DRLRISPERIDONE
SCHEDULING STATUS:
S5
PROPRIETARY NAME
(and dosage form):
DRLRISPERIDONE
DRLRISPERIDONE 0.5 (film-coated tablet)
DRLRISPERIDONE 1 (film-coated tablet)
DRLRISPERIDONE 2 (film-coated tablet)
DRLRISPERIDONE 3 (film-coated tablet)
DRLRISPERIDONE 4 (film-coated tablet)
COMPOSITION:
|
DRLRISPERIDONE0.5: |
Each film-coated tablet containsrisperidone 0,5mg |
|
DRLRISPERIDONE 1: |
Each film-coated tablet contains risperidone 1mg |
|
DRLRISPERIDONE 2: |
Each film-coated tablet contains risperidone 2mg |
|
DRLRISPERIDONE 3: |
Each film-coated tablet contains risperidone 3mg |
|
DRLRISPERIDONE 4: |
Each film-coated tablet contains risperidone 4mg |
Sugar-free
PHARMACOLOGICAL CLASSIFICATION
A 2.6.5 Central nervous system depressants. Miscellaneous structures.
PHARMACOLOGICAL ACTION
Risperidone is an antipsychotic of the benzisoxazol derivatives. It is a selective monoaminergic antagonist. Risperidone 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 dopamine D2-antagonist.
Pharmacokinetics
Risperidone is completely absorbed after oral administration. Peak plasma concentrations are attained within 1 - 2hours. Food does not affect the absorption of risperidone.
Risperidone is metabolized by cytochrome CYP2D6 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 the risperidone half-life is about 3hours. The elimination half-life of 9-hydroxy-risperidone and the active antipsychotic fraction is 24hours.
Bio-equivalence has been proven as a registration requirement. Interchangeability between strengths: tablets may be broken to achieve dosage titration.
Steady state is reached within 1day for risperidone in most patients and 4 –5days for 9-hydroxyrisperidone. Risperidone plasma concentration is dose-proportional within the therapeutic dose-range.
Risperidone is bound to albumin and alpha1-acid glycoprotein. Plasma protein binding of risperidone is 88hour and 77hour for 9-hydroxy-risperidone. One week after administration
70% of the dose is excreted in the urine and 14hour in the faeces. In the urine risperidone and 9-hydroxy-risperidone represent 35 –45hour of the dose.
Risperidone showed significantly higher active plasma concentrations and slower elimination in the elderly and in patients with moderately severe renal insufficiency. The plasma concentrations of risperidone were normal in patients with mild to moderate liver insufficiency.
The pharmacokinetics of risperidone, 9-hydroxy-risperidone and the active moiety in children are similar to those in adults.
INDICATIONS
DRLRISPERIDONE is indicated for the treatment of:
|
• |
Acute and chronic schizophrenic psychoses and related psychosis in which positive symptoms and/or the negative symptoms are prominent. DRLRISPERIDONE also alleviates affective symptoms associated with schizophrenia. In patients who have shown an initial treatment response DRLRISPERIDONE is also effective in maintaining the clinical improvement. |
|
• |
Behavioural disturbances in patients with dementia in whom symptoms such as aggressiveness, activity disturbances or psychotic symptoms are prominent. |
|
• |
Conduct and other disruptive behaviour disorders in children (aged 5 –12years), with sub-average intellectual functioning or mental retardation in whom destructive behaviours are prominent. |
CONTRAINDICATIONS
DRLRISPERIDONE is contraindicated in patients with known sensitivity to any of the components of the medicine.
Conduct and other disruptive behaviour disorders in children: DRLRISPERIDONE is contraindicated in children under 5years of age as efficacy and safety in these children have not been demonstrated.
