet are indicated for the treatment of
mania in bipolar disorder. These episodes are characterized by symptoms
such as elevated, expansive or irritable mood, inflated self-esteem,
decreased need for sleep, pressured speech, racing thoughts,
distractibility, or poor judgment, including disruptive or aggressive
behaviours.
Risperdal and Risperdal Quicklet are not licensed for the treatment of behavioural symptoms of dementia (see section 4.4).
4.2 Posology and method of administration
Risperdal Liquid:
1 ml of Risperdal liquid contains 1 mg risperidone. If necessary
Risperdal liquid may be diluted with mineral water, orange juice or
black coffee. When diluted in this way, the product should be used
immediately. The liquid should not be mixed with tea.
(See Section 6. Pharmaceutical Particulars).
4.2. a Schizophrenia:
Switching from other antipsychotics: where medically appropriate,
gradual discontinuation of the previous treatment while Risperdal or
Risperdal Quicklet therapy is initiated is recommended. Where medically
appropriate when switching patients from depot antipsychotics, consider
initiating Risperdal or Risperdal Quicklet therapy in place of the next
scheduled injection. The need for continuing existing antiparkinson
medication should be re-evaluated periodically.
Adults
Risperdal or Risperdal Quicklet may be given once or twice daily.
All patients, whether acute or chronic, should start with 2 mg/day
Risperdal or Risperdal Quicklet. The dosage may be increased to 4
mg/day on the second day. Some patients, such as first episode
patients, may benefit from a slower rate of titration. From then on the
dosage can be maintained unchanged, or further individualised, if
needed. Most patients will benefit from daily doses between 4 and 6
mg/day although in some, an optimal response may be obtained at lower
doses.
Doses above 10 mg/day generally have not been shown to provide
additional efficacy to lower doses and may increase the risk of
extrapyramidal symptoms. Doses above 10 mg/day should only be used in
individual patients if the benefit is considered to outweigh the risk.
Doses above 16 mg/day have not been extensively evaluated for safety
and therefore should not be used.
Elderly
A starting dose of 0.5 mg bd is recommended. This dosage can be individually adjusted with 0.5 mg bd increments to 1 to 2 mg bd.
Children
Use of Risperdal for schizophrenia in children aged less than 15 years has not been formally evaluated.
Renal and liver disease
A starting dose of 0.5 mg bd is recommended. This dosage can be individually adjusted with 0.5 mg bd increments to 1 to 2 mg bd.
Risperdal and Risperdal Quicklet should be used with caution in this group of patients until further experience is gained.
4.2. b Bipolar Mania:
Adults
Risperidone should be administered on a once daily schedule,
starting with 2 mg. Dosage adjustments, if indicated, should occur at
intervals of not less than 24 hours and in dosage increments of 1 mg
per day. A dosing range between 1 and 6 mg per day is recommended.
As with all symptomatic treatments, the continued use of Risperdal must be evaluated and justified on an ongoing basis.
Elderly
A starting dose of 0.5 mg bd is recommended. This dosage can be individually adjusted with 0.5 mg bd increments to 1 to 2 mg bd.
Renal and liver disease
A starting dose of 0.5 mg bd is recommended. This dosage can be individually adjusted with 0.5 mg bd increments to 1 to 2 mg bd.
Risperdal should be used with caution in this group of patients until further experience is gained.
Combined use with mood stabilisers
There is limited information on the combined use of Risperdal with
carbamazepine in bipolar mania. Carbamazepine has been shown to induce
the metabolism of risperidone producing lower plasma levels of the
antipsychotic fraction of Risperdal (see Section 4.5). It is therefore
not recommended to co-administer Risperdal with carbamazepine in
bipolar mania patients until further experience is gained. The combined
use with lithium or valproate does not require any adjustment of the
dose of Risperdal.
Method of administration
Oral use.
Risperdal Quicklet:
The Risperdal Quicklet tablet should be placed on the tongue. It
begins disintegrating in the mouth within seconds and can be swallowed
subsequently with or without water. The mouth should be empty before
placing the tablet on the tongue.
As the tablets are fragile, they should not be pushed through the
foil as this will cause damage. Open blister by pulling up the edge of
the foil and peeling it off, then tip the tablet out. After removal
from its blister, the Risperdal Quicklet tablet should be consumed
immediately as it cannot be stored once removed. Risperdal Quicklet
tablets begin disintegrating within seconds when placed on the tongue
and the use of water is unnecessary. No attempt should be made to split
the tablet.
