INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
RISPERDAL® 1 mg/mL oral solution

© J-C 2003                ZA-246330 V

SCHEDULING STATUS:
Schedule 5

PROPRIETARY NAME
(and dosage form):

RISPERDAL^® 1 mg/mL oral solution

COMPOSITION
Each mL contains risperidone 1 mg. Preservative: Benzoic acid 0,2% m/v.

PHARMACOLOGICAL CLASSIFICATION
A.2.6.5 Central nervous system depressants. Miscellaneous structures.

PHARMACOLOGICAL ACTION
RISPERDAL (risperidone) is an antipsychotic of the benzisoxazol derivatives. It is a selective monoaminergic antagonist. RISPERDAL has affinity for serotonin-5-HT2, dopamine-D2, H1-histamine alpha1–and alpha2–adrenergic receptors. Risperidone has no affinity for cholinergic receptors. It is a potent D2–antagonist.
Pharmacokinetic properties
Risperidone is completely absorbed after oral administration. Peak plasma concentrations are attained within 1 to 2 hours. Food does not affect the absorption of risperidone.
RISPERDAL is metabolized by cytochrome P-450-IID6 to 9-hydroxy-risperidone which has a similar pharmacological activity to risperidone. Risperidone and 9-hydroxy-risperidone form the active antipsychotic fraction.
After oral administration to psychotic patients, risperidone's half-life is about 3 hours. The elimination half-life of 9-hydroxy-risperidone and the active antipsychotic fraction is 24 hours.
Steady state is reached within 1 day for risperidone in most patients and 4-5 days for 9-hydroxy-risperidone.
RISPERDAL plasma concentration is dose-proportional within the therapeutic dose-range. RISPERDAL is bound to albumin and alpha1-acid glycoprotein. Plasma protein binding of risperidone is 88% and 77% for 9-hydroxy-risperidone. One week after administration, 70% of the dose is excreted in the urine and 14% in the faeces. In urine, risperidone and 9-hydroxy-risperidone represent 35 - 45% of the dose.
RISPERDAL showed higher active plasma concentrations and slower elimination in the elderly and in patients with renal insufficiency. The plasma concentrations of RISPERDAL were normal in patients with liver insufficiency.

INDICATIONS
RISPERDAL is indicated for the treatment of:

•	acute and chronic schizophrenic psychoses and related psychosis in which positive symptoms (such as hallucinations, delusions, thought disturbances, hostility, suspiciousness) and/or the negative symptoms (such as blunted affect, emotional and social withdrawal, poverty of speech) are prominent. RISPERDAL also alleviates affective symptoms (such as depression, guilt feelings, anxiety) associated with schizophrenia. In patients who have shown an initial treatment response, Risperdal is also effective in maintaining the clinical improvement.
•	behavioural disturbances in patients with dementia in whom symptoms such as aggressiveness (verbal outbursts, physical violence), activity disturbances (agitation, wandering) or psychotic symptoms are prominent.
•	conduct and other disruptive behaviour disorders in children (aged 5 -12 years), with subaverage intellectual functioning or mental retardation in whom destructive behaviours (e.g. aggression, impulsivity and self-injurious behaviours) are prominent.

CONTRA-INDICATIONS
RISPERDAL is contra-indicated in patients with known sensitivity to the medicine.
Safety of RISPERDAL in pregnancy or lactating women has not been established. Risperidone and 9-hydroxy-risperidone are excreted in human breast milk. Therefore, women receiving RISPERDAL should not breast feed.
Conduct and other disruptive behaviour disorders children: Not for children under 5 years as efficacy and safety in children under the age of 5 years have not been demonstrated.