Lewy antibody dementia (see WARNINGS)
WARNINGS
Tardive dyskinesia
Tardive dyskinesia (TD), a syndrome consisting of potentially irreversible, involuntary dyskinetic movements, may develop in patients treated with DRLRISPERIDONE. Although this syndrome of TD appears to be most preva lent in the elderly, especially elderly females, it is impossible to predict at the onset of treatment which patients are likely to develop TD (see Special Precautions).
Neuroleptic Malignant Syndrome
Neuroleptic Malignant Syndrome (NMS) is a potentially fatal symptom complex that has been reported in association with the use of 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 arrhythmias and diaphoresis). Additional signs may include elevated creatine phosphokinase (CPK) levels, myoglobinuria (rhabdomyolysis), and acute renal failure (see Special Precautions).
Concomitant use with furosemide
In risperidone placebo controlled trials in elderly patients with dementia there was a higher mortality in patients treated with furosemide and risperidone when compared to patients treated with risperidone alone. Caution is advised in these patients. Dehydration was an overall risk for mortality and should be carefully avoided in these patients.
Hyperglycaemia and diabetes mellitus
Hyperglycaemia, in some cases extreme and associated with ketoacidosis and hyperosmolar coma or death, has been reported in patients treated with risperidone. Patients with an established diagnosis of diabetes mellitus who are started on DRLRISPERIDONE should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with DRLRISPERIDONE should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness. Patients who develop symptoms of hyperglycaemia during treatment with DRLRISPERIDONE should undergo fasting blood glucose testing. In some cases hyperglycaemia has resolved when risperidone was discontinued. However, some patients required continuation of anti-diabetic treatment despite discontinuation of risperidone.
Cerebrovascular Adverse Events
Cerebrovascular adverse events (CAE), including cerebrovascular accidents and transient ischaemic attacks, have been reported during treatment with risperidone. In placebo-controlled clinical trials in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse events, including cerebrovascular accidents and transient ischaemic attacks, in patients treated with risperidone compared to patients receiving placebo (mean age 85years; range 73 –97years).
Dementia associated with Parkinson’s disease and senile dementia
Doctors should weigh the risks versus the benefits when prescribing DRLRISPERIDONE to patients with Parkinson’s disease or dementia with Lewy bodies (DLB) since both groups may be at risk of Neuroleptic Malignant Syndrome (NMS) as well as having an increased sensitivity to antipsychotic medications such as DRLRISPERIDONE. Manifestations of this increased sensitivity can include confusion, obtundation, and postural instability with frequent falls, in addition to extrapyramidal symptoms.
In addition, in clinical trials, elderly risperidone treated patients had a higher mortality than placebo treated elderly patients.
The risk of using DRLRISPERIDONE in combination with other medicines has not been systematically eva luated. Given the primary CNS depressive effects of DRLRISPERIDONE, it should be used with caution in combination with alcohol and other centrally acting medicines. DRLRISPERIDONE may antagonize the effect of levodopa and other dopamine agonists.
Alpha-blocking activity
Due to the alpha-blocking activity of DRLRISPERIDONE (orthostatic) hypotension can occur, especially during the initial dose-titration period. DRLRISPERIDONE 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.
Other
Seizures have been reported after treatment with risperidone. Caution is recommended when treating patients with epilepsy.
INTERACTIONS
Carbamazepine has been shown to decrease the plasma levels of the active antipsychotic fraction of risperidone by about 50hour. Similar effects may be observed with other hepatic enzyme inducers. On discontinuation of carbamazepine or other hepatic enzyme inducers the dosage of risperidone should be re-eva luated and if necessary, decreased.
Valproate: Valproate Tmax increased from 1,3hours to 2,0hours.
Topiramate: Modest decrease in risperidone bioavailability but not that of the active antipsychotic fraction. Therefore, this interaction is unlikely to be of clinical significance.
Phenothiazines, tricyclic antidepressants and some beta-blockers may increase the plasma concentration of risperidone but not that of the antipsychotic fraction.