4.3 Contraindications
Risperdal and Risperdal Quicklet are contraindicated in patients
with a known hypersensitivity to risperidone or any other ingredients
in the product.
Risperdal Quicklet contains aspartame and therefore should not be taken by patients with phenylketonuria.
4.4 Special warnings and precautions for use
Elderly patients with dementia
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
Risperdal. In placebo-controlled trials with Risperdal in this
population, the incidence of mortality was 4.0% for Risperdal –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.
Cerebrovascular Adverse Events (CVAE)
Risperdal and Risperdal Quicklet are not recommended for the
treatment of behavioural symptoms of dementia because of an increased
risk of cerebrovascular adverse events (including cerebrovascular
accidents and transient ischaemic attacks). Treatment of acute
psychoses in patients with a history of dementia should be limited to
short term only and should be under specialist advice.
Data from randomised clinical trials conducted in elderly (>65
years) patients with dementia indicate that there is an approximately
3-fold increased risk of cerebrovascular adverse events (including
cerebrovascular accidents and transient ischaemic attacks) with
risperidone, compared with placebo. Cerebrovascular adverse events
occurred in 3.3% (33/989) of patients treated with risperidone and 1.2%
(8/693) of patients treated with placebo. The Odds Ratio (95% exact
confidence interval) was 2.96 (1.33, 7.45).
Physicians should consider carefully the risk of cerebrovascular
adverse events with Risperdal (given the observations in elderly
patients with dementia detailed above) before treating any patient with
a previous history of CVA/TIA. Consideration should also be given to
other risk factors for cerebrovascular disease including hypertension,
diabetes, current smoking, atrial fibrillation, etc.
Alpha-blocking activity
Due to the alpha-blocking activity of Risperdal and Risperdal
Quicklet, orthostatic hypotension can occur, especially during the
initial dose-titration period. A dose reduction should be considered if
hypotension occurs.
Risperdal and Risperdal Quicklet should be used with caution in
patients with known cardiovascular disease including those associated
with prolongation of the QT interval and the dose should be gradually
titrated. In clinical trials, Risperdal was not associated with an
increase in QTc intervals. As with other antipsychotics, caution is
advised when prescribing with medications known to prolong the QT
interval.
If further sedation is required, an additional drug (such as a
benzodiazepine) should be administered rather than increasing the dose
of Risperdal or Risperdal Quicklet.
Drugs 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. It has been reported that the occurrence of extrapyramidal
symptoms is a risk factor for the development of tardive dyskinesia. If
signs and symptoms of tardive dyskinesia appear, the discontinuation of
all antipsychotic drugs should be considered.
Neuroleptic Malignant Syndrome (NMS)
Neuroleptic malignant syndrome, characterised by hyperthermia,
muscle rigidity, autonomic instability, altered consciousness and
elevated CPK levels, has been reported to occur with neuroleptics. In
this event all antipsychotic drugs including risperidone should be
discontinued.
It is recommended to halve both the starting dose and the
subsequent dose increments in geriatric patients and in patients with
renal or liver insufficiency.
Caution should also be exercised when prescribing Risperdal or
Risperdal Quicklet to patients with Parkinson's disease since,
theoretically, it may cause a deterioration of the disease.
Hyperglycemia
Hyperglycaemia or exacerbation of pre-existing diabetes has been
reported in very rare cases during treatment with Risperdal.
Appropriate clinical monitoring is advisable in diabetic patients and
in patients with risk factors for the development of diabetes mellitus
(see also section 4.8 Undesirable effects).
Other
Classical neuroleptics are known to lower the seizure threshold. Caution is recommended when treating patients with epilepsy.
As with other antipsychotics, patients should be advised of the potential for weight gain.
Acute withdrawal symptoms, including nausea, vomiting, sweating,
and insomnia have very rarely been described after abrupt cessation of
high doses of antipsychotic drugs. Recurrence of psychotic symptoms may
also occur, and the emergence of involuntary movement disorders (such
as akathisia, dystonia and dyskinesia) has been reported. Therefore,
gradual withdrawal is advisable.
Use of Risperdal for schizophrenia in children aged less than 15 years has not been formally evaluated.
4.5 Interaction with other medicinal products and other forms of interaction
Possible interactions of Risperdal and Risperdal Quicklet with
other drugs have not been systematically evaluated. Given the primary
CNS effects of risperidone, it should be used with caution in
combination with other centrally acting drugs including alcohol.