DOSAGE AND DIRECTIONS FOR USE
Schizophrenia
Switching from other antipsychotics to RISPERDAL:
When medically appropriate, gradual discontinuation of the previous treatment, while RISPERDAL therapy is initiated, is recommended. Also if medically appropriate, when switching patients from depot antipsychotics, initiate RISPERDAL therapy in place of the next scheduled injection. The need for continuing existing anti-Parkinson medications should be re-evaluated periodically.
Adults:
RISPERDAL may be given once or twice daily.
Patients should start with 2 mg/day RISPERDAL. The dosage may be increased on the second day to 4 mg/day. From then on, the dosage can be maintained unchanged, or further individualised. if needed. Most patients will benefit from daily doses of between 4 mg/day and 8 mg/day.
Doses above 6 mg/day (when administered twice daily) were associated with more extrapyramidal symptoms and other adverse effects and are not generally recommended. In some patients, particularly with first episode acute psychosis, a slower titration phase and a lower starling and maintenance dose may be appropriate.
Doses above 10 mg/day have not been shown to be superior in efficacy to lower doses and may cause an increased incidence of side-effects such as extrapyramidal symptoms. Dosages above 10 mg/day should only be considered if the benefits outweigh the risk. The maximum total daily dose is 16 mg/day.
A benzodiazepine may be added to RISPERDAL if additional sedation is required.
Renal and liver diseased patients:
Caution should be exercised with these groups of patients, as clinical experience is lacking in these patient populations. It is recommended to halve both the starting dose and the subsequent dose increments.
Elderly patients
A starting dose of 0,5 mg b.i.d. is recommended. This dosage can be individually adjusted with 0,5 mg b.i.d. increments to 1- 2 mg b.i.d.
Children:
Not for children under 15 years as efficacy and safety in children under the age of 15 years have not been demonstrated in schizophrenia.
Behavioural Disturbances in patients with Dementia:
A starting dose of 0,25 mg b.i.d. is recommended. This dosage can be individually adjusted by increments of 0,25 mg b.i.d., not more frequently than every other day, if needed. The optimum dose is 0,5 mg b.i.d. for most patients. Some patients, however, may benefit from doses up to 1 mg b.i.d.
Once patients have reached their target dose, a once daily dosing regimen can be considered.
Conduct and other disruptive behaviour disorders in children 5 -12 years of age:
Subjects < 50 kg:
A starting dose of 0.01 mg/kg once daily is recommended. This dosage can be individually adjusted by increments of 0.01 mg/kg once daily not more frequently than every other day, if needed. The recommended maintenance dose is 0.02 - 0.04 mg/kg once daily. The mean dose is 0.03 mg/kg once daily.
The continued use of RISPERDAL must be evaluated and justified on an ongoing basis.
Experience is lacking in children aged less than 5 years.

DIRECTIONS FOR OPENING THE BOTTLE AND USING THE PIPETTE

1.	Push the plastic screw cap down while turning it counter clockwise. Remove the unscrewed cap (Figure 1).
2.	Insert the pipette into the bottle. While holding the bottom ring, pull the top ring up to the level that corresponds with the dosage required for administration (Figure 2).
3.	Holding the bottom ring, remove the entire pipette from the bottle (Figure 3).
4.	Empty the pipette into any non-alcoholic drink, except for tea, by sliding the upper ring down.
5.	Close the bottle and rinse the pipette.
6.	To make a unit of pipette and bottle (Figure 4).
•	Take the holder and peel off the paper.
•	Stick the holder to the bottle so that the lip points down.
•	Insert the pipette into the holder to form the unit.

[Illustrated here]

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
In some instances it has been difficult to differentiate adverse events from symptoms of the underlying psychosis. The most frequent side effects observed with RISPERDAL are:
insomnia, agitation, extrapyramidal disorder, anxiety, headache. Sedation has been reported more frequently in children and adolescents than in adults.
Less commonly observed are: somnolence, fatigue, dizziness, impaired concentration, constipation, dyspepsia, nausea, vomiting, abdominal pain, weight gain, blurred vision, priapism, erectile dysfunction, ejaculatory dysfunction, orgastic dysfunction, urinary incontinence, rhinitis, rash and other allergic reactions have been observed.
The following dose dependent extrapyramidal symptoms have been observed: tremor, rigidity, hypersalivation, bradykinesia, oculogyric crisis, akathisia (hyperkinesia) and acute dystonia, hypokinesia. These are usually mild and reversible upon dose reduction and/or administration of anti-Parkinson medication, if necessary.
Tardive dyskinesia (TD), a syndrome consisting of potentially irreversible. involuntary dyskinetic movements may develop in patients treated with conventional neuroleptics. Although this syndrome of 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. 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 the antipsychotic 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 an established case of TD. The syndrome may remit partially or completely if the antipsychotic medicine treatment is withdrawn.
The antipsychotic medicine 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, RISPERDAL should be prescribed in a manner that is most likely to minimise the risk of TD. As with any antipsychotic medicine, RISPERDAL should be reserved for patients who appear to be obtaining substantial benefit from the medicine. In such patients, the smallest dose and the shortest duration of treatment should be sought. The benefit for continued treatment should be reassessed periodically. If signs and symptoms of TD appear in a patient on antipsychotics, medicine discontinuation should be considered. However, some patients may require treatment despite the presence of this syndrome.
Neuroleptic Malignant Syndrome (NMS) is a potentially fatal symptom complex that has been reported in association with antipsychotic medicines, including risperidone. Clinical manifestations of NMS are hyperthermia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, cardiac arrythmias and diaphoresis). Additional signs may include elevated creatine phosphokinase (CPK) levels, 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 illnesses (e.g. pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, medicine fever and primary central nervous system pathology.
The management of NMS should include