Fluoxetine and paroxetine increased the plasma concentration of risperidone but less so of the antipsychotic fraction. Fluoxetine kinetics were not changed in combination with risperidone. When concomitant fluoxetine or paroxetine is initiated or discontinued, the dosing of DRLRISPERIDONE should be re-eva luated.
Amytriptyline: Non-significant interactions.
Venlafaxine: Risperidone AUC increased and risperidone clearance decreased, but there was no effect on 9-OH-risperidone and the active moiety.
Quetiapine: No significant interaction.
Clozapine: No significant interaction.
Lithium: Cmax and AUC of lithium were non-significantly increased, but Tmax of lithium was increased from 2,4hours to 3,0hours.
Erythromycin: Non-significant increase in risperidone exposure.
There were non-significant effects on risperidone kinetics or that of the active fraction in combination with donepezil or galantamine.
Cimetidine and ranitidine increased the bioavailability of risperidone, but only marginally to that of the active antipsychotic fraction.
When DRLRISPERIDONE is taken together with other highly protein-bound medicines (e.g. diazepam, warfarin, digoxin, imipramine and propranolol) there is no clinically relevant displacement of either agent from the plasma proteins.
See Special Precautions and WARNINGSfor use regarding increased mortality in elderly patients with dementia concomitantly receiving furosemide.
PREGNANCY AND LACTATION
The safety of DRLRISPERIDONE in pregnancy and lactating women has not been established.
Reversible extrapyramidal symptoms including hypertonia, hypotonia, jitteriness, tremor, muscle rigidity, twitching and convulsions, feeding disorder and withdrawal symptoms have been observed in neonates following postmarketing use of risperidone during the last trimester of pregnancy.
Risperidone and 9-hydroxy-risperidone are excreted in human breast milk. Therefore, women receiving DRLRISPERIDONE should not breast feed (see CONTRAINDICATIONS).
DOSAGE AND DIRECTIONS FOR USE
Schizophrenia
Switching from other antipsychotics to DRLRISPERIDONE:
When medically appropriate, gradual discontinuation of the previous treatment while DRLRISPERIDONE therapy is initiated, is recommended. Also if medically appropriate, when switching patients from depot antipsychotics, initiate DRLRISPERIDONE therapy in place of the next scheduled injection. The need for continuing existing anti-Parkinson medications should be re-eva luated periodically.
Adults
DRLRISPERIDONE may be given once or twice daily.
Patients should start with DRLRISPERIDONE 2mg/day. The dosage may be increased on the second day to 4mg/day. From then on the dosage can be maintained unchanged or further individualized if needed. Most patients will benefit from daily doses of between 4mg/day and 8mg/day. Doses above 6mg/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 starting and maintenance dose may be appropriate.
Doses above 10mg/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 10mg/day should only be considered if the benefits outweigh the risk.
The maximum total daily dose is 16mg/day.
A benzodiazepine may be added to DRLRISPERIDONE if additional sedation is required.
Elderly patients
A starting dose of 0,5mg twice daily is recommended. This dosage can be individually adjusted with 0,5mg twice daily increments to 1 –2mg twice daily.
Children
Not for children under 15years as efficacy and safety in children under the age of 15years have not been demonstrated in schizophrenia.
Behavioural disturbances in adult patients with dementia
A starting dose of 0,25mg twice daily is recommended. This dosage can be individually adjusted by increments of 0,25mg twice daily, not more frequently than every other day, if needed. The optimum dose is 0,5mg twice daily for most patients. Some patients, however, may benefit from doses up to 1mg twice daily.
Once patients have reached their target dose a once-daily dosing regimen can be considered. The continued use of DRLRISPERIDONE must be eva luated and justified on an ongoing basis.
Conduct and other disruptive behaviour disorders in children 5 –12years of age.
Subjects <50kg
A starting dose of 0,01mg/kg once daily is recommended. This dosage can be individually adjusted by increments of 0,01mg/kg once daily, not more frequently than every other day, if needed. The recommended maintenance dose is 0,02 –0,04mg/kg once daily. The mean dose is 0,03mg/kg once daily.