Risperdal and Risperdal Quicklet may antagonise the effect of levodopa and other dopamine-agonists.
Carbamazepine has been shown to decrease the plasma levels of the
antipsychotic fraction of Risperdal and Risperdal Quicklet. A similar
effect might be anticipated with other drugs which stimulate
metabolising enzymes in the liver. On initiation of carbamazepine or
other hepatic enzyme-inducing drugs, the dosage of Risperdal or
Risperdal Quicklet should be re-evaluated and increased if necessary.
Conversely, on discontinuation of such drugs, the dosage of Risperdal
or Risperdal Quicklet should be re-evaluated and decreased if necessary.
Phenothiazines, tricyclic antidepressants and some beta-blockers
may increase the plasma concentrations of risperidone but not those of
the active antipsychotic fraction. Fluoxetine and paroxetine, CYP2D6
inhibitors, may increase the plasma concentration of risperidone but
less so of the active antipsychotic fraction. When concomitant
fluoxetine or paroxetine is initiated or discontinued, the physician
should re-evaluate the dosing of Risperdal. Based on in vitro
studies, the same interaction may occur with haloperidol. 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 cholinesterase inhibitor galantamine does not show a
clinically relevant effect on the pharmacokinetics of risperidone and
the active antipsychotic fraction. A study of donepezil in non-elderly
healthy volunteers also showed no clinically relevant effect on the
pharmacokinetics of risperidone and the antipsychotic fraction.
When Risperdal or Risperdal Quicklet is taken together with other
highly protein-bound drugs, there is no clinically relevant
displacement of either drug from the plasma proteins.
See section 4.4 (Special warnings and special precautions for use)
regarding increased mortality in elderly patients with dementia
concomitantly receiving furosemide.
Risperdal does not show a clinically relevant effect on the
pharmacokinetics of valproate or topiramate. The potential for reduced
toleration of the combination treatment should be taken into
consideration when coadministering risperidone and topiramate.
In patients on long-term lithium and older/typical neuroleptic
therapy, no significant change occurred in the pharmacokinetics of
lithium after substitution of the concomitant neuroleptic with
risperidone.
Food does not affect the absorption of risperidone from the
stomach. The effect of food particles in the mouth on absorption from
Risperdal Quicklet has not been studied.
4.6 Pregnancy and lactation
Although, in experimental animals, risperidone did not show direct
reproductive toxicity, some indirect, prolactin- and CNS-mediated
effects were observed, typically delayed oestrus and changes in mating
and nursing behaviour in rats. No teratogenic effect of risperidone was
noted in any study. The safety of Risperdal and Risperdal Quicklet for
use during human pregnancy has not been established. Reversible
extrapyramidal symptoms in the neonate were observed following
postmarketing use of risperidone during the last trimester of
pregnancy. Therefore, Risperdal or Risperdal Quicklet should only be
used during pregnancy if the benefits outweigh the risks.
In animal studies, risperidone and 9-hydroxyrisperidone are
excreted in the milk. It has been demonstrated that risperidone and
9-hydroxyrisperidone are also excreted in human breast milk. Therefore,
women receiving Risperdal or Risperdal Quicklet should not breast feed.
4.7 Effects on ability to drive and use machines
Risperdal and Risperdal
Quicklet may interfere with activities requiring mental alertness.
Therefore, patients should be advised not to drive or operate machinery
until their individual susceptibility is known.
4.8 Undesirable effects
Risperdal and Risperdal Quicklet are generally well tolerated and
in many instances it has been difficult to differentiate adverse events
from symptoms of the underlying disease. Adverse events observed in
association with the use of Risperdal and Risperdal Quicklet include:
Common: insomnia, agitation, anxiety, headache.
Less common: somnolence, fatigue, dizziness, impaired
concentration, constipation, dyspepsia, nausea/vomiting, abdominal
pain, blurred vision, priapism, erectile dysfunction, ejaculatory
dysfunction, orgasmic dysfunction, urinary incontinence, rhinitis, rash
and other allergic reactions.
Cerebrovascular accidents have been observed during treatment with
risperidone (see Section 4.4 Special warnings and precautions for use).
Hyperglycemia and exacerbation of pre-existing diabetes have been reported in very rare cases during risperidone treatment.