1.	immediate discontinuation of all antipsychotic medicines and other medicines 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 medicine treatment after recovery from NMS, the potential reintroduction of medicine therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
Classical neuroleptics are known to lower the seizure threshold. Seizures have been reported after treatment with RISPERDAL. Caution is recommended when treating patients with epilepsy.
(Orthostatic) hypotension and (reflex) tachycardia or hypertension have been observed. A mild fall in neutrophil and/or thrombocyte count has been reported.
RISPERDAL can induce a dose-dependent increase in plasma prolactin concentration. Possible associated manifestations are: galactorrhoea, gynaecomastia, disturbances of the menstrual cycle and amenorrhoea. Premenopausal women who develop secondary amenorrhea of greater than six months duration should receive appropriate preventative therapy to avoid hypo-oestrogenic bone loss.
Cerebrovascular accidents have been observed during treatment with risperidone.
Water intoxication, either due to polydipsia or the syndrome of inappropriate secretion of the antidiuretic hormone (SIADH), and body temperature disregulation, have been reported.
Precautions:
RISPERDAL may impair mental alertness. Therefore patients should be advised not to drive or operate machinery until their individual susceptibility is known.
It is recommended to halve both the starting dose and the subsequent dose increments in geriatric patients and patients with renal or liver insufficiency.
Due to the alpha-blocking activity of RISPERDAL, (orthostatic) hypotension can occur, especially during the initial dose-titration period. RISPERDAL should be used with caution in patients with known cardiovascular disease, and the dosage should be gradually titrated as recommended. A dose reduction should be considered if hypotension occurs.
Caution should be used when prescribing RISPERDAL to patients with Parkinson disease since, theoretically, it might cause a deterioration of the disease.
Patients may be advised to refrain from excessive eating in view of the possibility of weight gain.
Interactions:
The risk of using RISPERDAL in combination with other medicines has not been systematically evaluated.
RISPERDAL should be used with caution in combination with alcohol and other centrally acting medicines. It may antagonise the effect of levodopa and other dopamine agonists.
Carbamazepine has been shown to decrease the plasma levels of the active antipsychotic fraction of RISPERDAL. Similar effects may be observed with other hepatic enzyme inducers. On discontinuation of carbamazepine or other hepatic enzyme inducers the dosage of RISPERDAL should be re-evaluated and, if necessary, decreased.
Phenothiazines, tricyclic antidepressants and some beta-blockers may increase the plasma concentration of risperidone but not that of the antipsychotic fraction. Fluoxetine may increase the plasma concentration of risperidone but less so of the anti-psychotic fraction.
When RISPERDAL is taken together with other highly protein-bound medicines (e.g. diazepam, warfarin, digitoxin, imipramine and propranolol), there is no clinically relevant displacement of either agent from the plasma proteins.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Reported signs and symptoms have been those resulting from an exaggeration of the medicine's known pharmacological effects. Symptoms of acute overdosage include drowsiness, sedation, hypotension, tachycardia and extrapyramidal symptoms. In overdose, rare cases of QT-prolongation have been reported.
In the case of acute overdosage, the possibility of multiple medicine 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. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
Since there is no known antidote if accidental poisoning or overdosage is suspected, 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.

IDENTIFICATION
A clear, colourless solution.

PRESENTATION
Risperdal 1 mg/mL is supplied in 30 mL amber glass bottles with 3 mL pipettes.

STORAGE INSTRUCTIONS
Store below 25°C. Do not freeze.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
30/2.6.5/0215

NAME AND BUSINESS ADDRESS OF THE APPLICANT
JANSSEN-CILAG
JANSSEN PHARMACEUTICA (PTY) LTD
(Reg. No.1980/011122/07;
15th Road
HALFWAY HOUSE
1685
web site: www.janssencilag.co.za

DATE OF PUBLICATION OF THIS PACKAGE INSERT
7 February 2003

JANSSEN-CILAG

Updated on this site: May 2004
Source: Pharmaceutical Industry
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