The continued use of DRLRISPERIDONE must be eva luated and justified on an ongoing basis.
Evidence is lacking in children aged less than 5years (see CONTRAINDICATIONS).
Renal and liver impairment
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.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-effects:
Very common (>1/10); Common (> 1/100 and <1/10); Uncommon (> 1/1000 and <1/100); Rare (> 1/10 000 and <1/1000); Very rare (<1/10000)
The adverse events considered at least possibly related to the treatment, are listed below by body system, organ class and frequency (wherever applicable). Where the incidence or frequency is not known it is indicated as ‘incidence unknown’or ‘less frequent’.
General disorders
Weight gain, headache, fatigue, angioedema and other allergic reactions
Blood and lymphatic system disorders
Incidence unknown: Neutropenia (mild), thrombocytopenia (mild)
Respiratory, thoracic and mediastinal disorders
Less frequent: Rhinitis
Endocrine disorders
Incidence unknown: Hyperprolactinaemia. Water intoxication, either due to polydipsia or the syndrome of inappropriate secretion of the antidiuretic hormone (SIADH0, and body temperature disregulation (see Reproductive system and Special Precautions)
Psychiatric disorders
Frequent: Insomnia, somnolence, impaired concentration, agitation, anxiety.In some cases it has been difficult to differentiate adverse events from symptoms of the underlying psychosis.
Central and peripheral nervous system disorders
Frequent: Headache, dose dependent extrapyramidal effects including tremor, rigidity, hypersalivation, bradykinesia, oculogyric crisis, akathisia (hyperkinesias) and acute dystonia, hypokinesia, sedation (more frequent in children and adolescents than in adults). These may be reversible upon dose reduction and/or administration of anti-Parkinson medication if necessary.
Less frequent: Fatigue, dizziness, tardive dyskinesia (see Special Precautions), Neuroleptic Malignant Syndrome (see Special Precautions)
Rare: Seizures
Eye disorders
Less frequent: Blurred vision
Cardiac disorders
Incidence unknown: Tachycardia including reflex tachycardia
Vascular disorders
Incidence unknown: Peripheral oedema, orthostatic hypotension, hypertension. Cerebrovascular accidents have been observed with risperidone
Gastrointestinal disorders
Less frequent: Constipation, dyspepsia, nausea, vomiting, abdominal pain
Skin and subcutaneous tissue disorders
Less frequent: Rash
Renal and urinary disorders
Less frequent: Urinary incontinence
Reproductive system and breast disorders
Less frequent: Priapism, erectile dysfunction, ejaculatory dysfunction, orgasmic dysfunction
Incidence unknown: Gynaecomastia, galactorrhoea, disturbances of the menstrual cycle, amenorrhoea(see Special Precautions)
Special Precautions
Tardive dyskinesia
Tardive dyskinesia (TD), a syndrome consisting or potentially irreversible, involuntary dyskinetic movements may develop in patients treated with DRLRISPERIDONE. Although this syndrome of TD appears to be most preva lent 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.
DRLRISPERIDONE 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, DRLRISPERIDONE should be prescribed in a manner that is most likely to minimise the risk of TD. DRLRISPERIDONE 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, DRLRISPERIDONE discontinuation should be considered. However, some patients may require treatment despite the presence of this syndrome.
Neuroleptic Malignant Syndrome
Neuroleptic Malignant Syndrome (NMS) is a potentially fatal symptom complex that has been reported in association with the use of 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 arrhythmias 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 drugs not essential to concurrent therapy; |
|
2. |
Intensive symptomatic treatment and medical monitoring; and |
|
3. |
Treatment of any concomitant serious medical problems for which specific treatments are available. |
There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic 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.
Seizures have been reported after treatment with risperidone. Caution is recommended when treating patients with epilepsy.