The incidence and severity of extrapyramidal symptoms are
significantly less than with haloperidol. However, in some cases the
following extrapyramidal symptoms may occur: tremor, rigidity,
hypersalivation, bradykinesia, akathisia, acute dystonia including
oculogyric crisis. If acute in nature, these symptoms are usually mild
and are reversible upon dose reduction and/or administration of
antiparkinson medication, if necessary. In clinical trials in patients
with acute mania risperidone treatment resulted in an incidence of EPS
>10%. This is lower than the incidence observed in patients treated
with classical neuroleptics.
Occasionally, orthostatic dizziness, hypotension including
orthostatic, tachycardia including reflex tachycardia and hypertension
have been observed following administration of Risperdal and Risperdal
Quicklet.
Risperdal and Risperdal Quicklet can induce a dose-dependent
increase in plasma prolactin concentration. Possible associated
manifestations are: galactorrhoea, gynaecomastia, disturbances of the
menstrual cycle and amenorrhoea.
Weight gain, oedema and increased hepatic enzyme levels have been
observed during treatment with Risperdal and Risperdal Quicklet.
A decrease in neutrophil and/or thrombocyte count has been reported.
As with classical neuroleptics, rare cases of the following have
been reported in schizophrenic patients: water intoxication with
hyponatraemia, either due to polydipsia or to the syndrome of
inappropriate secretion of antidiuretic hormone; tardive dyskinesia,
body temperature dysregulation and seizures.
Benign pituitary adenomas have been reported very rarely in
risperidone users during postmarketing surveillance. No causal
association has been established.
Very rare cases of angioedema have been reported in postmarketing experience.
Sedation has been reported more frequently in children and
adolescents than in adults. In general, sedation is mild and transient.
Withdrawal reactions have been reported in association with
antipsychotic drugs (see 4.4 Special warnings and special precautions
for use).
4.9 Overdose
In general, reported signs and symptoms have been those resulting
from an exaggeration of the drug's known pharmacological effects. These
include drowsiness and sedation, tachycardia and hypotension, and
extrapyramidal symptoms. In overdose, rare cases of QT-prolongation
have been reported. In case of acute overdosage, the possibility of
multiple drug involvement should be considered.
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. Cardiovascular
monitoring should commence immediately and should include continuous
electrocardiographic monitoring to detect possible arrhythmias.
There is no specific antidote to Risperdal or Risperdal Quicklet.
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, anticholinergic medication
should be administered. Close medical supervision and monitoring should
continue until the patient recovers.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Risperidone is a novel antipsychotic belonging to a new class of antipsychotic agents, the benzisoxazole-derivatives.
Risperidone is a selective monoaminergic antagonist with a high affinity for both serotonergic 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, that is considered to improve the positive symptoms of
schizophrenia, it causes less depression of motor activity and
induction of catalepsy than classical neuroleptics. Balanced central
serotonin and dopamine antagonism may reduce the tendency to cause
extrapyramidal side effects, and extend the therapeutic activity to the
negative and affective symptoms of schizophrenia.
5.2 Pharmacokinetic properties
Risperidone is completely absorbed after oral administration,
reaching peak plasma concentrations within 1 to 2 hours. Food does not
affect the absorption of risperidone from the stomach. The effect of
food particles in the mouth on absorption has not been studied.
The most important route of metabolism of risperidone is
hydroxylation by cytochrome CYP 2D6 to 9-hydroxy-risperidone which has
a similar pharmacological activity to risperidone. This hydroxylation
is subject to debrisoquine-type genetic polymorphism but this does not
affect the active antipsychotic fraction since this consists of
risperidone and its active metabolite 9-hydroxyrisperidone. After oral
administration, the elimination half-life of the active antipsychotic
fraction is 24 hours.
A single-dose study showed higher active plasma concentrations and
a slower elimination of risperidone in the elderly and in patients with
renal insufficiency. Risperidone plasma concentrations were normal in
patients with liver insufficiency.
Topiramate modestly reduces the bioavailability of risperidone, but
not that of the active antipsychotic fraction. Therefore, this
interaction is unlikely to be of clinical significance. The
bioavailability of topiramate is slightly decreased when administered
in combination with risperidone. This interaction is not likely to be
clinically significant.
Risperdal oro-dispersible tablets and oral solution are bio-equivalent to Risperdal oral tablets.
5.3 Preclinical safety data
There are no preclinical data of relevance to the prescriber other than those already provided in other sections of the SPC.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Risperdal Tablets: All tablet strengths contain the following excipients.