A dose-dependent increase in plasma prolactin concentration may occur. Possible associated manifestations are: galactorrhoea, gynaecomastia, disturbances of the menstrual cycle and amenorrhoea. Premenopausal women who develop secondary amenorrhoea of greater than six months duration should receive appropriate preventative therapy to avoid hypo-oestrogenic bone loss.
Concomitant use with furosemide
In risperidone placebo-controlled trials in elderly patients with dementia there was a higher mortality in patients treated with furosemide and risperidone when compared to patients treated with risperidone alone. Caution is advised in these patients. Dehydration was an overall risk for mortality and should be carefully avoided in these patients.
Effects on ability to drive or operate machinery
DRLRISPERIDONE may impair mental alertness. Patients should therefore 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.
Caution should be used when prescribing DRLRISPERIDONE to patients with Parkinson’s 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.
Hyperglycaemia and exacerbation of pre-existing diabetes mellitus have been reported on risperidone treatment (see WARNINGS).
Benign pituitary adenomas have been reported during postmarketing surveillance. No causal association could be detected.
Alpha-blocking activity
Due to the alpha-blocking activity of DRLRISPERIDONE, (orthostatic) hypotension can occur, especially during the initial dose-titration period.
DRLRISPERIDONE 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.
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, cases of QT-prolongation have been reported.
In the case of acute overdosage the possibility of multiple medicine ingestion 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
|
DRLRISPERIDONE0.5: |
Brown, capsule shaped, biconvex film-coated tablets embossed with ‘0.5’on one side and ‘RSP’on other side with straight line separating ‘R’& ‘SP’. |
|
DRLRISPERIDONE1: |
White, capsule shaped, biconvex film-coated tablets embossed with ‘1’on one side and ‘RSP’on other side with straight line separating ‘R’& ‘SP’ |
|
DRLRISPERIDONE2: |
Orange, capsule shaped, biconvex film-coated tablets embossed with ‘2’on one side and ‘RSP’on other side with straight line separating ‘R’& ‘SP’ |
|
DRLRISPERIDONE3: |
Yellow, capsule shaped, biconvex film-coated tablets embossed with ‘3’on one side and ‘RSP’on other side with straight line separating ‘R’& ‘SP’ |
|
DRLRISPERIDONE 4: |
Green, capsule shaped, biconvex film-coated tablets embossed with ‘4’on one side and ‘RSP’on other side with straight line separating ‘R’& ‘SP’ |
PRESENTATION
|
DRLRISPERIDONE0.5: |
Alu/Alu or Triplex/Alu blisters of 30 film-coated tablets in a carton |
|
DRLRISPERIDONE1: |
Alu/Alu or Triplex/Alu blisters of 30 film-coated tablets in a carton |
|
DRLRISPERIDONE2: |
Alu/Alu or Triplex/Alu blisters of 30 film-coated tablets in a carton |
|
DRLRISPERIDONE3: |
Alu/Alu or Triplex/Alu blisters of 30 film-coated tablets in a carton |
|
DRLRISPERIDONE4: |
Alu/Alu or Triplex/Alu blisters of 30 film-coated tablets in a carton |
STORAGE INSTRUCTIONS
Store below 25ºC.
Keep blisters in carton until required for use.
KEEP OUT OF REACH OF CHILDREN
REGISTRATION NUMBERS
|
DRLRISPERIDONE0,5: |
40/2.6.5/0688 |
|
DRLRISPERIDONE1: |
40/2.6.5/0689 |
|
DRLRISPERIDONE2: |
40/2.6.5/0690 |
|
DRLRISPERIDONE3: |
40/2.6.5/0691 |
|
DRLRISPERIDONE4: |
40/2.6.5/0692 |
NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Dr Reddy’s Laboratories (Pty) Ltd
381 Rossouw Street
Murrayfield
Pretoria
0184
DATE OF PUBLICATION OF PACKAGE INSERT
February 2009
New addition to this site: March 2010
Source: Pharmaceutical Industry |