Lactose
Maize starch
Microcrystalline cellulose
Hypromellose 2910 5 mPa.s
Magnesium stearate
Colloidal anhydrous silica
Sodium lauryl sulphate
Propylene glycol
Purified water*
* not present in the final product.
In addition, the tablets also contain the following excipients:
0.5 mg
Hypromellose 2910 15 mPa.s
Titanium dioxide (E171)
Talc
Red ferric oxide (E172)
1 mg
Hypromellose 2910 15 mPa.s
2 mg
Hypromellose 2910 15 mPa.s
Titanium dioxide (E171)
Talc
Orange yellow S (E110) aluminium lake
3 mg
Hypromellose 2910 15 mPa.s
Titanium dioxide (E171)
Talc
Quinoline yellow (E104)
4 mg
Hypromellose 2910 15 mPa.s
Titanium dioxide (E171)
Talc
Quinoline yellow (E104)
Indigotine disulphonate (E132) aluminium lake
6 mg
Titanium dioxide (E171)
Talc
Quinoline yellow (E104)
Orange yellow S (E110)
Risperdal Liquid
Tartaric acid
Benzoic acid
Sodium hydroxide
Purified water
Risperdal Quicklet:
Polacrilex resin (methacrylic acid polymer with divinylbenzene)
Gelatin type A
Mannitol
Glycine
Simethicone
Carbomer
Sodium hydroxide
Aspartame
Red ferric oxide (E172)
Peppermint oil
Xantham gum (3 and 4mg only)
6.2 Incompatibilities
Risperdal tablets and Risperdal Quicklet: No incompatibilities known.
Risperdal Liquid: Risperdal Liquid should only be diluted with
those beverages listed in Posology and method of administration (see
section 4.2).
6.3 Shelf life
Risperdal 1, 2 , 3 and 4 mg Tablets: 36 months.
0.5, 6 mg Tablets: 24 months.
Liquid: The unopened bottles have a shelf life of 36 months. Once
opened, the contents of the bottle should be used within 3 months.
Risperdal Quicklet 0.5, 1 and 2 mg: 36 months
Risperdal Quicklet 3 and 4 mg: 24 months
6.4 Special precautions for storage
Risperdal Tablets: Do not store above 30°C.
Risperdal Liquid: Do not store above 30°C. Do not refrigerate.
Risperdal Quicklet: Do not store above 30°C. Store in the original container.
6.5 Nature and contents of container
Risperdal Tablets: Blister strips consisting of 200 μm polyvinylchloride (PVC)/25 μm low density polyethylene (LDPE)/90 g/m2 polyvinylidene chloride (PVDC) and 20 μm
aluminium foil. The strips are packed in cardboard cartons to contain
either 20 (0.5, 1 mg tablets only), 60 tablets (1, 2, 3 and 4 mg
tablets) or 28 tablets (6 mg tablets) per pack.
Risperdal Liquid: Amber glass bottle with a plastic child-resistant and tamper-evident cap. Each bottle contains 100 ml.
Risperdal Quicklet: Blister strips consisting of
polychlorotrifluoroethylene/polyvinylchloride/polyethylene film and
aluminium foil (film/foil) or aluminium foil and aluminium foil
(foil/foil). The strips are packed in cardboard cartons to contain 28
tablets per pack.
6.6 Special precautions for disposal and other handling
Risperdal Tablets: Not applicable.
Risperdal Liquid: A special dosing pipette is supplied with each pack of Risperdal
Instructions for using the pipette with Risperdal liquid
1. Remove the child-resistant cap from the bottle by pushing down on the cap while turning it anti-clockwise (Fig. 1).
2. Place the bottle on a flat surface.
3. Insert the pipette into the liquid in the bottle.
4. While holding the lower ring, pull the top ring upwards until
the mark that matches the number of mg or ml to be taken is just
visible (Fig. 2).
5. Holding the lower ring, remove the whole pipette from the bottle (Fig. 3).
6. To empty the pipette, push down on the top ring while still holding the lower ring.
7. The contents of the pipette may be emptied directly into the
mouth or into a drink of mineral water, orange juice or black coffee.
8. Rinse the pipette with some water.
9. Replace the child-resistant cap on the bottle by screwing it down clockwise until it locks fully.
Risperdal Quicklet: Please refer to Section 4.2. Posology and Method of Administration.
